Managing menopause. Raloxifene reduces risk of vertebral fractures [corrected] in postmenopausal women regardless of prior hormone therapy. Characteristics of hormone therapy, cognitive function, and dementia Aerobic exercise as a treatment for vasomotor menopausal symptoms: randomised controlled trial protocol. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women The effect of hormone therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone Therapy trial A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease Reproductive hormone exposure timing and ischemic heart disease: Complicated answers to a simple question. Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Long-Term Prevention with Hormone-Replacement Therapy after the Menopause: Which Women should be Targeted? Epidemiology of risk factors and symptoms associated with menopause in Spanish women. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial Hormone therapy in menopausal women with cognitive complaints The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy NIH asks participants in Women's Health Initiative estrogen-alone study to stop study pills, begin follow-up phase. Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. Estrogen + progestin therapy and cognition: a randomized placebo-controlled double-blind study. Hormone therapy and Alzheimer disease dementia Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Fragility fractures and the osteoporosis care gap in women: the Canadian Multicentre Osteoporosis Study 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial Sex Hormone Levels and Risk of Cardiovascular Events in Postmenopausal Women The rationale, design, and baseline characteristics of the Women's Health Initiative Memory Study of Younger Women (WHIMS-Y) The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. A Multi-center, Randomized, Controlled and Open Clinical Trial of Heyan Kuntai Capsule (和颜坤泰胶囊) and Hormone Therapy in Perimenopausal Women Postmenopausal Hormone Use and Secondary Prevention of Coronary Events in the Nurses' Health Study: A Prospective, Observational Study Healthy women with a family history of breast cancer: impact of a tailored genetic counseling intervention on risk perception, knowledge, and menopausal therapy decision making. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study. Postmenopausal hormone therapy and cognitive outcomes: The Women's Health Initiative Memory Study (WHIMS) Randomized trial of hormone therapy in women after coronary bypass surgery. Evidence of differential effect of hormone therapy on angiographic progression of disease in saphenous vein grafts and native coronary arteries. Hormone replacement therapy use and menopausal symptoms among women participating in a behavioral lifestyle intervention. Efficacy and safety of DT56a compared to hormone therapy in Greek post-menopausal women Screening for Postmenopausal Osteoporosis: A Review of the Evidence for the U.S. Preventive Services Task Force Osteoporosis in menopause. Hormone replacement therapy in previously treated breast cancer patients. Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study Effects of hormone therapy on soluble cell adhesion molecules in postmenopausal women with coronary artery disease Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Comparison of fracture, cardiovascular event, and breast cancer rates at 3 years in postmenopausal women with osteoporosis. Breast Tumor Prognostic Characteristics and Biennial vs Annual Mammography, Age, and Menopausal Status. Women's willingness to accept perceived risks for vasomotor symptom relief. Women’s Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy Red clover isoflavones enriched with formononetin lower serum LDL cholesterol—a randomized, double-blind, placebo-controlled study Osteoporosis medication and reduced mortality risk in elderly women and men. Changes in the Use of Postmenopausal Hormone Therapy after the Publication of Clinical Trial Results Risk Factors for Perimenopausal Distal Forearm Fracture The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy. The ERA trial: findings and implications for the future Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Aerobic exercise training in healthy postmenopausal women: effects of hormone therapy Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. UK clinical guideline for the prevention and treatment of osteoporosis The effects of hormone therapy on pulmonary function tests in postmenopausal women. Evidence-based review of therapies at the menopause. Short-term hormone therapy improves sCD40L and endothelial function in early menopausal women: potential role of estrogen receptor polymorphisms. The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Women's Health Initiative Memory Study. Exercise frequency and calcium intake predict 4-year bone changes in postmenopausal women Walking and leisure-time activity and risk of hip fracture in postmenopausal women. Characterisation of Patients with Postmenopausal Osteoporosis in French Primary Healthcare Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Effect of nicotine replacement therapy on post-cessation weight gain and nutrient intake: a randomized controlled trial of postmenopausal female smokers. Alendronate Prevents Postmenopausal Bone Loss in Women without Osteoporosis: A Double-Blind, Randomized, Controlled Trial Health-related quality of life during hormone therapy after breast cancer: a randomized trial A cognitive model of menopausal hot flushes and night sweats. Osteoporosis and fractures in postmenopausal women using estrogen. Validation of a 5-year risk score of hip fracture in postmenopausal women. The Danish Nurse Cohort Study Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. Minimal-trauma fracture in women with breast cancer surviving for at least 5 years from diagnosis Some problems with Cochrane reviews of diet and chronic disease Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS). The Effects of Hormone Therapy Decision Support for Women With Mobility Impairments Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes Efficacy of citalopram on climacteric symptoms Comparison of the effects of hormone therapy regimens, oral and vaginal estradiol, estradiol + drospirenone and tibolone, on sexual function in healthy postmenopausal women. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Design and baseline characteristics of the soy phytoestrogens as replacement estrogen (SPARE) study--a clinical trial of the effects of soy isoflavones in menopausal women. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: A randomized, double-blind, placebo-controlled study Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians Osteoporosis prevalence and levels of treatment in primary care: the Australian BoneCare Study. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women. Effectiveness of a modified version of the applied relaxation technique in treatment of perimenopausal and postmenopausal symptoms Bone mineral density at menopause does not predict breast cancer incidence Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial. Derivation and validation of updated QFracture algorithm to predict risk of osteoporotic fracture in primary care in the United Kingdom: prospective open cohort study Rosiglitazone for type 2 diabetes mellitus. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. C-Reactive Protein Levels Are Not Associated with Increased Risk for Colorectal Cancer in Women Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials. Awareness of risk of osteoporosis may cause uncertainty and worry in menopausal women Age at natural menopause in relation to all-cause and cause-specific mortality in a follow-up study of US black women. Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study. Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective derivation and validation of QFractureScores Calcium Supplementation with and without Hormone Replacement Therapy To Prevent Postmenopausal Bone Loss Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies? Comparison of Pueraria lobata with hormone replacement therapy in treating the adverse health consequences of menopause Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study Continued Breast Cancer Risk Reduction in Postmenopausal Women Treated with Raloxifene: 4-Year Results from the MORE Trial Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS cognitive and affective sub study (KEEPS Cog) A randomized controlled study of taper-down or abrupt discontinuation of hormone therapy in women treated for vasomotor symptoms Women and Menopause: Beliefs, Attitudes, and Behaviors. The North American Menopause Society 1997 Menopause Survey Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: a secondary analysis of the randomized protocol RTOG 86-10. Soymilk or progesterone
for prevention of bone loss A double-blind, placebo-controlled trial of donepezil for the treatment of menopause-related cognitive loss. Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women. Decision-making at menopause: a randomized controlled trial of a computer-based hormone therapy decision-aid. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Endurance exercise effect on quality of life and menopausal symptoms in Nigerian women. Menopausal Symptoms in Older Women and the Effects of Treatment With Hormone Therapy Effects of hormone replacement therapy on cognitive performance in elderly women. The Role of Hormone Replacement Therapy in the Risk for Breast Cancer and Total Mortality in Women with a Family History of Breast Cancer Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. Prevalence of menopause symptoms and their association with lifestyle among Finnish middle-aged women. The effects of postmenopausal hormone therapy on social activity, partner relationship, and sexual life – experience from the EPHT trial Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. Tibolone low dose (1.25 mg/d) therapy and postural balance in elderly women. Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. effect of adding hormone replacement therapy. Effectiveness of general practice nurse interventions in cardiac risk factor reduction among adults The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. The effects of tibolone in older postmenopausal women. Incidence of dementia in long-term hormone users. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Effects of weight control during the menopausal transition on bone mineral density. Food selection based on high total antioxidant capacity improves endothelial function in a low cardiovascular risk population. Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. Hormone replacement therapy and the prevention of postmenopausal osteoporosis Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study Total hip bone mass predicts survival in chronic hemodialysis patients. The Effect of Sodium Monofluorophosphate plus Calcium on Vertebral Fracture Rate in Postmenopausal Women with Moderate Osteoporosis A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Rationale, design, and conduct of the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions. Long-term follow-up of acupuncture and hormone therapy on hot flushes in women with breast cancer: a prospective, randomized, controlled multicenter trial Evaluation of Bone Mineral Density Loss in Morbidly Obese Women After Gastric Bypass: 3-Year Follow-Up
OBJECTIVE To provide up date d guidelines for health care providers on the management of menopause in asymptomatic healthy women as well as in women presenting with vasomotor or urogenital symptoms and on considerations related to cardiovascular disease , breast cancer , urogynaecology , and sexuality . OUTCOMES Lifestyle interventions , prescription medications , and complementary and alternative therapies are presented according to their efficacy in the treatment of menopausal symptoms . Counselling and therapeutic strategies for sexuality concerns in the peri- and postmenopausal years are review ed . Approaches to the identification and evaluation of women at high risk of osteoporosis , along with options for prevention and treatment , are presented in the companion osteoporosis guideline . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library in August and September 2012 with the use of appropriate controlled vocabulary ( e.g. , hormone therapy , menopause , cardiovascular diseases , and sexual function ) and key words ( e.g. , hormone therapy , perimenopause , heart disease , and sexuality ) . Results were restricted to clinical practice guidelines , systematic review s , r and omized control trials/controlled clinical trials , and observational studies . Results were limited to publication date s of 2009 onwards and to material in English or French . Search es were up date d on a regular basis and incorporated in the guideline until January 5 , 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , national and international medical specialty societies , and clinical practice guideline collection OBJECTIVE We examined whether past use of hormone therapy influences the effects of raloxifene on the risk of new vertebral fracture , cardiovascular events , or breast cancer . STUDY DESIGN The Multiple Outcomes of Raloxifene Evaluation ( MORE ) trial examined vertebral fracture incidence as the primary endpoint , breast cancer incidence as a secondary endpoint . Cardiovascular events were collected as secondary safety endpoints . POPULATION The MORE trial enrolled 7705 postmenopausal women . Of the 7682 women who reported their previous HT use status , 29 % used HT before screening . OUTCOMES MEASURED Separate logistic regression models analyzed the relationships between prior HT use and the risk of vertebral fracture , cardiovascular events , or breast cancer . Interaction terms with P<.10 were considered to be statistically significant . Confidence intervals for relative risks ( RR ) were calculated using the Mantel-Haenszel method . RESULTS Raloxifene 60 mg/d , the clinical ly approved dose for osteoporosis prevention and treatment , reduced the risk of vertebral fractures by 54 % ( RR=0.46 ) and 29 % ( RR=0.71 ) in women with and without prior HT use , respectively ( interaction P=.05 ) . A lower incidence of invasive breast cancer in women with prior HT use ( RR=0.23 ) and in women without prior HT use [ RR=0.31 ; interaction P=.60 ] was observed in women receiving raloxifene ( pooled doses ) . Irrespective of prior HT use , women treated with raloxifene ( pooled doses ) had no change in incidence of cardiovascular events ( interaction P=.56 ) . CONCLUSIONS The risk of vertebral fractures was lower in women treated with raloxifene , regardless of prior HT use , but there was a suggestion that the effect was greater in women who had used HT . Women r and omized to receive raloxifene exhibited a decreased incidence of invasive breast cancer , compared with women receiving placebo . No change occurred in the incidence of cardiovascular events , regardless of prior HT use Objectives : To examine the association between hormone therapy ( HT ) and cognitive performance or dementia , focusing on the duration and type of treatment used , as well as the timing of initiation of HT in relation to the menopause . Methods : Women 65 years and older were recruited in France as part of the Three City Study . At baseline and 2- and 4-year follow-up , women were administered a short cognitive test battery and a clinical diagnosis of dementia was made . Detailed information was also gathered relating to current and past HT use . Analysis was adjusted for a number of sociodemographic , behavioral , physical , and mental health variables , as well as APOE ε4 . Results : Among 3,130 naturally postmenopausal women , current HT users performed significantly better than never users  on verbal fluency , working memory , and psychomotor speed . These associations varied according to the type of treatment and a longer duration of HT appeared to be more beneficial . However , initiation of HT close to the menopause was not associated with better cognition . HT did not significantly reduce dementia risk over 4 years but current treatment diminished the negative effect associated with APOE ε4 . Conclusions : Current hormone therapy ( HT ) was associated with better performance in certain cognitive domains but these associations are dependent on the duration and type of treatment used . We found no evidence that HT needs to be initiated close to the menopause to have a beneficial effect on cognitive function in later life . Current HT may decrease the risk of dementia associated with the APOE ε4 allele BACKGROUND Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience vasomotor symptoms ( hot flushes/night sweats ) that can be severe and disruptive and which are the principal reason for seeking medical intervention . Hormone therapy ( HT ) is known to be an effective treatment for troublesome hot flushes/night sweats but research has raised questions about the safety of HT and there have been negative high profile media reports about its use . Consequently many women are seeking alternatives and exercise might be one such option but there is a lack of high quality evidence on its effectiveness . AIMS This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study in 165 women , and if found to be feasible/acceptable , continue to recruit sufficient women ( n=261 ) to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women . METHOD We aim to recruit inactive perimenopausal and menopausal symptomatic women not using HT and r and omise them to one of two exercise interventions or usual care for six months . RESULTS We will assess outcomes at baseline and 6 and 12 months from r and omisation . CONCLUSION We hope this RCT will contribute towards increasing the evidence regarding the question of whether exercise is an effective treatment for vasomotor symptoms in women not taking HT Objective To assess the long term risks and benefits of hormone replacement therapy ( combined hormone therapy versus placebo , and oestrogen alone versus combined hormone therapy ) . Design Multicentre , r and omised , placebo controlled , double blind trial . Setting General practice s in UK ( 384 ) , Australia ( 91 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 years at r and omisation . At early closure of the trial , 56 583 had been screened , 8980 entered run-in , and 5692 ( 26 % of target of 22 300 ) started treatment . Interventions Oestrogen only therapy ( conjugated equine oestrogens 0.625 mg orally daily ) or combined hormone therapy ( conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ) . Ten years of treatment planned . Main outcome measures Primary outcomes : major cardiovascular disease , osteoporotic fractures , and breast cancer . Secondary outcomes : other cancers , death from all causes , venous thromboembolism , cerebrovascular disease , dementia , and quality of life . Results The trial was prematurely closed during recruitment , after a median follow-up of 11.9 months ( interquartile range 7.1 - 19.6 , total 6498 women years ) in those enrolled , after the publication of early results from the women 's health initiative study . The mean age of r and omised women was 62.8 ( SD 4.8 ) years . When combined hormone therapy ( n=2196 ) was compared with placebo ( n=2189 ) , there was a significant increase in the number of major cardiovascular events ( 7 v 0 , P=0.016 ) and venous thromboembolisms ( 22 v 3 , hazard ratio 7.36 ( 95 % CI 2.20 to 24.60 ) ) . There were no statistically significant differences in numbers of breast or other cancers ( 22 v 25 , hazard ratio 0.88 ( 0.49 to 1.56 ) ) , cerebrovascular events ( 14 v 19 , 0.73 ( 0.37 to 1.46 ) ) , fractures ( 40 v 58 , 0.69 ( 0.46 to 1.03 ) ) , and overall deaths ( 8 v 5 , 1.60 ( 0.52 to 4.89 ) ) . Comparison of combined hormone therapy ( n=815 ) versus oestrogen therapy ( n=826 ) outcomes revealed no significant differences . Conclusions Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause . The results are consistent with the findings of the women 's health initiative study and secondary prevention studies . Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause , when the effect may be different . Trial registration Current Controlled Trials IS RCT N Background For postmenopausal women , the main reason to start hormone therapy ( HT ) is to reduce menopausal symptoms and to improve quality of life ( QOL ) . The aim of this study was to analyse the impact of HT on different aspects of symptom experience and QOL during a r and omised trial . A total of 1823 postmenopausal women were recruited into the Estonian Postmenopausal Hormone Therapy ( EPHT ) trial in 1999–2001 . Women were r and omised to blind HT , open-label HT , placebo or non-treatment arm . After one year in the trial , a question naire was mailed and 1359 women ( 75 % ) responded , 686 in the HT arms and 673 in the non-HT arms . Mean age at filling in the question naire was 59.8years . The question naire included Women 's Health Question naire ( WHQ ) to assess menopause specific QOL of middle-aged women together with a 17-item question naire on symptoms related to menopause , a question about painful intercourse , and a question about women 's self-rated health . Results After one year in the trial , fewer women in the HT arms reported hot flashes , trouble sleeping , and sweating on the symptom question naire . According to WHQ , women in the HT arms had fewer vasomotor symptoms , sleep problems , and problems with sexual behaviour , but more menstrual symptoms ;  HT had no effect on depression , somatic symptoms , memory , attractiveness , or anxiety . A smaller proportion of women reported painful intercourse in the HT arms . There were no significant differences between the trial arms in women ’s self-rated subjective health . Conclusions The results from the EPHT trial confirm that HT is not justified for treating symptoms , other than vasomotor symptoms , among postmenopausal women . WHQ proved to be a useful and sensitive tool to assess QOL in this age group of women Whether to take hormone therapy is one of the most difficult medical decisions that healthy postmenopausal women face . The apparent coronary benefits ( 1 ) of hormone use are an important part of that decision . Although the data appear consistent in suggesting long-term coronary benefits , the Heart and Estrogen/progestin Replacement Study ( 2 ) showed an increased risk for coronary events during the first year of therapy in women with existing heart disease ; we also found such an elevated risk in an examination of secondary prevention in the Nurses ' Health Study ( 3 ) . More recently , a report from the Women 's Health Initiative , an ongoing r and omized clinical trial of hormone therapy for primary prevention of cardiovascular disease , suggested similar findings in healthy women ( National Institutes of Health . Press release ) . However , additional data on short-term effects of hormone use in women without previous cardiovascular disease are sparse . Many further questions also remain . Among them is the cardiovascular effect of daily doses lower than the st and ard 0.625 mg of oral conjugated estrogen . Recent studies suggest that lower doses of hormone therapy provide bone benefits ( 4 ) and , compared with higher doses , might decrease the risk for thromboembolism ( 5 ) and reduce endometrial hyperplasia ( 4 ) . However , few data are currently available on the relation between low-dose estrogen and primary prevention of heart disease and stroke . In an earlier report , we examined the relation between postmenopausal hormone therapy and primary prevention of cardiovascular disease based on 16 years of follow-up from the Nurses ' Health Study ( 6 ) . In the current analysis , we have almost 50 % more follow-up time among women taking daily doses less than 0.625 mg and more than 800 additional cases of cardiovascular disease , allowing more precise assessment of specific associations . Thus , we now report on the relation among  low-dose estrogen , short-term hormone use , and cardiovascular events in 70 533 postmenopausal women with no previous cardiovascular disease who were followed for up to 20 years . We also provide additional information on the effects of estrogen combined with progestin . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about their postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . We up date information with biennial follow-up question naires . Dietary and physical activity question naires were added in 1980 . Cohort follow-up is greater than 90 % . Ascertainment of Hormone Use In 1976 , women were asked about use and duration of hormone therapy after menopause . Beginning in 1978 , we collected information on type of hormones taken , and starting in 1980 , we asked about the dose of oral conjugated estrogen . All information is up date d biennially . Identification of Cardiovascular Disease We identified first occurrences of nonfatal myocardial infa rct ion , fatal coronary disease , and fatal and nonfatal stroke between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion or stroke were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met World Health Organization criteria ( 7 ) ( symptoms plus either elevated levels of cardiac enzymes or diagnostic electrocardiograms ) . Infa rct ions that required hospitalization and were corroborated by interview or letter but for which medical records were unobtainable were included as probable . Infa rct ions of indeterminate age discovered on routine examination were excluded . Nonfatal strokes were confirmed by review of medical records if they were characterized by a typical neurologic deficit , were rapid in onset , lasted at least 24 hours , and met the criteria of the National Survey of Stroke ( 8) . We classified strokes as ischemic ( thrombotic or embolic occlusion of a cerebral artery ) , subarachnoid hemorrhage , or intraparenchymal hemorrhage . We excluded subdural hematomas and strokes caused by infection or neoplasia . Strokes that required hospitalization and were corroborated by letter or interview but for which medical records were unavailable were included as probable . Most deaths were reported by the participants ' families . We search ed the National Death Index to identify deaths among nonrespondents to each 2-year question naire ; mortality follow-up was more than 98 % complete ( 9 ) . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered to be due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . We also included coronary disease listed on the death certificate as the underlying cause without another , more plausible cause , if the nurse was known ( from hospital records , family , or other sources ) to have had coronary disease before death . In no case was the cause listed on the death certificate used as the sole criterion for coronary death . Sudden death within 1 hour of the onset of symptoms in participants with no other plausible cause of death besides coronary disease was also included . Fatal strokes were documented by autopsy or hospital records or if stroke was listed as the underlying cause on the death certificate . The category of major coronary heart disease combines nonfatal myocardial infa rct ion and coronary death ; similarly , total stroke includes nonfatal and fatal cases . The category of combined cardiovascular disease includes major coronary heart disease and stroke . Confirmed and probable cases in each category were analyzed together ( 80 % of major coronary events and 73 % of strokes were confirmed ) . In this and previous analyses ( 6 ) , results for probable cases were similar to those for confirmed cases . The investigators conducted all interviews and record review s without knowledge of participants ' hormone use status . Population for Analysis Women who reported stroke , myocardial infa rct ion , angina , coronary revascularization , or cancer ( except nonmelanoma skin cancer ) on the 1976 question naire were excluded because their disease may have caused them to alter their hormone use . Similarly , women who reported such diagnoses on a subsequent question naire were excluded from further analysis . Thus , at the start of each 2-year interval , the base population included no women reporting these diagnoses . Our own studies ( 6 , 10 ) and other studies ( 11 ) have suggested that hormone therapy may differentially affect incident and fatal strokes ; thus , we separately examined deaths due to stroke . In these analyses , we excluded women with cancer and cardiovascular disease at baseline but did not up date the exclusions because the women who develop cardiovascular disease during follow-up are those most likely to die of stroke . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy  were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) . In this cohort , the women 's reports of age at menopause ( 12 ) and type of menopause ( 13 ) were highly accurate . In 1976 , 21 947 postmenopausal women entered the analysis , and 48 586 women were added during follow-up as they became postmenopausal , for a total of 70 533 participants ; 808 825 person-years of follow-up were accrued from 1976 to 1996 . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the 1976 data and were up date d every 2 years ( for estrogen dose , follow-up began in 1980 ) . For analyses of type of hormone therapy , we assigned the regimen reported on the 1978 question naire to women who reported hormone use in 1976 . Analyses of type of hormone therapy were limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate  , since these were the most common hormone regimens . If no data were available on hormones in a given time period , women were assigned to a missing category for that time period . To maintain the prospect i ve nature of the study , hormone use ( including duration ) during each 2-year period was established from women 's reports at the start of the period ; thus , we probably underestimate duration of use by an average of 1 year . Follow-up for a participant ended at the first diagnosis of cardiovascular disease , death , or 1 June 1996 , whichever came first . The primary analysis is based on incidence rates for which person-months of follow-up were used as the denominator . We used relative risk as the measure of association , defined as the incidence of cardiovascular events among women in various categories of hormone use divided by the incidence among women who never used hormones . We computed age-specific rates by using 5-year categories ( 14 ) and age-adjusted relative risks by using MantelHaenszel rate ratios ( 15 ) with 95 % CIs ( 16 ) . We used pooled logistic regression  across the ten 2-year time periods to adjust simultaneously for potential confounding factors ( 17 ) . In this approach , independent blocks of person-time are pooled for regression analysis , and time-varying covariates are readily accommo date d by assigning successive blocks of person-time to the covariate values at the start of each follow-up cycle . The dependence of the incidence rates on time is modeled nonparametrically with indicator variables . Simulation studies have established the asymptotic equivalence of pooled logistic regression to Cox regression with time-dependent covariates ( 18 ) . The necessary conditions for this equivalence include relatively short time intervals and small probability of the outcome during each interval , both Premenopausal women have a relatively lower risk of ischemic heart disease ( IHD )  compared to age matched men and this gender gap narrows after menopause . The observation that the onset of IHD occurs 10 years later in women than it does in men is said to suggest that endogenous reproductive hormones play a protective role . Indeed , animal models and human epidemiological studies suggest that oophorectomy is a risk factor for accelerated IHD . In animal models , hormone therapy ( HT ) has anti-atherosclerotic effects after oophorectomy , HT in the form of oral contraceptives ( OCs ) prevents atherosclerosis in anovulatory cycling women , and large numbers of premenopausal women taking OCs have relative safety from an IHD st and point ( 1 ) . Further , observational epidemiological studies in humans have consistently demonstrated protective effects for IHD among HT users . Such studies are typically performed on relatively younger women where  HT  is prescribed for  vasomotor symptoms during menopausal transition or shortly following menopause . In contrast , clinical trials in older , postmenopausal and often asymptomatic women have demonstrated no overall benefit and early adverse effects when r and omized to a variety of forms of HT ( 1 ) . These data discrepancies have called into question the validity of the reproductive hormone estrogen protection hypothesis , and raise the alternative possibility that  HT efficacy may differ according to the timing of exposure . Stated as a simple question , is the effect of HT on the risk of IHD in relatively young pre- or early menopausal women with vasomotor symptoms , different than it is in older , fully menopausal women ? Data from the Women ’s Ischemia Syndrome Evaluation ( WISE ) , a prospect i ve multi-center NHLBI-sponsored study design ed to explore female-specific pathophysiology in a large sample of women undergoing coronary angiography for suspected IHD ( 2 ) , may shed light on this controversy . These new data , prospect ively obtained using novel methods , including detailed reproductive health question naires , menopausal adjudication algorithms , and quantitative coronary angiography as a measure of atherosclerosis , allow a more precise inspection of this question . However , to answer this simple question we need to first answer others . Specifically , how can we integrate and underst and the findings from the available observational , animal and clinical trial data ? And to interpret these data other questions become relevant : 1 ) How accurately was menopause assessed in prior observational HT studies ? 2 ) Does HT in premenopausal women in the form of OC therapy confirm atherosclerosis benefit ? and 3 ) Does HT in early menopausal women confer reduced atherosclerosis and benefit on the risk of IHD OBJECTIVE Use of estrogen-based hormone therapy ( HT ) as a protection from cognitive decline and Alzheimer disease ( AD ) is controversial , although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17β-estradiol preferable to conjugated equine estrogen formulations . Little is known regarding specific population s of women who may derive benefit from HT . METHODS Women with heightened risk for AD ( aged 49 - 69 ) , all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset , underwent  cognitive assessment  followed by r and omization to continue or discontinue HT . Assessment s were repeated at 2 years after r and omization . RESULTS Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention , working memory , and processing speed measures . Women who used 17β-estradiol versus conjugated equine estrogen , whether r and omized to continue or discontinue HT , showed better verbal memory performance at the 2-year follow-up assessment . An interaction was also found with HT r and omization and family history of AD in a first-degree relative . All female offspring of patients with AD declined in verbal memory ; however , women who continued HT declined less than women who discontinued HT . Women without a first-degree relative with AD showed verbal memory improvement ( likely because of practice effects ) with continuance and declined with discontinuance of HT . CONCLUSION Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset BACKGROUND Apparently discrepant findings have been reported by the Women 's Health Initiative ( WHI ) trial compared with observational studies of postmenopausal hormone therapy ( HT ) and coronary heart disease ( CHD ) . METHODS We prospect ively examined the relation of HT to CHD , according to timing of hormone initiation relative to age and time since menopause . Participants were postmenopausal women in the Nurses ' Health Study , with follow-up from 1976 to 2000 . Information on hormone use was ascertained in biennial , mailed question naires . We used proportional hazards models to calculate multivariable adjusted relative risks ( RR ) and 95 % confidence intervals ( CI ) . We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT . RESULTS Women beginning HT near menopause had a significantly reduced risk of CHD ( RR = 0.66 , 95 % CI 0.54 - 0.80 for estrogen alone ; RR = 0.72 , 95 % CI 0.56 - 0.92 for estrogen with progestin ) . In the subgroup of women demographically similar to those in the WHI , we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause ( RR = 0.87 , 95 % CI 0.69 - 1.10 for estrogen alone ; RR = 0.90 , 95 % CI 0.62 - 1.29 for estrogen with progestin ) . Among women who began taking hormones at older ages , we also found no relation between current use of estrogen alone and CHD ( for women aged 60 + years , RR = 1.07 , 95 % CI 0.65 - 1.78 ) , although there was a suggestion of possible reduced risk for combined HT ( RR = 0.65 , 95 % CI 0.31 - 1.38 ) . In sensitivity analyses , we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT . CONCLUSIONS These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk For decades , hormone-replacement therapy ( HRT ) was considered safe and was the first choice in prevention of postmenopausal osteoporosis induced by estrogen deficiency . Numerous experimental and epidemiological studies further supported a protective effect of exogenous female sex hormones on atherogenesis and coronary heart disease ( CHD ) in women after the menopause . However , the fact that these promising results were not translated into lower incidences of CHD events in hormone-treated women compared with placebo in subsequent , large , r and omized studies of healthy subjects as well as women with known CHD raised a very intense debate concerning the safety of HRT in terms of cardiovascular risk . A critical mass of data points toward a protective influence of HRT on cardiovascular disease end points in early postmenopausal women , but increased harm in elderly women , especially those with abdominal adiposity or metabolic syndrome . Once the quasi-hysterical reaction to the largest of the r and omized studies ( the Women 's Health Initiative ) has abated , a future strategy should be to concentrate on identifying those relatively few individuals who are not suitable for HRT , as HRT still remains the most thoroughly investigated pharmacological prevention strategy of osteoporosis OBJECTIVES ( 1 ) To assess the prevalence of risk factors for osteoporosis and cardiovascular disease and the prevalence and severity of the appearance of menopausal symptoms among Spanish menopausal women . ( 2 ) To identify the main factors responsible for this severity . ( 3 ) To detect symptom differences between perimenopausal and postmenopausal women . METHODS Cross-sectional descriptive study encompassing women aged 45 - 65 years in the whole Spanish territory . The study population sample was collected through r and om sampling . A total of 10,514 women were included . The sociodemographic , medical history and lifestyle data were assessed by means of a survey . The Kupperman scale was used to assess the severity of menopausal symptoms . RESULTS The prevalence of risk factors for osteoporosis and cardiovascular disease were 67.6 % and 74.8 % , respectively . The most common risk factors were physical inactivity ( 53.6 % ) , obesity ( 44.3 % ) , arterial hypertension ( 36.6 % ) , hypercholesterolemia ( 31.4 % ) , low calcium intake ( 30.1 % ) and smoking ( 28.7 % ) . The predominant symptoms experienced by menopausal women were hot flushes ( 51.4 % ) , insomnia ( 45.7 % ) and irritability ( 42.2 % ) . These were severe in 3.3 % of the sample , moderate in 27.3 % , mild in 24.6 % while 44.8 % had no symptoms . The prevalence of joint pain ( 40.1 % ) and depressive mood ( 40 % ) was higher in perimenopausal than in postmenopausal women . Logistic regression analysis showed that there were differences for age , BMI , smoking , social class and poor consumption of dairy products in the severity of menopausal symptoms . CONCLUSIONS A high prevalence of risk factors for osteoporosis and cardiovascular disease was observed in our study . The main factors contributing to more severe menopausal symptoms were age , BMI , smoking social class and poor consumption of dairy products . In general , postmenopausal women presented significantly higher rates of menopausal symptoms when compared to perimenopausal women Objective This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol ( ELITE ) , the only clinical trial design ed to specifically test the timing hypothesis of postmenopausal hormone therapy ( HT ) . The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause . Methods ELITE is a r and omized , double-blind , placebo-controlled trial with a 2 × 2 factorial design . Six hundred forty-three healthy postmenopausal women without cardiovascular disease were r and omized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause ( < 6 or ≥10 y ) . Carotid artery intima-media thickness ( CIMT ) and cardiac computed tomography  were conducted to determine HT effects on sub clinical atherosclerosis across menopause strata . Results Participants in the early and late postmenopausal strata were well-separated by mean age ( 55.4 vs 65.4 y ) and median time since menopause ( 3.5 vs 14.3 y ) . Expected risk factors ( age , blood pressure , and body mass index ) were associated with CIMT at baseline in both strata . In the early postmenopausal group , but not in the late postmenopausal group , we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation . These include low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , sex hormone – binding globulin , and serum total estradiol . Conclusions The ELITE r and omized controlled trial is timely and unique . Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease Background At the time of feasibility work and final design of the trial there was no r and omised control trial evidence for the long-term risks and benefits of hormone replacement therapy . Observational studies had suggested that long term use of estrogen was likely to be associated , amongst other things , with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer . Concomitant use of progestogens had been shown to protect against endometrial cancer , but there were few data showing how progestogen might affect estrogen actions on other conditions . Disease specific risks from observational studies suggested that , overall , long-term HRT was likely to be beneficial . Several studies showed that mortality from all causes was lower in HRT users than in non-users . Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women . The WISDOM trial was design ed to compare combined estrogen and progestogen versus placebo , and estrogen alone versus combined estrogen and progestogen . During the development of WISDOM the Women 's Health Initiative trial was design ed , funded and started in the US . Design R and omised , placebo , controlled , trial . Methods The trial was set in general practice s in the UK ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . In these practice s 284175 women aged 50–69 years were registered with 226282 potentially eligible . We sought to r and omise 22300 postmenopausal women aged 50 – 69 and treat for ten years . The interventions were : conjugated equine estrogens , 0.625 mg orally daily ; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ; matched placebo . Primary outcome measures were : major cardiovascular disease , osteoporotic fractures , breast cancer and dementia . Secondary outcomes were : other cancers , all cause death , venous thromboembolism and cerebro-vascular disease . Results The trial was prematurely closed during recruitment following publication of early results from the Women 's Health Initiative . At the time of closure , 56583 had been screened , 8980 entered run-in , and 5694 ( 26 % of target of 22,300 ) r and omised . Those women r and omised had received a mean of one year of therapy , mean age was 62.8 years and total follow-up time was 6491 person years . Discussion The WISDOM experience leads to some simple messages . The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery . When a trial is very costly and beyond the re sources of one country , funders and investigators should make every effort to develop international collaboration with joint funding Objective : To evaluate the effects of hormone therapy ( HT ) on cognition and subjective quality of life ( QoL ) in recently postmenopausal women with cognitive complaints . Methods : Cognitive Complaints in Early Menopause Trial ( COGENT ) was a r and omized , double-blind , placebo-controlled , multicenter , pilot study of 180 healthy postmenopausal women aged 45 to 55 years , r and omly assigned to receive either placebo or conjugated equine estrogen 0.625 mg/medroxyprogesterone acetate 2.5 mg for 4 months . Outcome measures included memory , subjective cognition , QoL , sexuality , and sleep , which were assessed at baseline and month 4 . Results : The study was terminated before the expected final sample size of 275 due to a decrease in enrollment coinciding with the publication of findings from the Women ’s Health Initiative . There were no differences between groups on any cognitive or QoL measures , except for an increase in sexual interest and thoughts with HT . Modest negative effects on short- and long-term verbal memory approached significance ( p < 0.10 ) . Women with baseline vasomotor symptoms ( VMS ) showed a decrease in VMS and an improvement in general QoL , but no cognitive benefit vs placebo . Conclusions : With the power to detect an effect size of ≥0.45 , this study suggests potential modest negative effects on verbal memory that are consistent with previous hormone therapy trials in older women . GLOSSARY : BTA = Brief Test of Attention ; BVRT = Benton Visual Retention Test ; COGENT = Cognitive Complaints in Early Menopause Trial ; CRT = Educational Testing Service Card Rotation Test ; CVLT = California Verbal Learning ; FAS = Letter Fluency Test ; HERS = Heart and Estrogen/progestin Replacement Study ; HT = hormone therapy ; MFSQ = McCoy Female Sexuality Scale Question naire ; MFQ = The Memory Functioning Question naire ; PANAS = Positive and Negative Affect Scale ; PSQI = The Pittsburgh Sleep Quality Index ; QoL = subjective quality of life ; SWAN = Study of Women ’s Health Across the Nation ; UQoL = Utian Quality of Life ; VMS = vasomotor symptoms Test ; WHI = Women ’s Health Initiative ; WHISCA = WHI Study of Cognitive Aging ; WMS-R/DGT-F , MS-R/DGT-B = Digit Span Forward and Backward Subtests of the Wechsler Memory Scale – Revised Menopause impacts 25 million women world wide each year , and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030 . Menopause has been associated with symptoms of hot flashes , night sweats , dysphoric mood , sleep disturbance , and conditions of cardiovascular disease , depression , osteoporosis , osteoarthritis , depression , dementia , and frailty . Conventional hormone replacement therapy results in increased thrombotic events , and an increased risk of breast cancer and dementia as evidence d in large prospect i ve clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women 's Health Initiative . A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors . Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile , yet long-term studies of this treatment model are lacking . The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol , estradiol , progesterone , DHEA , and testosterone on cardiovascular biomarkers , hemostatic , inflammatory , immune signaling factors ; quality -of-life measures ; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care . A prospect i ve , cohort , closed-label study received approval from the Human Subjects Committee . Recruitment from outpatient clinics at an academic medical center and the community at large result ed in three hundred women giving signed consent . Seventy-five women who met strict inclusion /exclusion criteria were enrolled .  Baseline hormone evaluation was performed along with baseline experimental measures . Following this , women received compounded transdermal bioidentical hormone therapy of BiEst ( 80%Estriol/20%Estradiol ) , and /or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women . The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic , ischemic , or neuronal injury . Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of and rogens of DHEA and Testosterone if indicated . Experimental subjects were monitored for 36 months . Baseline , 2-month , and annual values were obtained for : blood pressure , body mass index , fasting glucose , Homeostasis Metabolic Assessment of Insulin Resistance ( HOMA-IR ) , fasting triglycerides , total Factor VII , Factor VIII , fibrinogen , Antithrombin III , Plasminogen Activator Inhibitor1(PAL-1 ) , C-reactive protein ( CRP ) , Interleukin-6 ( IL-6 ) , Matrix Metalloproteinase-9 ( MMP-9 ) , Tumor Necrosis Factor-alpha ( TNF ) , Insulin-like Growth Factor ( IGF-1 ) , and sex steroid levels . Psychosocial measures included : Greene Climacteric Scale , Visual Analog Pain Scale , Hamilton Anxiety Scale , Hamilton Depression Scale , Holmes Rahe Stress Scale , Job Strain , and Home Strain . Health outcome measures included the number of prescribed medications used , number of co-morbidities , and endometrial thickness in postmenopausal women with intact uteri . Subjects receiving  compounded transdermal bioidentical hormone therapy showed significant favorable changes in : Greene Climacteric Scale scores , Hamilton Anxiety Scale , Hamilton Depression Scale , Visual Analog Pain Scale , fasting glucose , fasting triglycerides , MMP-9 , C-reactive Protein , fibrinogen , Factor VII , Factor VIII , Insulin-Like Growth Factor 1 , and health outcomes of co-morbidities and a number of prescribed medications . Antithrombin III levels were significantly decreased at 36 months . All other measures did not exhibit significant effects . Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women . Cardiovascular biomarkers , inflammatory factors , immune signaling factors , and health outcomes were favorably impacted , despite very high life stress , and home and work strain in study subjects . The therapy did not adversely alter the net prothrombotic potential , and there were no associated adverse events . This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in population s with high perceived stress and a history of stressful life events prior to , or during the menopausal transition Introduction Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy ( HT ) . We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes . Methods Healthy , non-smoking freshly postmenopausal women ( n = 150 ) with no previous HT use were studied . Seventy-two women reported intolerable hot flushes ( ≥7 moderate/severe episodes/day ) and 78 women tolerable hot flushes ( ≤3 mild episodes/day ) . The participants were treated in r and omized order with either transdermal estradiol gel ( 1 mg ) , oral estradiol valerate ( 2 mg ) with or without medroxyprogesterone acetate ( 5 mg ) , or placebo for 6 months . Treatment-induced changes in lipids , lipoproteins , apolipoproteins , sex hormone binding globulin ( SHBG ) and high-sensitivity C-reactive protein were compared . The trial is registered in the US National Institutes of Health Clinical Research Registry ( no. NCT00668603 ) . Results Pretreatment hot flush status was not related to the responses of these markers to different forms of HT . However , when all active regimens were evaluated together as a post-hoc analysis , 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes . Furthermore , in women with intolerable hot flushes and with HT use , the increases in SHBG ( Spearman 's rho = − 0.570 , p < 0.001 ) were related to the reductions in hot flushes during the use of HT . Conclusions Hot flushes appear to be no significant determinant for the responses of vascular  markers to HT use The National Institutes of Health ( NIH ) has instructed participants in the estrogen-alone study of the Women ’s Health Initiative ( WHI ) , a large multi-center trial , to stop taking their study pills and to begin the follow-up phase of the study . Letters have been sent to all participants in the estrogenalone study , 11,000 healthy postmenopausal women who have had a hysterectomy , informing them of a recent NIH review of the study data . After careful consideration of the data , NIH has concluded that with an average of nearly 7 years of follow-up completed , estrogen alone does not appear to affect ( either increase or decrease ) heart disease , a key question of the study . At the same time , estrogen alone appears to increase the risk of stroke and decrease the risk of hip fracture . It has not increased the risk of breast cancer during the time period of the study . The increased risk of stroke in the estrogen-alone study is similar to what was found in the WHI study of estrogen plus progestin when that trial was stopped in July 2002 . In that study , women taking estrogen plus progestin had 8 more strokes per year for every 10,000 women than those taking the placebo . The NIH believes that an increased risk of stroke is not acceptable in healthy women in a research study . This is especially true if estrogen alone does not affect ( either increase or decrease ) heart disease , as appears to be the case in the current study . The NIH has determined that the results would not likely change if the estrogen trial continued to its planned completion in 2005 . Furthermore , enough data have been obtained to assess the overall risks and benefits of the use of estrogen in this trial . WHI research ers have begun a detailed analysis of the data from the estrogen-alone study and expect to report full results in the next two months . The report , to be published in a peer- review ed journal , will include additional data collected through the end of February 2004 . A separate report will contain information on  probable dementia or mild cognitive impairment in the women age 65 and older who participated in the estrogen-alone WHI-Memory Study ( WHIMS ) , an ancillary study of the WHI Hormone Trials . Preliminary data suggest that for the WHIMS participants who were on estrogen  alone when compared to the women who were taking the placebo , there was a trend toward increased risk of probable dementia and /or mild cognitive impairment . The WHI estrogen study was design ed to assess the effect of long-term use of hormone therapy in healthy postmenopausal women on the prevention of heart disease and hip fractures , and any associated change in risk for breast cancer . It was not design ed to evaluate the short-term risks and benefits of hormones for the treatment of moderate to severe menopausal symptoms . The estrogen-alone study involved women ages 50 to 79 years . Study participants were r and omly assigned to a daily dose of estrogen—0.625 mg/day of conjugated equine estrogen — or a placebo . The NIH decision to stop the estrogen-alone trial was made on February 2 , 2004 . In November and December 2003 , the WHI Data and Safety Monitoring Board ( DSMB ) , an independent advisory committee which regularly review s study data and oversees the safety of study participants , review ed the latest data from the estrogen-alone study . The DSMB was split as to whether the study pills should be stopped or whether the pills should be continued , provided that a letter would be sent to the participants clearly informing them of the stroke risks and other findings . After careful review , the NIH decided that women in the estrogen-alone study should stop taking their study pills . From the National Heart , Lung , and Blood Institute of the National Institutes of Health The objective of this study was to examine the effects of estrogen-based hormone therapy ( HT ) on regional cerebral metabolism in postmenopausal women ( mean age = 58 , SD = 5 ) at risk for development of dementia . The prospect i ve clinical trial design included pre- and post-intervention neuroimaging of women r and omized to continue ( HT+ ) or discontinue ( HT− ) therapy following an average of 10 years of use . The primary outcome measure was change in brain metabolism during the subsequent two years , as assessed with  fluorodeoxyglucose-18 positron emission tomography ( FDG-PET ) . Longitudinal FDG-PET data were available for 45 study completers . Results showed that women r and omized to continue HT experienced relative preservation of frontal and parietal cortical metabolism , compared with women r and omized to discontinue HT . Women who discontinued 17-β estradiol (17βE)-based HT , as well as women who continued conjugated equine estrogen (CEE)-based HT , exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical ( PCC ) area . Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins ( with either 17βE or CEE ) . Together , these findings suggest that among postmenopausal subjects at risk for developing dementia , regional cerebral cortical metabolism is relatively preserved for at least two years in women r and omized to continue HT , compared with women r and omized to discontinue HT . In addition , continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC , known to undergo the most significant decline in the earliest stages of Alzheimer 's disease . Trial Registration Clinical Trials.gov OBJECTIVE To eluci date the effects of low-dose 17beta-estradiol and norethisterone ( hormone therapy [ HT ] ) versus placebo in women with Alzheimer Disease ( AD ) on cognition , depressive symptoms , and activities of daily living . DESIGN A 12-month r and omized , double-blind , placebo-controlled study , stratified by apolipoprotein E ( ApoE ) genotype ( with versus without the epsilon4 allele ) , duration of education ( < or = 9 versus > 9 years ) , and age ( < or = 75 versus > 75 years ) performed during 2000 - 2004 . SETTING Ambulatory memory clinic in a general hospital . PARTICIPANTS Sixty-five female out patients aged 65 - 89 years who met criteria for probable AD according to Diagnostic and Statistical Manual of Mental Disorders , fourth edition and International Classification of Diseases , tenth edition . Ten patients were excluded , result ing in 55 participants who had at least one posttreatment efficacy evaluation . INTERVENTION R and omly assigned to receive either 1-mg estradiol and 0.5-mg norethisterone or placebo once daily . MEASUREMENTS Cognitive variables were the Dementia Rating Scale , tests from Consortium to Establish a Registry for AD , Global Deterioration Scale ( GDS ) and Barthel Index . RESULTS When only treatment effects were compared by analysis of variance , there were nonsignificant differences between treatment groups for all efficacy variables . A linear model analysis , including stratifying factors in addition to treatment in the model , revealed a significant main effect on mood . The depressive symptoms were lower in the HT group than in the placebo group . Those treated with HT without the ApoE epsilon4 allele had better mood , Word Learning Memory score , and GDS score . Those in the HT group with a higher level of education obtained a better GDS score . Adverse events did not differ between the groups . CONCLUSION HT interacts with ApoE genotype in women with AD . Women without an ApoE epsilon4 allele may get better mood and cognition with HT . HT may reduce depressive mood and give less cognitive decline AIMS The use of hormone therapy ( HT ) is a relevant and topical issue in the treatment of menopausal symptoms in women . Information regarding the effects of combination treatment with estrogen and progesterone as well as treatment timing on cognitive function is lacking and was evaluated in healthy pre- and postmenopausal women . METHODS Sixteen premenopausal ( 45 - 51 years ) and 16 postmenopausal ( 58 - 70 years ) women were r and omly assigned to receive either estrogen + progestin therapy ( HT ) or placebo ( PL ) for six months . The study was double-blind . Cognitive performance was measured at baseline and follow up with tests of verbal and visuomotor functions , verbal and visual memory , and attention . RESULTS In premenopausal women , cognitive attention , when compared to baseline , improved with HT but declined slightly with PL in the two-choice reaction time task ( P = 0.049 ) , while PL was associated with better performance in tests of shared attention ( P = 0.024 ) and auditory attention ( P < 0.05 ) . In postmenopausal women , HT was associated with improved performance in verbal episodic memory ( P = 0.024 ) and a minor decline in auditory attention ( P = 0.025 ) . CONCLUSIONS HT , with estradiol valerate and norethisterone , in healthy women showed only minor effects on attention around the menopausal transition and on memory in postmenopause Objectives : Observational studies suggest reduced risk of Alzheimer disease ( AD ) in users of hormone therapy ( HT )  , but trials show higher risk . We examined whether the association of HT with AD varies with timing or type of HT use . Methods : Between 1995 and 2006 , the population -based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT .  During this interval , 176 women developed incident AD . Cox proportional hazard models evaluated the association of HT use with AD , overall and in relation to timing , duration of use , and type ( opposed vs unopposed ) of HT . Results : Women who used any type of HT within 5 years of menopause had 30 % less risk of AD ( 95 % confidence interval 0.49–0.99 ) , especially if use was for 10 or more years . By contrast , AD risk was not reduced among those who had initiated HT 5 or more years after menopause . Instead , rates were increased among those who began “ opposed ” estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline ( adjusted hazard ratio 1.93 ; 95 % confidence interval 0.94–3.96 ) . This last hazard ratio was similar to the ratio of 2.05 reported in r and omized trial participants assigned to opposed HT . Conclusions : Association of HT use and risk of AD may depend on timing of use . Although possibly beneficial if taken during a critical window near menopause , HT ( especially opposed compounds ) initiated in later life may be associated with increased risk . The relation of AD risk to timing and type of HT deserves further study Estrogen-only  menopausal hormone therapy ( HT ) increases the risk of endometrial cancer , but less is known about the association with other types of HT . Using Cox proportional hazards regression , the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospect i ve Investigation into Cancer and Nutrition between 1992 and 2000 . After a mean follow-up period of 9 years , 601 incident cases of endometrial cancer were identified . In comparison with never users of  HT  , risk of endometrial cancer was increased among current users of estrogen-only HT ( hazard ratio ( HR ) = 2.52 , 95 % confidence interval ( CI ) : 1.77 , 3.57 ) , tibolone ( HR = 2.96 , 95 % CI : 1.67 , 5.26 ) , and , to a lesser extent , estrogen-plus-progestin HT ( HR = 1.41 , 95 % CI : 1.08 , 1.83 ) , although risks differed according to regimen and type of progestin constituent . The association of HT use with risk was stronger among women who were older , leaner , or had ever smoked cigarettes . The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk . The increased risk associated with tibolone use requires further investigation Description This guideline up date s the 2008 American College of Physicians ( ACP ) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women . This guideline is endorsed by the American Academy of Family Physicians . Methods The ACP Clinical Guidelines Committee based these recommendations on a systematic review of r and omized controlled trials ; systematic review s ; large observational studies ( for adverse events ) ; and case reports ( for rare events ) that were published between 2 January 2005 and 3 June 2011 . The review was up date d to July 2016 by using a machine-learning method , and a limited up date to October 2016 was done . Clinical outcomes evaluated were fractures and adverse events . This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density , including pharmaceutical prescriptions , calcium , vitamin D , and estrogen . Evidence was grade d according to the GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) system . Target Audience and Patient Population The target audience for this guideline includes all clinicians . The target patient population includes men and women with low bone density and osteoporosis . Recommendation 1 ACP recommends that clinicians offer pharmacologic treatment with alendronate , risedronate , zoledronic acid , or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis . ( Grade : strong recommendation ; high- quality evidence ) . Recommendation 2 ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 3 ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinical ly recognized osteoporosis . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 4 ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women . ( Grade : weak recommendation ; low- quality evidence ) . Recommendation 5 ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women . ( Grade : strong recommendation ; moderate- quality evidence ) . Recommendation 6 ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences , fracture risk profile , and benefits , harms , and costs of medications . ( Grade : weak recommendation ; low- quality evidence ) Summary Canadian women over 50 years old were studied over a 10-year period to see if those who sustained a fracture ( caused by minimal trauma ) were receiving the recommended osteoporosis therapy . We found that approximately half of these women were not being treated , indicating a significant care gap in osteoporosis treatment . Introduction Prevalent fragility fracture strongly predicts future fracture . Previous studies have indicated that women with fragility fractures are not receiving the indicated treatment . We aim ed to describe post fracture care in Canadian women using a large , population -based prospect i ve cohort that began in 1995–1997 . Methods We followed 5,566 women over 50 years of age from across Canada over a period of 10 years in the Canadian Multicentre Osteoporosis Study . Information on medication use and incident clinical fragility fractures was obtained during a yearly question naire or interview and fractures were confirmed by radiographic/medical reports . Results Over the 10-year study period , 42–56 % of women with yearly incident clinical fragility fractures were not treated with an osteoporosis medication . During year 1 of the study , 22 % of the women who had experienced a fragility fracture were on treatment with a bisphosphonate and 26 % were on hormone therapy ( HT ) . We were not able to differentiate HT use for menopause symptoms vs osteoporosis . Use of bisphosphonate therapy  increased over time ; odds ratio ( OR ) for use at year 10 compared to use at year 1 was 3.65 ( 95 % confidence interval ( CI ) 1.83–7.26 ) . In contrast , HT use declined , with an OR of 0.07 ( 95%CI 0.02–0.24 ) at year 10 compared to year 1 of the study . Conclusion In a large population -based cohort study , we found a therapeutic care gap in women with osteoporosis and fragility fractures . Although bisphosphonate therapy usage improved over time , a substantial gap remains Several formulations combining estrogens and progestins for hormone therapy ( HT ) have been approved worldwide for the treatment of menopausal symptoms , yet recent data indicate a decline in their use and an increase in compounded bioidentical HT . Up to now , no single product combining natural 17β-estradiol and progesterone has been approved by the US Food and Drug Administration ( FDA ) or the European Medicines Agency ( EMA ) . A phase 3 trial ( REPLENISH ) is underway to study a novel oral formulation of solubilized 17β-estradiol and natural progesterone combined in a single gelatin capsule ( TX-001HR ; TherapeuticsMD , Inc , Boca Raton , FL ) for treating vasomotor symptoms ( VMS ) in postmenopausal women . The REPLENISH trial evaluates the efficacy and safety of TX-001HR ( 4 doses ) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year . TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones ; further , it does not contain peanut oil , a common allergen . The constituents of TX-001HR , in a pharmacokinetic report , showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together . Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins . This report summarizes the methodology of the REPLENISH trial and review s the evidence suggesting clinical differences between HT containing progesterone or progestins , and estradiol or conjugated equine estrogens OBJECTIVE In older women , higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes . We examined whether the effect of postmenopausal hormone therapy ( HT ) on cognitive impairment incidence differs depending on type 2 diabetes . RESEARCH DESIGN AND METHODS The Women ’s Health Initiative ( WHI ) r and omized clinical trials assigned women to HT ( 0.625 mg/day conjugated equine estrogens with or without [ i.e. , unopposed ] 2.5 mg/day medroxyprogesterone acetate ) or matching placebo for an average of 4.7–5.9 years . A total of 7,233 women , aged 65–80 years , were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment ( mild cognitive impairment or dementia ) . RESULTS Through a maximum of 18 years of follow-up , women with diabetes had increased risk of probable dementia ( hazard ratio [ HR ] 1.54 [ 95 % CI 1.16–2.06 ] ) and cognitive impairment ( HR 1.83 [ 1.50–2.23 ] ) . The combination of diabetes and r and om assignment to HT increased their risk of dementia ( HR 2.12 [ 1.47–3.06 ] ) and cognitive impairment ( HR 2.20 [ 1.70–2.87 ] ) compared with women without these conditions , interaction P = 0.09 and P = 0.08 . These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens . CONCLUSIONS These analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women . The role estrogen plays in suppressing non – glucose-based energy sources in the brain may explain this interaction Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women . Design Open label , r and omised controlled trial . Setting Denmark , 1990 - 93 . Participants 1006 healthy women aged 45 - 58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values . 502 women were r and omly allocated to receive hormone replacement therapy and 504 to receive no treatment ( control ) .  Women who had undergone hysterectomy were included if they were aged 45 - 52 and had recorded values for postmenopausal serum follicle stimulating hormone . Interventions In the treatment group , women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day . Intervention was stopped after about 11 years owing to adverse reports from other trials , but participants were followed for death , cardiovascular disease , and cancer for up to 16 years . Sensitivity analyses were carried out on women who took more than 80 % of the prescribed treatment for five years . Main outcome measure The primary endpoint was a composite of death , admission to hospital for heart failure , and myocardial infa rct ion . Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months . After 10 years of intervention , 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group ( hazard ratio 0.48 , 95 % confidence interval 0.26 to 0.87 ; P=0.015 ) and 15 died compared with 26 ( 0.57 , 0.30 to 1.08 ; P=0.084 ) . The reduction in cardiovascular events was not associated with an increase in any cancer ( 36 in treated group v 39 in control group , 0.92 , 0.58 to 1.45 ; P=0.71 ) or in breast cancer ( 10 in treated group v 17 in control group , 0.58 , 0.27 to 1.27 ; P=0.17 ) . The hazard ratio for deep vein thrombosis ( 2 in treated group v 1 in control group ) was 2.01 ( 0.18 to 22.16 ) and for stroke ( 11 in treated group v 14 in control group ) was 0.77 ( 0.35 to 1.70 ) . After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer . Conclusions After 10 years of r and omised treatment , women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality , heart failure , or myocardial infa rct ion , without any apparent increase in risk of cancer , venous thromboembolism , or stroke . Trial registration Clinical Trials.gov NCT00252408 Background —Despite diffuse effects of sex hormones on the cardiovascular system , few prospect i ve studies have examined the relationship of plasma and rogens and estrogens with risk of cardiovascular disease ( CVD ) in postmenopausal women . Methods and Results —A nested case-control study was performed among women in the Women ’s Health Study . Two hundred women who developed CVD were matched 1:1 by age , smoking , and postmenopausal hormone therapy ( HT ) to controls who remained free of CVD . We measured testosterone , estradiol , and sex hormone binding globulin ( SHBG ) levels and calculated free and rogen index ( FAI ) , free estradiol index , and the FAI/free estradiol index ratio .  Results were stratified by HT use . Among HT nonusers , cases had significantly higher and rogen profiles ( higher median FAI and lower SHBG levels ) than controls . After adjustment for age , smoking , use of aspirin , vitamin E , and alcohol , family history of myocardial infa rct ion , and physical activity , nonusers in the lowest SHBG quartile had an OR of 2.25 ( 95 % CI , 1.03 to 4.91 ) for CVD , and there were significant trends across FAI quartiles ( P for trend=0.03 ) . Additional adjustment for body mass index , hypertension , diabetes , and elevated cholesterol eliminated associations with SHBG and FAI . Among women using HT , no significant differences in hormones or SHBG were observed among women who developed CVD and controls . Conclusions —Among HT nonusers , lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events , but this was not independent of body mass index and other cardiovascular risk factors . Estradiol levels were not associated with risk of CVD in  HT  users or nonusers The Women 's Health Initiative Memory Study -Younger ( WHIMS-Y ) was design ed to assess the effect of prior r and om assignment to hormone therapy ( HT ) ( conjugated equine estrogen ( CEE ) alone or CEE plus medroxyprogesterone acetate ( MPA ) ) on global cognitive function in younger middle-aged women relative to placebo . WHIMS-Y was an ancillary study to the Women 's Health Initiative ( WHI ) HT trial and enrolled 1361 women who were aged 50 - 55 years and postmenopausal at WHI enrollment . WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen , time between menopause and study initiation , and prior use of HT . We present the study rationale and design . We describe enrollment , adherence to assigned WHI therapy , and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment . Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups , st and ardized and masked data collection , and high rates of retention and on-trial adherence and exposure . In addition , the telephone-administered cognitive battery showed adequate construct validity . WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50 - 55 years . Integrated into the WHI , WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites . This article is part of a Special Issue entitled Hormone Therapy The postmenopausal hormone therapy ( PHT ) component of the Women ’s Health Initiative ( WHI ) is composed of two r and omized , placebo-controlled , double-blind trials in postmenopausal women aged 50 to 79 years at initial screening , testing the effects of estrogen alone ( E-alone ) and estrogen plus progestin ( E P ) on coronary heart disease ( CHD ) as the primary outcome , hip and other fractures and colorectal cancer as secondary outcomes , and pulmonary embolism , breast and endometrial cancers as potential risks . The design and rationale of the PHT trials , including general eligibility and exclusion criteria and considerations regarding sample size and statistical power , have been described previously ( 1 ) . Postmenopausal hormones have been initiated in menopausal women for the treatment of vasomotor symptoms , mood disturbances , vaginal dryness , and prevention of rapid bone loss for several decades . Despite a paucity of data on effects of initiating hormone use in older women , postmenopausal hormones have also been promoted for the prevention of CHD , osteoporotic fractures , and other diseases that occur years after menopause ( 2 ) . It is generally recommended ( 2 ) that women with a uterus be prescribed a combination of estrogen and progestin to prevent Objective To evaluate the efficacy and safety of Heyan Kuntai Capsule ( 和颜坤泰胶囊 , HYKT ) and hormone therapy ( HT ) on perimenopausal syndromes ( PMSs ) . Methods From 2005 to 2008 , 390 women with PMSs were recruited from 4 clinic centers . The inclusion criteria included ages 40 to 60 years , estradiol ( E2 ) below 30 ng/L , and follicle stimulating hormone ( FSH ) above 40 IU/L , etc . The patients were r and omly assigned to HYKT group or HT group by r and om number table method , administrated HYKT or conjugated estrogen with/without medroxyprogesterone acetate tablets for 12 months . During treatment , the patients were interviewed quarterly , Kupperman Menopausal Index ( KMI ) scores , hot flush scores , insomnia scores , Menopause-Specific Quality of Life ( MENQOL ) scores and adverse effects were used for evaluating drug efficacy and safety respectively . The last interview was made at the end of 12-month treatment Results After treatment , KMI scores of HYKT group and HT group were both significantly decreased compared with baseline ( P < 0.01 ) and there was no significant difference between groups ( P > 0.05 ) , except that KMI of HYKT group was higher after 3-month treatment ( P < 0.05 ) . After treatment , hot flush and insomnia scores were both improved significantly in two groups ( P < 0.01 ) ; and HT had a better performance than HYKT in improving hot flush ( P < 0.05 ) . MENQOL were significantly improved in both groups after treatment ( P < 0.01 ) ; but there was no significant difference between two groups ( P > 0.05 ) . The incidence of adverse event in the HYKT group was much lower than that in the HT group ( P < 0.01 ) . Conclusions HYKT could effectively relieve PMSs and improve patients quality of life without severe adverse reactions . Although HYKT exerted curative effects more slowly than hormone , it possessed better safety profile than hormone The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of postmenopausal hormone  use in 2763 women ( 1 ) . Unlike previous observational studies , it included only women with previous coronary heart disease , and hormone therapy was exclusively oral conjugated estrogen plus progestin . In HERS , overall rates of recurrent coronary heart disease did not differ between the treated and nontreated groups . However , in additional , unplanned analyses , the results of HERS were not uniformly null . A marked and statistically significant trend toward decreasing risk was observed with increasing duration of hormone use ( 1 ) ; in the first year , the rate of major coronary events was 52 % higher in the treatment group . In the second year , rates were equal , but during the final fourth and fifth years , women assigned to hormone therapy had a 33 % lower risk for coronary events . The overall results of HERS and the apparent changes in risk over time were both unexpected . Since no previous investigations have examined the relation between duration of hormone use or combined hormone treatment to secondary prevention of coronary heart disease events , it remains unclear whether the time trend was authentic and whether the observations in HERS are limited to that hormone regimen ( 2 ) . In addition , we were interested in underst and ing how women 's use of hormone therapy before their initial coronary disease event might affect the outcome of their hormone use after that event . In HERS , duration of hormone therapy before trial entry was necessarily disregarded ( although 23 % of participants had previously taken hormones ) ; thus , it remains unknown how , or whether , to account for hormone use or duration of use before a patient 's initial coronary event . To further examine the effects of duration of hormone therapy and to explore the effect of different hormone regimens , we investigated the relation between  postmenopausal hormone use and secondary prevention of major coronary events in 2489 women with established coronary disease in the Nurses ' Health Study , a large observational cohort . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 , when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about  postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . Every 2 years , we mail follow-up question naires to the original participants to up date information on risk factors and to identify newly diagnosed cases of major illnesses . The total follow-up for the cohort to date exceeds 92 % . Sample for Analysis For this analysis , we limited the cohort to postmenopausal women who reported a previous myocardial infa rct ion or documented coronary atherosclerosis ( coronary artery bypass graft surgery , percutaneous coronary revascularization , or angiographic evidence of 70 % occlusion of one or more major coronary arteries ) . Such women were identified on the baseline question naire in 1976 ; postmenopausal women who reported one of these conditions on a subsequent follow-up question naire were added to the sample at that time . Women ranged in age from 34 to 73 years at entry into the sample for analysis ; 60 % of women had a natural menopause . These criteria closely parallel those used in HERS ( 1 ) ; however , in HERS , women with hysterectomy were excluded , occlusion was defined as at least 50 % , and participants ranged in age from 44 to 79 years . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) ( 3 ) . The women 's reports of age at menopause and type of menopause were highly accurate ( 4 ) . In HERS , women with a history of breast or endometrial cancers were excluded . In the current study , we excluded women who reported stroke or cancer ( except nonmelanoma skin cancer ) on the 1976 baseline question naire at the outset and excluded women from further follow-up if they reported these diseases on a subsequent biennial question naire . This was done to avoid potential bias , in which major diseases such as stroke or cancer may have caused women to alter their hormone use and may be related to risk for coronary heart disease . This type of bias could not have occurred in a r and omized trial , such as HERS . Two hundred forty-eight postmenopausal women with coronary disease entered the analysis in 1976 , and 2241 postmenopausal women were added during follow-up as they reported heart disease ; thus , 17 239 person-years accrued during up to 20 years of follow-up from 1976 to 1996 . Ascertainment of Hormone Use In 1976 , women were asked about current and past use and duration of hormone therapy ;  this information was up date d on each biennial question naire . Beginning in 1978 and on each subsequent question naire , we collected information on type of hormone used . For the period 19761978 , we assigned women to the type of hormone reported on the 1978 question naire . If no data were available on hormone therapy for a given 2-year period , those women were assigned to a missing category for that period . In the HERS trial , women who had taken hormones in the 3 months before their screening visit were excluded ( although 23 % to 24 % of the enrolled participants had previously used hormones ) . Because this study is observational , we could not impose a 3-month washout period ; thus , we could not duplicate that aspect of the HERS protocol . We analyzed duration of hormone use in two different ways . In the main analysis , we performed a HERS replication and used a method similar to that in HERS to calculate duration of use . In HERS , duration of hormone therapy began to accrue at r and omization ( regardless of previous hormone use ) ; r and omization occurred sometime after the participant 's initial coronary disease event . Therefore , in our main analysis , we began accruing duration of hormone use for each participant immediately after her initial coronary disease event ( regardless of hormone use before this event ) . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 4 years . In an alternative analysis , we considered the women 's full experience with hormone therapy ( both before and after the initial coronary disease event ) . Thus , duration of hormone use accumulated continuously from start to termination of therapy . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 6 years . Similar to HERS participants , 29 % of the nurses had taken hormones before their first coronary disease event . Identification of Second Coronary Disease Events Similar to HERS , in our study the category of recurrent major coronary heart disease included nonfatal myocardial infa rct ion and fatal coronary disease that occurred between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met the World Health Organization criteria ( 5 ) ( symptoms , plus either elevated cardiac enzyme levels or diagnostic electrocardiograms ) . Infa rct ions requiring hospitalization and corroborated by interview or letter , but for which medical records were unobtainable , were included as probable . Most deaths were reported by the participants ' families . Every 2 years , we search the National Death Index ( 6 ) to identify deaths among nonrespondents ; follow-up for death remains more than 98 % complete to date . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . Cases in which coronary disease was listed on the death certificate as the underlying cause of death and another , more plausible cause could not be discerned were included as probable cases , since the nurse was known to have had coronary disease before death . The investigators conducted all interviews and medical record review s without knowledge of participants ' hormone use status . In separate analyses , results for probable cases of coronary disease ( 20 % ) were almost identical to those for confirmed cases ( 80 % ) ; thus , we present data from analyses in which confirmed and probable cases are combined . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the baseline data and were up date d every 2 years according to information received on follow-up question naires . Examination of type of hormone therapy was limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate , as this was the most common hormone regimen . If information on hormone use was missing during a follow-up period , then person-time was assigned to a missing category for that time period . So that the study would be prospect i ve , we established hormone status during each 2-year follow-up period from women 's reports at the start of the time period ; thus , we probably underestimate duration of use by an average of 1 year in both the main analysis and the alternate analysis . Follow-up for a participant ended with diagnosis of myocardial infa rct ion , death , or 1 June 1996 , whichever came first . The analysis is based on incidence rates , using person-months of follow-up as the denominator . We used relative risk as the measure of association , defined as the incidence of second major coronary events among women in various categories of hormone use divided by the rate among women who never used hormones BACKGROUND Women with a family history of breast cancer have several menopausal therapy options , including tamoxifen , hormone therapy ( HT ) , alternative medications , or no treatment . This complex decision should be based on each woman 's risk to develop breast cancer , menopausal symptoms , preferences , and risks for other conditions . The authors determined the effects of a personalized risk assessment and genetic counseling intervention on knowledge , risk perception , and decision making in a group of healthy women who had a first-degree relative with breast cancer . METHODS Forty-eight cancer-free menopausal women age > or = 40 years who had at least one first-degree relative with breast cancer were r and omized to a genetic counseling intervention or control .  Intervention participants were given a personalized risk assessment for breast cancer , heart disease , osteoporosis , and uterine cancer based on family history and personal health data . Knowledge , risk perception , and medication usage were measured at baseline , 1 month , and 6 months . RESULTS Knowledge was higher in the intervention group at both follow-up time points postintervention . Perceived risk for developing breast cancer was significantly lower and more accurate in the intervention group at 1 and 6 months postintervention than at baseline , as was perceived risk of developing heart disease . Although the counseling intervention did affect both knowledge and risk perception , overall , both groups were reluctant to take any form of menopausal therapy . CONCLUSIONS A personalized risk assessment and genetic counseling intervention improves patient knowledge and risk perception ; however , it is unclear that the intervention influenced menopausal treatment decisions AIMS At the time of the design of the Osteoporosis Prevention and Arterial effects of tiboLone ( OPAL ) study in 1996 , oral hormone therapy ( HT ) was assumed to reduce cardiovascular risk . The evidence mainly came from the effects of combined conjugated equine oestrogens plus medroxyprogesterone acetate ( CEE/MPA ) therapy . Other HT regimes had not been studied widely . Tibolone , a selective tissue oestrogenic activity regulator , has several effects on cardiovascular risk factors , one of which is HDL lowering . Because the overall effect of tibolone on cardiovascular risk was unknown , the OPAL study was design ed . METHODS AND RESULTS The OPAL study was a three-arm , r and omized , placebo-controlled , double-blind study to determine the effect of tibolone ( 2.5 mg daily ) and of CEE/MPA ( 0.625/2.5 mg daily ) over 3 years on progression of carotid intima-media thickness ( CIMT ) in 866 healthy post-menopausal women . The women were recruited from six US and five European centres . The primary outcome was change in mean common CIMT . Annual common CIMT progression rates in the tibolone and CEE/MPA groups were higher than in the placebo group : 0.0077 mm [ 95 % confidence interval ( CI ) 0.0051 - 0.0103 ] in the tibolone group , 0.0074 mm ( 0.0048 - 0.0099 ) in the CEE/MPA group , and 0.0035 mm ( 0.009 - 0.0061 ) in the placebo group . The differences with placebo ( 0.0042 mm/year for tibolone and 0.0039 mm/year for CEE/MPA ) were statistically significant . HDL cholesterol increased in CEE/MPA group and was lowered in the tibolone group . CONCLUSION Both tibolone and CEE/MPA showed increased progression of common CIMT . Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the Women 's Health Initiative study . This suggests that the net effect of tibolone and CEE/MPA on cardiovascular events may depend on the combined effects on the arterial wall , clotting factors , and possibly inflammation This review discusses major findings from the Women 's Health Initiative Memory Study ( WHIMS ) . WHIMS reported hormone therapy (HT)--conjugated equine estrogen ( CEE ) with or without medroxyprogesterone acetate (MPA)--increased the risk for dementia ( HR 1.76 [ 95 % CI , 1.19 - 2.60 ] ; P=0.005 ) and global cognitive decline , with a mean decrement relative to placebo of 0.21 points on the Modified Mini Mental State Examination ( 3MS ) ( P=0.006 ) in women age 65 and older . A subset of WHIMS participants joined the ancillary WHI Study of Cognitive Aging ( WHISCA ) trials , in which domain-specific cognitive tests and mood were measured annually . Compared with placebo , CEE+MPA had a negative impact on verbal memory over time ( P=0.01 ) ; and CEE-Alone was associated with lower spatial rotational ability ( P < or = 0.01 ) at the initial assessment , but the difference diminished over time . The ancillary WHIMS-MRI study measured sub clinical cerebrovascular disease to possibly explain the negative cognitive findings reported by WHIMS and the increased clinical stroke in older women reported by the WHI . WHIMS-MRI reported that while CEE+MPA and CEE-Alone were not associated with increased ischemic brain lesion volume relative to placebo ; both CEE+MPA and CEE-Alone were associated with lower mean brain volumes in the hippocampus ( P=0.05 ) ; frontal lobe ( P=0.004 ) ; and total brain ( P=0.07 ) . HT-associated reductions in hippocampal volumes were greatest in women with baseline 3MS scores < or = 90 Clinical trials indicate that hormone therapy ( HT ) does not decrease cardiovascular disease events or angiographic coronary disease progression . The effects of HT on SVG vessels are unknown . To determine whether postmenopausal hormone therapy started after coronary bypass surgery ( CABG ) decreases saphenous vein graft ( SVG ) disease , we conducted a multicenter r and omized placebo-controlled angiographic study of estradiol+/-medroxyprogesterone started within 6 months of CABG in 83 postmenopausal women .  Angiographic and intravascular ultrasound ( IVUS ) assessment at 6 and 42 months was planned to assess SVG disease progression . The study was stopped early following publication of the Women 's Health Initiative Estrogen/Progestin study . Eighty-three subjects underwent a 6-month angiogram with 63 undergoing IVUS . Forty-five subjects completed the 42-month  angiogram  ( 20 underwent 42-month IVUS ) . In analysis of paired 6- and 42-month angiogram and IVUS studies , HT slowed angiographic progression of SVG disease assessed by mean percent stenosis ( p<0.001 ) , minimal lumen diameter ( p=0.029 ) , and total plaque volume ( p=0.006 ) . In contrast , HT accelerated disease progression in non-bypassed native coronary arteries ( minimum lumen diameter , p=0.01 ) . SVG disease and closure occurred in 38 % subjects within 1-year post-CABG . The groups had similar frequency of cardiovascular events expect for angioplasty that occurred in eight HT compared to one placebo subject ( p<0.05 ) . In HT subjects angioplasty was indicated for native coronary arterial stenoses while in the placebo subject angioplasty was indicated for SVG stenosis . This study suggests that hormone treatment may slow SVG disease progression while accelerating atherosclerosis in non-bypassed native coronary arteries BACKGROUND The decision to take hormone replacement therapy ( HRT ) is a choice many women encounter when entering menopause . The purpose of this study was to examine the choice to take HRT while participating in a lifestyle intervention to reduce cardiovascular risk through the menopause . METHODS The Women 's Healthy Lifestyle Project is a r and omized clinical trial design ed to examine whether a behavioral lifestyle intervention can decrease the expected rise in cardiovascular risk through the menopause . Participants ( N = 535 ) completed question naires and were interviewed regarding menopausal symptoms , menopausal status , hot flashes , and  HRT  use at baseline and 54 months . RESULTS The intervention was successful in preventing risk elevation through the 54-month visit . At the final visit , there was no difference between the intervention and control groups in the percentage who had become postmenopausal ( 32.9 % vs 35.0 % , respectively ) , there was no difference between control and intervention with  HRT  use , with 31.2 % reporting use of HRT , and there was no difference between groups with menopausal symptoms . The women started HRT an average of 6 months after they missed a period . Baseline risk factors did not predict HRT use at the 54-month visit . CONCLUSIONS A sizable number of women reported HRT use . The decision to use HRT was not influenced by the lifestyle intervention or their baseline cardiovascular risk , and these women started HRT very early in the peri- to postmenopause . Further , weight loss in the perimenopause did not affect menopausal symptoms Background : Hormone therapy ( HT ) is the treatment of choice for the alleviation of menopausal symptoms ; concerns , however , about its concomitant long-term health risks have limited its use . DT56a is a unique enzymatic isolate of soybeans . The purpose of our study was to evaluate the efficacy and safety of DT56a , compared to HT , in symptomatic post-menopausal women . Subjects and methods : Eighty-nine post-menopausal women were studied prospect ively . Women with climacteric symptoms were r and omly assigned to receive eitherDT56a ( no.=27 ) or oral low dose continuous combined HT ( no.=26 ) . Symptomatic women not wishing to receive any treatment served as controls ( no.=36 ) . Menopausal symptoms as assessed through the Kupperman index , serum lipids and lipoproteins , calcium , as well as bone mineral density ( BMD ) , endometrial thickness , and mammography were assessed at baseline and at 12 months . Results : Patients receiving HT and DT56a showed a significant and independent decrease in menopausal symptoms ( mean difference in Kupperman score , DT56a group : −3.98 , HT group −5.601 , no treatment group + 1.76 , p-value < 0.001 ) . Lumbar spine BMD T-score was significantly lower in women receiving no treatment , as opposed to the two treatment arms which showed no significant change ( No treatment , baseline : −0.60 , final : −0.85 , p=0.001 ; HT , baseline : −84 , final −0.99 , p=0.79 ; DT56a , baseline −0.51 , final : −0.76 , p=0.75 ) . No differences in femoral bone density , ET or mammography classification were detected in any of the treatment arms . Likewise , serum lipids or lipoproteins did not differ between the three groups . Conclusions : DT56a decreased menopausal symptoms significantly and in the same degree as HT Half of all postmenopausal women will have an osteoporosis-related fracture during their lives , including one quarter who will develop a vertebral deformity ( 1 ) and 15 % who will suffer a hip fracture ( 2 ) . Hip fractures are associated with high mortality rates and loss of independence ( 3 , 4 ) . Although many vertebral fractures are detected only incidentally on radiography , some cause severe pain , leading to 150 000 hospital admissions per year in persons older than 65 years of age , 161 000 physician office visits , and more than 5 million days of restricted activity in those 45 years of age or older ( 5 ) . Low bone density has been used to predict risk for fractures as well as to diagnose osteoporosis . Osteoporosis has been defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue , leading to enhanced bone fragility and a consequent increase in fracture risk ( 6 , 7 ) . This definition emphasizes that , in addition to bone mass , the structure of bone is an important factor in the pathogenesis of fractures . A World Health Organization working group ( 8) proposed that osteoporosis should be diagnosed in epidemiologic studies when  bone mineral density  is 2.5 SDs or more below the mean for healthy young adult women at the spine , hip , or wrist ( corresponding to a T-score 2.5 ) or when patients have a history of atraumatic fracture ( 9 ) . By the World Health Organization definition , up to 70 % of women older than 80 years of age have osteoporosis ( 10 ) . Age is also an important factor in the relationship between bone density and the absolute risk for fracture . Older women have a much higher fracture rate than younger women with the same bone density because of increasing risk from other factors , such as bone quality and tendency to fall ( 11 ) . Despite the high prevalence of osteoporosis and the effect of fractures on mortality , independence , and quality of life , it is not clear whether it is appropriate to screen asymptomatic postmenopausal women . Recent systematic review s and guidelines disagree about which women should be screened and when ( 12 - 20 ) . This disagreement reflects , in part , gaps in the evidence . For example , most guidelines recommend using risk factors to select patients for bone density testing , but because of inadequate data there is no consensus on which risk factors to use . As part of the U.S. Preventive Services Task Force up date of its 1996 recommendation ( 21 ) , we examined evidence on the benefits and harms of screening postmenopausal women for osteoporosis . Specifically , we addressed the role of risk factors in identifying high-risk women , techniques of bone density testing to identify fracture risks , effectiveness of treatment in reducing fracture risk , and harms of screening and treatment . Methods Additional methods used for this review , including determination of the quality of studies ( 22 ) , are detailed in Appendix Tables 1 , 2 , and 3 and in a separate report ( 23 ) . The analytic framework and key questions are detailed in the Appendix Figure . Relevant studies were identified from multiple search es of MEDLINE ( 1966 to May 2001 ) , HealthSTAR ( 1975 to May 2001 ) , and Cochrane data bases ; reference lists of systematic review s ; and experts . We also sent letters to manufacturers of bone density devices requesting additional information about the performance of their instruments , but we received no new data . Two review ers read each abstract to determine its eligibility . We included English- language abstract s that contained original data about postmenopausal women and osteoporosis and addressed screening or the effectiveness of risk factor assessment , bone density testing , or treatment . We considered screening to be the process of assessing postmenopausal women without known osteoporosis for risk of osteoporotic fractures by identification of risk factors , including low bone density . Postmenopausal women were those who had experienced surgical or natural menopause , regardless of age . Women with preexisting atraumatic fractures were not considered in the screening population because they had confirmed osteoporosis according to the World Health Organization definition . For studies of prediction , we selected articles that reported the relationship between risk factor assessment methods or bone density tests and bone density , bone loss , or fractures . We review ed studies of medications used for treatment and present results for bisphosphonates . We focused on r and omized , controlled trials of therapies reporting radiographically verified , nontraumatic fracture outcomes because fractures are a stronger measure of effectiveness than bone density . We excluded studies of primary prevention of osteoporosis , such as the role of nutrition , calcium consumption , and physical activity . We also excluded secondary causes of osteoporosis , such as corticosteroid use and certain chronic diseases , and studies that did not provide sufficient information to allow determination of the method for selecting patients and for analyzing data . Investigators read the full-text versions of the retrieved papers and reapplied the initial eligibility criteria . To assess the internal validity of individual studies , we applied a set of criteria developed by the third U.S. Preventive Services Task Force ( Appendix Table 1 ) ( 22 ) . In this paper , we highlight studies that are applicable to current practice st and ards , have high- quality internal validity ratings , and are most generalizable to the U.S. population of postmenopausal women under consideration for screening . We created an outcomes table to summarize the number of  hip and vertebral fractures  prevented based on age-specific prevalence rates and treatment effects obtained from results of the review ed studies . We conducted a sensitivity analysis to determine the influence of risk factors on the number needed to screen . This research was funded by the Agency for Healthcare Research and Quality under a contract to support the work of the U.S. Preventive Services Task Force . Agency staff and Task Force members participated in the initial design of the study and review ed interim analyses and the final manuscript . Additional reports were distributed for review to content experts and revised accordingly before preparation of this manuscript ( 23 , 24 ) . The authors are responsible for the content of the manuscript and the decision to su bmi t it for publication . Results Studies of Screening We identified no studies about the effectiveness of screening in reducing osteoporotic fractures . Without direct evidence from screening studies , recommendations about screening need to rely on evidence that risk factor assessment or bone density testing can adequately identify women who could ultimately benefit from treatment . Risk Factor Assessment Hundreds of studies report associations between risk factors and low bone density and fractures in postmenopausal women ( 24 ) . The most comprehensive study of risk factors in a U.S. population is the Study of Osteoporotic Fractures , a good- quality prospect i ve study of 9516 women 65 years of age and older ( 25 ) . In this study , 14 clinical risk factors were identified as significant predictors of hip fracture in multivariable models ( age ; maternal hip fracture ; no weight gain ; height ; poor self-rated health ; hyperthyroidism ; current use of benzodiazepines , anticonvulsants , or caffeine ; not walking for exercise ; lack of ambulation ; inability to rise from a chair ; poor scores on two measures of vision ; high resting pulse ; and any fracture since 50 years of age ) . The relative risk for hip fracture per decrease of 1 SD in calcaneal bone density was 1.6 ( 95 % CI , 1.3 to 1.9 ) . This was comparable to the magnitude of the relative risks of most of the other significant predictors in the model , which ranged from 1.2 to 2.0 . Women with at least 5 of the 14 risk factors had increased rates of hip fractures compared with those who had 0 to 2 risk factors at all levels of calcaneal bone density . To determine which risk factors could be important in women younger than 65 years of age , we review ed eight observational studies of risk factors and fractures of various types conducted in population s in which at least 50 % of participants were younger than 65 years of age . Table 1 lists risk factors that were statistically significant predictors for fractures in multivariable models ( 26 - 33 ) . These results could not be quantitatively combined because risk factors were defined differently in each study . Table 1 . Risk Factors for Fractures in Women 5065 Years of Age Results of risk factor studies have been used to assess risk in individuals . We identified 10 cross-sectional studies that described methods of determining risk for low bone density for individual women based on selected clinical risk factors ( Table 2 ) ( 34 - 43 ) . The most common method ologic limitations of these studies are lack of validation and lack of generalizability because of small numbers of patients or nonrepresentative patients . We also identified 8 studies of clinical risk factors to determine fracture risk ( Table 2 ) ( 44 - 51 ) . None of these studies received a good rating for internal validity . Four studies evaluated hip fracture outcomes , two evaluated vertebral fractures , and two evaluated all types of fractures . These studies described the association of risk factors with fractures known to have occurred already ( four casecontrol studies ) or how well they would predict fractures in the future ( four prospect i ve cohort studies ) . Table 2 . Studies of Risk Factor Assessment A recent study compared the performance of five clinical decision rules for bone density testing among 2365 postmenopausal women 45 years of age or older who were enrolled in a community-based study of osteoporosis in Canada ( 52 ) . These rules included guidelines from the National Osteoporosis Foundation ( 53 ) ; the Simple Calculated Osteoporosis Risk Estimation ( SCORE ) rule ( age , weight , ethnicity , estrogen use , OBJECTIVE To provide guidelines for the health care provider on the prevention , diagnosis , and clinical management of postmenopausal osteoporosis . OUTCOMES Strategies for identifying and evaluating high-risk individuals , the use of bone mineral density ( BMD ) and bone turnover markers in assessing diagnosis and response to management , and recommendations regarding nutrition , physical activity , and the selection of pharmacologic therapy to prevent and manage osteoporosis . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library on August 30 and September 18 , 2012 , respectively . The strategy included the use of appropriate controlled vocabulary ( e.g. , oteoporosis , bone density , menopause ) and key words ( e.g. , bone health , bone loss , BMD ) . Results were restricted to systematic review s , practice guidelines , r and omized and controlled clinical trials , and observational studies published in English or French . The search was limited to the publication years 2009 and following , and up date s were incorporated into the guideline to March 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , clinical practice guideline collection s , clinical trial registries , and national and international medical specialty societies We report our experience with 25 women previously treated for breast cancer who subsequently received hormone replacement therapy ( HRT ) for the relief of menopausal symptoms and the prevention of postmenopausal cardiovascular disease and osteoporosis . Two patients had in situ disease , 13 had stage I disease , 7 had stage II disease , 1 had stage III disease , and 2 had invasive cancer of undetermined stage . Seventeen patients ( group I ) began HRT less than 24 months after primary breast cancer therapy , and 8 patients ( group II ) began HRT more than 24 months after breast cancer therapy . The HRT-free interval for group I patients averaged 7.9 months and for group II patients averaged 64.5 months . The average period of observation while receiving HRT for the entire group was 35.2 months ( range : 24 to 82 months ) . Three of 25 patients have had a recurrence , all in group I. One patient developed local recurrence after breast conservation treatment , and her condition was salvaged by further wide excision . Two patients developed recurrence after mastectomy , and one patient ultimately died of systemic disease . The overall survival rate for the entire group was 96 % . Overall survival of high-risk group I patients , with a mean follow-up of 30.4 months , was 94 % . We recognize that this report of HRT in a small group of patients does not have the power to demonstrate an adverse effect of HRT on breast cancer . However , the lack of an obvious adverse effect of HRT in this group of breast cancer patients and the known beneficial effect of HRT on postmenopausal cardiovascular disease and osteoporosis warrant formal prospect i ve trials of HRT in such patients Objective : To evaluate vaginal , endometrial , and reproductive hormone effects of three herbal regimens compared with placebo and hormone therapy ( HT ) . Design : This was a 1-year , r and omized , double-blind , placebo-controlled trial of 351 women , ages 45 to 55 , with two or more vasomotor symptoms per day . Women were r and omly assigned to ( 1 ) black cohosh , ( 2 ) a multibotanical containing black cohosh , ( 3 ) the same multibotanical plus dietary soy counseling , ( 4 ) HT , or ( 5 ) placebo .  Women were ineligible if they had used HT in the previous 3 months or menopausal herbal therapies in the previous month . Data on vaginal cytology and dryness were collected ( at baseline and 3 and 12 mo ) . Daily menstrual diaries were maintained by 313 women with a uterus , and abnormal bleeding was evaluated . Serum estradiol , follicle-stimulating hormone , luteinizing hormone , and steroid hormone-binding globulin were assessed ( baseline and 12 mo ) among 133 postmenopausal women . Gynecologic outcomes of the five groups were compared . Results : The five groups did not vary in baseline vaginal cytology profiles , vaginal dryness , menstrual cyclicity , or hormone profiles . The HT group had a lower percentage of parabasal cells and vaginal dryness than the placebo group at 3 and 12 months ( P < 0.05 ) . Abnormal bleeding occurred in 53 of 313 ( 16.9 % ) women . There were no differences in frequency of abnormal bleeding between any of the herbal and placebo groups , whereas women in the HT group had a greater risk than those in the placebo group ( P < 0.001 ) . Among postmenopausal women , HT significantly decreased follicle-stimulating hormone and increased estradiol ; none of the herbal interventions showed significant effects on any outcomes at any time point . Conclusion : Black cohosh , used alone or as part of a multibotanical product with or without soy dietary changes , had no effects on vaginal epithelium , endometrium , or reproductive hormones Objective : Although observational studies showed an apparent lower ischemic coronary disease risk in postmenopausal women receiving hormone therapy ( HT )  , r and omized clinical trials in postmenopausal women showed an increase in ischemic cardiovascular events . Soluble cell adhesion molecules have been associated with cardiovascular risk factors and events . HT reduces circulating levels of soluble cell adhesion molecules in healthy postmenopausal women , but its effects in postmenopausal women with coronary artery disease are less clear . We assessed the effect of HT on soluble cell adhesion molecules in the Estrogen Replacement and Atherosclerosis trial . Design : The Estrogen Replacement and Atherosclerosis trial was a double-blind , placebo-controlled study that r and omized 309 postmenopausal women ( mean age , 65.8 y ) to daily unopposed estrogen ( conjugated estrogens 0.625 mg ) , estrogen plus 2.5 mg of medroxyprogesterone acetate , or placebo  , with a mean follow-up period of 3.2 years . Soluble intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin were measured in serum obtained from participants at baseline and after 12 months of follow-up . Results : Of the 265 women with complete data , 87 women were assigned to unopposed estrogen , 88 women to estrogen plus medroxyprogesterone acetate , and 90 women to placebo . Compared with placebo , 12 months of HT ( n = 175 ) was associated with reductions in soluble intercellular adhesion molecule-1 ( 25.6 ± 4.7 vs 10.6 ± 6.4ng/mL , P = 0.06 ) , soluble vascular cell adhesion molecule-1 ( 80.2± 10.6 vs 28.8 ± 14.7 ng/mL , P = 0.005 ) , and E-selectin ( 8.8 ± 0.9 vs −1.1 ± 1.2 ng/mL , P < 0.001 ) . Conclusions : Twelve months of HT in postmenopausal women with established coronary artery disease was associated with reductions in serum markers of endothelial cell activation/injury such as soluble intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue OBJECTIVES To compare event rates for osteoporotic fractures , cardiovascular events , and breast cancer in postmenopausal women with osteoporosis . DESIGN A prospect i ve , observational study of the placebo group in the double-blind , r and omized Multiple Outcomes of Raloxifene Evaluation trial . SETTING One hundred eighty clinical research centers in 25 countries . PARTICIPANTS Postmenopausal women ( n=2,565 , mean age=67 ) with osteoporosis were given calcium ( 500 mg/d ) and vitamin D ( 400 - 600 IU/d ) supplements . MEASUREMENTS The occurrence of at least one new fracture , cardiovascular event , or breast cancer diagnosis at 3 years was identified and adjudicated . RESULTS The occurrence of any fracture was the most common event in these women . In women without prevalent vertebral fractures ( n=1,627 ) , the event rates per 1,000 patient-years were 45.4 for any fracture , 15.2 for vertebral fracture , 4.7 for clinical vertebral fracture , 0.9 for hip fracture , 8.3 for any cardiovascular event , and 5.2 for all breast cancer . In women with prevalent vertebral fractures ( n=938 ) , the event rates per 1,000 patient-years were 117.4 for any new fracture , 77.1 for new vertebral fracture , 25.7 for clinical vertebral fracture , 5.8 for hip fracture , 15.1 for any cardiovascular event , and 2.6 for all breast cancer . The effect of prevalent fracture status on event rates was not dependent on whether women were older or younger than 65 , but women aged 65 and older had a 3.6 times greater occurrence of cardiovascular events than younger women , irrespective of prevalent fracture status . CONCLUSION These data on the relative incidence of clinical ly significant skeletal and extra-skeletal outcomes may be useful in choosing an agent for health maintenance for postmenopausal women with osteoporosis IMPORTANCE Screening mammography intervals remain under debate in the United States . OBJECTIVE To compare the proportion of breast cancers with less vs more favorable prognostic characteristics in women screening annually vs biennially by age , menopausal status , and postmenopausal hormone therapy ( HT ) use . DESIGN , SETTING , AND PARTICIPANTS This was a study of a prospect i ve cohort from 1996 to 2012 at Breast Cancer Surveillance Consortium facilities . A total of 15,440 women ages 40 to 85 years with breast cancer diagnosed within 1 year of an annual or within 2 years of a biennial screening mammogram .  EXPOSURES We up date d previous analyses by using narrower intervals for defining annual ( 11 - 14 months ) and biennial ( 23 - 26 months ) screening . MAIN OUTCOMES AND MEASURES We defined less favorable prognostic characteristics as tumors that were stage IIB or higher , size greater than 15 mm , positive nodes , and any 1 or more of these characteristics . We used log-binomial regression to model the proportion of breast cancers with less favorable characteristics following a biennial vs annual screen by 10-year age groups and by menopausal status and current postmenopausal HT use . RESULTS Among 15,440 women with breast cancer , most were 50 years or older ( 13,182 [ 85.4 % ] ) , white ( 12,063 [ 78.1 % ] ) , and postmenopausal ( 9823 [ 63.6 % ] ) . Among 2027 premenopausal women ( 13.1 % ) , biennial screeners had higher proportions of tumors that were stage IIB or higher ( relative risk [ RR ] , 1.28 [ 95 % CI , 1.01 - 1.63 ] ; P=.04 ) , size greater than 15 mm ( RR , 1.21 [ 95 % CI , 1.07 - 1.37 ] ; P=.002 ) , and with any less favorable prognostic characteristic ( RR , 1.11 [ 95 % CI , 1.00 - 1.22 ] ; P=.047 ) compared with annual screeners . Among women currently taking postmenopausal HT , biennial screeners tended to have tumors with less favorable prognostic characteristics compared with annual screeners ; however , 95 % CIs were wide , and differences were not statistically significant ( for stage 2B+ , RR , 1.14 [ 95 % CI , 0.89 - 1.47 ] , P=.29 ; size>15 mm , RR , 1.13 [ 95 % CI , 0.98 - 1.31 ] , P=.09 ; node positive , RR , 1.18 [ 95 % CI , 0.98 - 1.42 ] , P=.09 ; any less favorable characteristic , RR , 1.12 [ 95 % CI , 1.00 - 1.25 ] , P=.053 ) . The proportions of tumors with less favorable prognostic characteristics were not significantly larger for biennial vs annual screeners among postmenopausal women not taking HT  ( eg , any characteristic : RR , 1.03 [ 95 % CI , 0.95 - 1.12 ] ; P=.45 ) , postmenopausal HT users after subdividing by type of hormone use ( eg , any characteristic : estrogen+progestogen users , RR , 1.16 [ 95 % CI , 0.91 - 1.47 ] ; P=.22 ; estrogen-only users , RR , 1.14 [ 95 % CI , 0.94 - 1.37 ] ; P=.18 ) , or any 10-year age group ( eg , any characteristic : ages 40 - 49 years , RR , .1.04 [ 95 % CI , 0.94 - 1.14 ] ; P=.48 ; ages 50 - 59 years , RR , 1.03 [ 95 % CI , 0.94 - 1.12 ] ; P=.58 ; ages 60 - 69 years , RR , 1.07 [ 95 % CI , 0.97 - 1.19 ] ; P=.18 ; ages 70 - 85 years , RR , 1.05 [ 95 % CI , 0.94 - 1.18 ] ; P=.35 ) . CONCLUSIONS AND RELEVANCE Premenopausal women diagnosed as having breast cancer following biennial vs annual screening mammography are more likely to have tumors with less favorable prognostic characteristics . Postmenopausal women not using HT who are diagnosed as having breast cancer following a biennial or annual screen have similar proportions of tumors with less favorable prognostic characteristics BACKGROUND Evidence that long-term hormone therapy ( HT ) may increase the risk of serious adverse events led to a sharp reduction in all HT use , including short-term use for vasomotor symptom relief . We estimated women 's willingness to accept adverse event risks in exchange for vasomotor symptom relief when risks are communicated in absolute vs. relative terms . METHODS We developed a conjoint survey to elicit preferences across benefit and risk attributes of HT . The survey was administered via the Internet to 523 U.S. women aged 46 - 60 years . Participants evaluated pairs of hypothetical treatments and indicated preferences using a Likert-based scale . Risks were presented in absolute and relative terms . Satisfaction scores for HT risks and benefits were estimated using r and om-effects , ordered-probit regression . Maximum acceptable risk ( MAR ) was calculated as the increase in risk that reduces the satisfaction score for a given level of HT benefit to 0 . RESULTS For both risk versions , the least important attribute ( smallest difference in satisfaction scores ) was night sweat frequency ; heart attack risk was the most important ( largest difference in scores ) . Participants were more willing to accept risks in return for symptom relief when shown absolute vs. relative risks , although differences in MAR were statistically significant only for breast cancer risk . MARs for breast cancer and heart attack exceeded reported rates in most cases . CONCLUSIONS Many women may be willing to accept risks to control vasomotor symptoms . However , describing risks in different , but technically equivalent , ways affects women 's willingness to trade risks for benefits Objective This study aims to test the added value of calcium and vitamin D ( CaD ) in fracture prevention among women taking postmenopausal hormone therapy ( HT ) . Methods This is a prospect i ve , partial-factorial , r and omized , controlled , double-blind trial among Women ’s Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years . A total of 27,347 women were r and omized to HT ( 0.625 mg of conjugated estrogens alone , or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily ) , and 36,282 women were r and omized to 1,000 mg of elemental calcium ( carbonate ) plus 400 IU of vitamin D3 daily , each compared with placebo .  A total of 16,089 women participated in both arms . The predefined outcomes were adjudicated hip fractures and measured bone mineral density . Results Interaction between HT and CaD on hip fracture ( P interaction = 0.01 ) was shown . The effect of CaD  was stronger among women assigned to HT ( hazard ratio [ HR ] , 0.59 ; 95 % CI , 0.38 - 0.93 ) than among women assigned to placebo ( HR , 1.20 ; 95 % CI , 0.85 - 1.69 ) . The effect of HT on hip fracture was stronger among women assigned to active CaD ( HR , 0.43 ; 95 % CI , 0.28 - 0.66 ) than among women assigned to placebo ( HR , 0.87 ; 95 % CI , 0.60 - 1.26 ) . CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake . There was no interaction between HT and  CaD  on change in hip or spine bone mineral density .  Conclusions Postmenopausal women at normal risk for hip fracture who are on CaD supplementation  experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake Background : Although postmenopausal combined hormone replacement therapy reduces the risk of hip fracture , long-term use may be associated with an increased risk of breast cancer , and in women more than 10 years after menopause it is associated with an increased risk of cardiovascular disease . Isoflavones , because of preferential binding to estrogen receptor beta , may retain the beneficial effects on bone but lessen the adverse effects on the breast . Objective : The objective of this study was to study the effects of an isoflavone obtained from red clover ( Rimostil ) on bone mineral density , and on low-density lipoprotein ( LDL ) cholesterol . Design : In a double-blind , r and omized , placebo-controlled trial , 50 mg of Rimostil was given to women who were menopausal for at least 1 year .  Bone mineral density of the spine , femoral neck and forearm and serum LDL cholesterol were measured at baseline and at 6-month intervals . The duration of follow-up was 2 years . Results : There was no beneficial effect of Rimostil  on bone density at any site . There was a 12 % fall in serum LDL cholesterol in the Rimostil-treated arm , which was significantly greater than the 2 % drop seen in the control arm ( P=0.005 ) CONTEXT Osteoporotic fractures are associated with premature mortality .  Antiresorptive treatment reduces refracture but mortality reduction is unclear . OBJECTIVE The objective of the study was to examine the effect of osteoporosis treatment [ bisphosphonates ( BP ) , hormone therapy ( HT ) , and calcium ± vitamin D only ( CaD ) ] on mortality risk . DESIGN This was a prospect i ve cohort study ( April 1989 to May 2007 ) . SETTING The study was conducted with community-dwelling elderly ( aged 60 + yr ) subjects in Dubbo , a semiurban city , Australia . SUBJECTS Subjects included 1223 and 819 women and men in the Dubbo Osteoporosis Epidemiology Study . MAIN OUTCOME MEASURE Mortality according to treatment group was recorded . RESULTS There were 325 ( BP , n = 106 ; HT , n = 77 ; CaD , n = 142 ) women and 37 men ( BP , n = 15 ; CaD , n = 22 ) on treatment . In women , mortality rates were lower with BP 0.8/100 person-years ( 0.4 , 1.4 ) and HT 1.2/100 person-years ( 0.7 , 2.1 ) but not CaD 3.2/100 person-years ( 2.5 , 4.1 ) vs. no treatment 3.5/100 person-years ( 3.1 , 3.8 ) . Accounting for age , fracture occurrence , comorbidities , quadriceps strength , and bone mineral density , mortality risk remained lower for women on BP [ hazard ratio ( HR ) 0.3 ( 0.2 , 0.6 ) ] but not HT [ HR 0.8 ( 0.4 , 1.8 ) ] . For 429 women with fractures , mortality risk was still reduced in the BP group [ adjusted HR 0.3 ( 0.2 , 0.7 ) ] , not accounted for by a reduction in subsequent fractures . In men , lower mortality rates were observed with BP but not CaD [ BP 1.0/100 person-years ( 0.3 , 3.9 ) and CaD 3.1/100 person-years ( 1.5 , 6.6 ) vs. no treatment 4.3/100 person-years ( 3.9 , 4.8 ) ] . After adjustment , mortality was similar , although not significant [ HR 0.5 ( 0.1 , 2.0 ) ] . CONCLUSIONS Osteoporosis therapy appears to reduce mortality risk in women and possibly men Context Since 1998 , 2 large trials have drastically changed the evidence for the preventive health benefits of postmenopausal hormone replacement therapy .  However , changes in practice often lag behind changes in evidence . Contribution Among mammography recipients in San Francisco , California , the use of  hormone replacement therapy decreased 1 % per quarter after publication of the Heart and Estrogen/progestin Replacement Study and 18 % per quarter after publication of results from the Women 's Health Initiative ( WHI ) . Reduction in use was unrelated to a woman 's age , hysterectomy status , or race or ethnicity . Implication s The WHI result ed in more dramatic changes in practice than are often associated with changes in evidence . The vigorous media coverage of the WHI may have contributed to rapid changes in practice . The Editors In 1995 , approximately 38 % of postmenopausal women in the United States were taking hormone therapy  ( 1 ) . At that time , several observational studies had suggested that hormone therapy offered women some protection against coronary heart disease and osteoporosis ( 2 - 5 ) . A decision analysis published in 1997 concluded that the benefits of hormone therapy outweighed its risks for nearly all women ( 6 ) . More recently , the results from 2 large r and omized clinical trials , the Heart and Estrogen/progestin Replacement Study ( HERS ) ( 7 ) and the Women 's Health Initiative ( WHI ) , have been published ( 8) . These clinical trials demonstrated that the risks associated with hormone therapy outweigh the benefits for women taking continuous estrogen and progestin regimens . As a result of these trial results , the U.S. Food and Drug Administration required new warning labels for all estrogen products ( 9 ) , and the U.S. Preventive Services Task Force revised its assessment of hormone therapy to recommend against the routine use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women ( 10 ) . It is important to underst and whether this new scientific evidence is changing the use of hormone therapy . Of note , the results of the WHI were widely disseminated . Despite this publicity , differential access to new information , varied interpretations of study findings , and individual perceptions of menopausal symptoms and hormone side effects may have result ed in different patterns of use . An underst and ing of how use is changing over time provides important information about the dissemination of clinical trial results to women . We design ed our analysis to examine whether the use of hormone therapy  has changed among postmenopausal women as a result of the publication of the results from HERS and the WHI . We were also interested in examining whether patterns of use differ by patient characteristics . Because HERS examined the outcomes of older women , we hypothesized that there would be earlier and more substantial declines in hormone therapy use among this group . We also expected that there would be variation in use by race or ethnicity because white women may have better access to new information ( 11 ) . Finally , because the WHI study results were specific to women taking continuous estrogen plus progestin , we hypothesized that hormone use would be more stable among women who had had hysterectomies because such women typically take only estrogen and may believe that the findings do not apply to them . Methods Sample The San Francisco Mammography Registry is a population -based registry of women undergoing mammography in San Francisco , California . It is 1 of 7 registries participating in the National Cancer Institute Breast Cancer Surveillance Consortium ( 12 ) . This registry began to prospect ively collect patient data and mammography results in 1995 and currently captures about 90 % of mammography examinations performed in San Francisco . Data from 11 mammography facilities are included in this analysis . Women were eligible for this analysis if they were between the ages of 50 to 74 years , were postmenopausal , did not report a personal history of breast cancer , and underwent screening or diagnostic mammography between January 1997 and 19 May 2003 . Women 55 years of age and older were assumed to be menopausal . Women 50 to 54 years of age were considered to be menopausal if both ovaries had been removed or if they reported that their periods had stopped permanently . For women who had mammography more than once in any calendar year , we included only the first instance of mammography in that year to prevent overrepresentation of women undergoing an evaluation of an abnormal mammogram because this experience may influence use of hormone therapy . Our final sample included 15 1862 mammograms received by 71 219 women . Data At the facilities that participate in the San Francisco Mammography Registry , each woman completes a brief , scannable question naire at the time of mammography . This question naire collects information about current use of hormone therapy  and several personal characteristics , including race or ethnicity ( categorized as white , African American , Latina , Chinese , Filipina , other Asian , other ) , family history of breast cancer ( including mother , sisters , and daughters ) , history of childbirth , whether the woman had undergone a hysterectomy , menopausal status , history of breast biopsy ( including fine-needle aspiration , core biopsy , and surgical biopsy ) . Information about age at the time of mammography , date of mammography , and ZIP code of residence is reported by the facility . Data from the year 2000 U.S. Census was used to assign median income for each woman 's ZIP code of residence as a proxy for socioeconomic status . Variables Our outcome variable for this analysis was the current use of hormone therapy . Date of mammography  was represented as a linear term . Binary variables were created for the publication date s of HERS ( before 19 August 1998 vs. that date or later ) and the publication of the principal findings from the WHI ( before 17 July 2002 vs. that date or later ) . Other independent variables examined were age at the time of mammography  , race or ethnicity , median income of the ZIP code of residence , history of childbirth , family history of breast cancer , history of breast biopsy , and previous hysterectomy . Statistical Analysis Because some of the women in this sample had more than 1 mammogram represented in this data set , which spanned a 7-year period , we conducted a repeated- measures logistic regression to adjust the variance estimates for clustering of hormone therapy use over time for individual women and for the clustering of women within mammography facilities ( 13 ) . Generalized estimating equations were implemented by using the SUDAAN statistical package , version 8.0.0 ( Research Triangle Institute , Research Triangle Park , North Carolina ) assuming an exchangeable correlation matrix . These models included a linear term indicating quarter from January 1997 to the first quarter of 2003 to control for temporal trends ( the last quarter included mammograms through 19 May 2003 ) , the variables specified above to indicate the date s of publication of HERS and the WHI , and an interaction term between each of these publication indicators and the time ( in quarters ) following each of these publications to measure changes in use after the publication of these clinical trials . These models also controlled for the individual characteristics described earlier ( that is , age , race or ethnicity , history of childbirth , family history of breast cancer , history of breast biopsy , previous hysterectomy , median income for the ZIP code of residence ) . To specifically test our hypotheses about differential changes in the use of hormone therapy  for subgroups of women on the basis of age , hysterectomy status , and race or ethnicity , we examined interaction terms to test for effect modification . For the main effects , a P value less than 0.05 was considered statistically significant , and for the interaction terms , a P value less than 0.01 was considered to be statistically significant . The likelihood ratio test compared the null model with the fitted model . Role of the Funding Source This work was supported by a National Cancer Institutefunded Breast Cancer Surveillance Consortium agreement . The funding source did not participate in the design , conduct , or reporting of this analysis or in the decision to su bmi t the manuscript for publication . Results The Table shows the characteristics of the sample for each of the study years . Over the time period of the study , the median age decreased from 61 years to 59 years . The racial and ethnic composition of the sample also changed somewhat across the study years . Fewer women undergoing mammography  in 2003 reported a history of childbirth ( 71.7 % vs. 75.2 % ) or hysterectomy than did women undergoing mammography in 1997 . Conversely , more women reported a family history of breast cancer ( 17.1 % vs. 11.8 % ) or a personal history of a previous breast biopsy or aspiration . The average number of mammograms obtained for each woman in our sample across the 7-year study period was 2.1 ( range , 1 to 7 ) . Table . Description of the Sample ( 151 862 Mammograms ) The Figure shows the unadjusted rates of current hormone therapy use by month for all of the women in the sample . Among menopausal women who had received mammography , we estimated that the average proportion reporting the current use of hormone therapy  was 41 % in 1997 . In 1997 , hormone use was highest among white women ( 52.6 % ) and lowest among African-American women ( 34.1 % ) , Latina women ( 33.9 % ) , Chinese women ( 32.2 % ) , and Filipina women ( 29.6 % ) . In 1997 , hormone use was higher among younger women than older women ( 48.7 % vs. 28.7 % ; P < 0.001 ) and among women who had had a hysterectomy compared with women who had not had a hysterectomy ( 60.0 % vs. 36.4 % ; P < 0.001 ) . Figure . Rates of hormone therapy use among postmenopausal women , 1997 to 2003 HERS WHI The adjusted multivariate model estimates that before the publication of HERS , the use of hormone Abstract : This prospect i ve population -based cohort study investigated factors predicting  distal forearm fracture ( DFF ) in perimenopausal women . The study population consisted of 11 798 women from the Kuopio Osteoporosis Risk Factor and Prevention ( OSTPRE ) Study in Finl and . Mean baseline age of these women was 52.3 ( SD 2.9 ) years ( range 47–56 years ) and 68 % were postmenopausal . Three hundred and sixty-eight women ( 3.1 % ) had a vali date d DFF during the 5-year follow-up . Previous wrist fracture , postmenopausal state , age and nulliparity were independent predictors of DFF , while hormone replacement therapy ( HRT ) , dairy calcium and overweight protected against it in multivariate Cox regression analysis : previous wrist fracture increased the DFF risk by 158 % ( p<0.0001 ) , menopause by 69 % ( p= 0.002 ) and age by 6 % per year ( p= 0.010 ) , whereas the continuous use of HRT decreased the risk by 63 % ( p= 0.0001 ) , the use of dairy calcium at 1000–1499 mg/day ( vs < 500 mg/day ) by 39 % ( p= 0.004 ) , overweight ( BMI > 25 kg/m2 ) by 36 % ( p= 0.0002 ) and parity by 29 % ( p= 0.031 ) . Combining dichotomous low weight , low use of calcium , non-use of HRT and previous wrist fracture into a risk score gave a dose – response effect by score level : the presence ( vs absence ) of all four risk factors result ed in a 12-fold DFF risk . Nevertheless , the sensitivity and specificity of the score for detecting DFF remained low . It was concluded that HRT , high nutritional calcium intake and overweight protect against but a history of wrist fracture predisposes to perimenopausal distal forearm fracture . A simple risk factor inquiry would help to identify perimenopausal women at high risk of distal forearm fracture OBJECTIVE To provide up date d , evidence -based recommendations for the prevention and management of hypertension in adults . OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions , evidence was review ed from r and omized controlled trials and systematic review s of trials . Changes in cardiovascular morbidity and mortality were the primary outcomes of interest . However , for lifestyle interventions , blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field . For treatment of patients with kidney disease , the progression of kidney dysfunction was also accepted as a clinical ly relevant primary outcome . EVIDENCE A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to up date the 2006 Canadian Hypertension Education Program recommendations . In addition , reference lists were scanned and experts were contacted to identify additional published studies . All relevant articles were review ed and appraised independently by both content and method ological experts using prespecified levels of evidence . RECOMMENDATIONS Dietary lifestyle modifications for prevention of hypertension , in addition to a well-balanced diet , include a dietary sodium intake of less than 100 mmol/day . In hypertensive patients , the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day . Other lifestyle modifications for both normotensive and hypertensive patients include : performing 30 min to 60 min of aerobic exercise four to seven days per week ; maintaining a healthy body weight ( body mass index of 18.5 kg/m2 to 24.9 kg/m2 ) and waist circumference ( less than 102 cm in men and less than 88 cm in women ) ; limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women ; following a diet reduced in saturated fat and cholesterol , and one that emphasizes fruits , vegetables and low-fat dairy products , dietary and soluble fibre , whole grains and protein from plant sources ; and considering stress management in selected individuals with hypertension . For the pharmacological management of hypertension , treatment thresholds and targets should take into account each individual 's global atherosclerotic risk , target organ damage and any comorbid conditions : blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease . Most patients require more than one agent to achieve these blood pressure targets . In adults without compelling indications for other agents , initial therapy should include thiazide diuretics ; other agents appropriate for first-line therapy for diastolic and /or systolic hypertension include angiotensin-converting enzyme ( ACE ) inhibitors ( except in black patients ) , long-acting calcium channel blockers ( CCBs ) , angiotensin receptor blockers ( ARBs ) or beta-blockers ( in those younger than 60 years of age ) . First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs . Certain comorbid conditions provide compelling indications for first-line use of other agents : in patients with angina , recent myocardial infa rct ion , or heart failure , beta-blockers and ACE inhibitors are recommended as first-line therapy ; in patients with cerebrovascular disease , an ACE inhibitor plus diuretic combination is preferred ; in patients with nondiabetic chronic kidney disease , ACE inhibitors are recommended ; and in patients with diabetes mellitus , ACE inhibitors or ARBs ( or , in patients without albuminuria , thiazides or dihydropyridine CCBs ) are appropriate first-line therapies . All hypertensive patients with dyslipidemia should be treated using the thresholds , targets and agents outlined in the Canadian Cardiovascular Society position statement ( recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease ) . Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy . Once blood pressure is controlled , acetylsalicylic acid therapy should be considered . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence -Based Recommendations Task Force . All recommendations reported here achieved at least 95 % consensus . These guidelines will continue to be up date d annually Historically , estrogen replacement therapy has been advocated in postmenopausal women with anticipated benefits of alleviating perimenopausal symptoms , slowing osteoporosis and preventing heart disease . While the first two effects are known , estrogen ’s role in the prevention of heart disease is unclear . Recommendations for postmenopausal estrogen replacement therapy for heart disease prevention are largely based on clinical , animal model , and tissue-culture studies demonstrating improvements in cardiovascular risk factors and experimental atherosclerosis and numerous observational studies showing fewer cardiovascular events among estrogen users than among non-users1 - 4 . However , definite conclusions regarding estrogen use for the prevention of heart disease can not be ascertained based on these data , due to study limitations and biases . Thus , r and omized clinical trials were needed to further clarify the role of postmenopausal estrogen replacement in the prevention of heart disease . The Heart and Estrogen/progestin Replacement Study ( HERS ) sought to establish the role of hormone replacement therapy for secondary prevention of coronary heart disease5 . But , contrary to expectations , 4.1 years of oral conjugated estrogen plus medroxyprogesterone acetate demonstrated no favorable effects over placebo in either primary ( non-fatal myocardial infa rct ion and coronary heart disease death ) or secondary outcomes . In fact , there was a statistically significant increase in coronary heart disease events in the treatment group compared to the placebo group during the first year . Various theories emerged as research ers attempted to underst and the HERS findings . Some wondered if medroxyprogesterone acetate decreased estrogen ’s favorable effects6 , while others suggested that other unrecognized effects , such as proinflammatory or prothrombotic effects , could be negating estrogen ’s favorable effects on the endothelium and lipids7 Hormone replacement therapy ( HRT ) is often prescribed for a few years to suppress menopausal symptoms . Although its long-term use of HRT for the primary prevention of osteoporosis is not currently recommended , the long-term skeletal benefits of the limited therapy are of great interest . To determine whether administration of HRT for 2 - 3 years in the early postmenopausal years provides long-term benefits , such as prevention of bone loss and osteoporotic fractures , we studied a group of 347 healthy postmenopausal women with normal bone mass who had earlier completed one of four placebo-controlled HRT trials and who were reexamined 5 , 11 , or 15 years after stopping HRT .  Of these women , 263 received either  HRT or placebo for 2 - 3 years with no further bone-sparing treatment until follow-up , and the remaining 84 women reported either prolonged or current use of HRT at reexamination . Bone mineral density ( BMD ) at the spine ( L1-L4 ) and bone mineral content ( BMC ) in the forearm were measured at baseline , the end of the trials , and follow-up . At follow-up , we assessed the radiological presence of vertebral fracture and collected information on the new incidence of nonvertebral fractures . Compared with that of the placebo-treated women , the BMD and BMC of HRT-treated women continued to show significantly higher values ( > 5 % ) even many years after stopping HRT . After stopping treatment , the rate of bone loss returned to normal postmenopausal rates . The preservation of bone mass in the HRT group was accompanied by a significantly reduced risk of all osteoporotic fractures as compared with the placebo group [ OR = 0.48 ( 95 % CI , 0.26 - 0.88 ) ] . ' Fast losers ' on placebo had more than a 4-fold higher risk of fractures than had the women on limited HRT with a normal rate of bone loss after withdrawal . In conclusion , limited HRT administered in the early postmenopausal years offers long-lasting benefits for the prevention of postmenopausal bone loss and osteoporotic fracture The Women 's Health Initiative ( WHI ) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women , including cancer , cardiovascular disease , and osteoporotic fractures . The WHI was initiated in 1992 , with a planned completion date of 2007 . Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial ( CT ) that will include about 64,500 women or an observational study ( OS ) that will include about 100,000 women . The CT is design ed to allow r and omized controlled evaluation of three distinct interventions : a low-fat eating pattern , hypothesized to prevent breast cancer and colorectal cancer and , secondarily , coronary heart disease ; hormone replacement therapy , hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and , secondarily , to reduce the risk of hip and other fractures , with increased breast cancer risk as a possible adverse outcome ; and calcium and vitamin D supplementation , hypothesized to prevent hip fractures and , secondarily , other fractures and colorectal cancer . Overall benefit-versus-risk assessment is a central focus in each of the three CT components . Women are screened for participation in one or both of the components -- dietary modification ( DM ) or hormone replacement therapy (HRT)--of the CT , which will r and omize 48,000 and 27,500 women , respectively . Women who prove to be ineligible for , or who are unwilling to enroll in , these CT components are invited to enroll in the OS . At their 1-year anniversary of r and omization , CT women are invited to be further r and omized into the calcium and vitamin D ( CaD ) trial component , which is projected to include 45,000 women . The average follow-up for women in either CT or OS is approximately 9 years . Concerted efforts are made to enroll women of racial and ethnic minority groups , with a target of 20 % of overall enrollment in both the CT and OS . This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component . Some detail is provided on specific study design choices , including eligibility criteria , recruitment strategy , and sample size , with attention to the partial factorial design of the CT . Some aspects of the CT monitoring approach are also outlined . The scientific and logistic complexity of the WHI implies particular leadership and management challenges . The WHI organization and committee structure employed to respond to these challenges is also briefly described CONTEXT The timing of initiation of hormone therapy may influence its effect on  cardiovascular disease .  OBJECTIVE To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began . DESIGN , SETTING , AND PARTICIPANTS Secondary analysis of the Women 's Health Initiative ( WHI ) r and omized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were r and omized to conjugated equine estrogens ( CEE ) or placebo and  16,608 postmenopausal women who had not had a hysterectomy  were r and omized to CEE plus medroxyprogesterone acetate ( CEE + MPA ) or placebo .  Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998 . MAIN OUTCOME MEASURES Statistical test for trend of the effect of hormone therapy on coronary heart disease ( CHD ) and stroke across categories of age and years since menopause in the combined trials . RESULTS In the combined trials , there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [ corrected ] cases of CHD and 239 cases of stroke in the placebo group . For women with less than 10 years since menopause began , the hazard ratio ( HR ) for CHD was 0.76 ( 95 % confidence interval [ CI ] , 0.50 - 1.16 ) ; 10 to 19 years , 1.10 ( 95 % CI , 0.84 - 1.45 ) ; and 20 or more years , 1.28 ( 95 % CI , 1.03 - 1.58 ) ( P for trend = .02 ) . The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years ; for women 10 to 19 years since menopause began , 4 per 10,000 person-years ; and for women 20 or more years from menopause onset , 17 per 10,000 person-years . For the age group of 50 to 59 years , the HR for CHD was 0.93 ( 95 % CI , 0.65 - 1.33 ) and the absolute excess risk was -2 per 10,000 person-years ; 60 to 69 years , 0.98 ( 95 % CI , 0.79 - 1.21 ) and -1 per 10,000 person-years ; and 70 to 79 years , 1.26 ( 95 % CI , 1.00 - 1.59 ) and 19 per 10,000 person-years ( P for trend = .16 ) . Hormone therapy increased the risk of stroke ( HR , 1.32 ; 95 % CI , 1.12 - 1.56 ) . Risk did not vary significantly by age or time since menopause . There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women ( HR of 0.70 for 50 - 59 years ; 1.05 for 60 - 69 years , and 1.14 for 70 - 79 years ; P for trend = .06 ) . CONCLUSIONS Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause , but this trend test did not meet our criterion for statistical significance . A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause . These data should be considered in regard to the short-term treatment of menopausal symptoms . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 Objective : We investigated the influence of hormone therapy ( HT ) on submaximal central and peripheral function in healthy postmenopausal women after 12 weeks of endurance training . Methods : A r and omized , double-blind , placebo-controlled study in a research and clinical facility was conducted . All participants ( N = 23 ) underwent 12 weeks of aerobic exercise training ( walking 5 d/wk at 70%-80 % peak heart rate [ HR ] ) . Eleven participants received HT ; 12 received placebo . HT consisted of daily 17&bgr;-estradiol ( 1 mg ) with cyclic micronized progesterone ( 200 mg ) or placebo for 10 days per month . Participants were tested before and after exercise training . Primary outcome measures were submaximal stroke volume , cardiac output , and total peripheral resistance measured during cycling at 30W , 45W , and 60W . Secondary outcome measures were ventilatory threshold , peak oxygen uptake ( VO2 peak ) , and resting and peak-ischemic calf blood flow . Results : At baseline , HT and placebo groups were similar ( P > 0.05 ) in age ( mean ± SEM , 57 ± 1 y ) , height ( 162 ± 2 cm ) , weight ( 72 ± 4 kg ) , VO2 peak ( 21.5 ± 1.4 mL · kg−1 · min−1 ) , and all cardiovascular measures . Posttraining oxygen consumption and HR decreased ( P < 0.05 ) within groups during each submaximal exercise workload . Stroke volume , cardiac output , and total peripheral resistance remained unaltered ( P > 0.05 ) . VO2 peak and oxygen consumption at the ventilatory threshold increased ( P < 0.05 ) within groups . Resting and postischemic blood flow were unaltered . HT did not influence any of the cardiovascular responses . Conclusions : These findings suggest that in healthy postmenopausal women , 12 weeks of aerobic training is effective in eliciting favorable cardiovascular adaptations , regardless of the presence of short-term HT BACKGROUND Hormone replacement therapy ( HT ) is known to increase the risk of breast cancer in healthy women , but its effect on breast cancer risk in breast cancer survivors is less clear . The r and omized HABITS study , which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer , was stopped early due to suspicions of an increased risk of new breast cancer events following HT . We present results after extended follow-up . METHODS HABITS was a r and omized , non-placebo-controlled noninferiority trial that aim ed to be at a power of 80 % to detect a 36 % increase in the hazard ratio ( HR ) for a new breast cancer event following HT . Cox models were used to estimate relative risks of a breast cancer event , the maximum likelihood method was used to calculate 95 % confidence intervals ( CIs ) , and chi(2 ) tests were used to assess statistical significance , with all P values based on two-sided tests . The absolute risk of a new breast cancer event was estimated with the cumulative incidence function . Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone . RESULTS Of the 447 women r and omly assigned , 442 could be followed for a median of 4 years . Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event ( HR = 2.4 , 95 % CI = 1.3 to 4.2 ) . Cumulative incidences at 5 years were 22.2 % in the HT arm and 8.0 % in the control arm . By the end of follow-up , six women in the HT arm had died of breast cancer and six were alive with distant metastases . In the control arm , five women had died of breast cancer and four had metastatic breast cancer ( P = .51 , log-rank test ) . CONCLUSION After extended follow-up , there was a clinical ly and statistically significant increased risk of a new breast cancer event in survivors who took HT Introduction In 2008 , the UK National Osteoporosis Guideline Group ( NOGG ) produced a guideline on the prevention and treatment of osteoporosis , with an up date in 2013 . This paper presents a major up date of the guideline , the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men age 50 years or over . Methods Where available , systematic review s , meta-analyses and r and omised controlled trials were used to provide the evidence base . Conclusions and recommendations were systematic ally grade d according to the strength of the available evidence . Results Review of the evidence and recommendations are provided for the diagnosis of osteoporosis , fracture-risk assessment , lifestyle measures and pharmacological interventions , duration and monitoring of bisphosphonate therapy , glucocorticoid-induced osteoporosis , osteoporosis in men , postfracture care and intervention thresholds . Conclusion The guideline , which has received accreditation from the National Institute of Health and Care Excellence ( NICE ) , provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals who are involved in its management OBJECTIVE To investigate the effects of hormone therapy ( HT ) administered to postmenopausal women on pulmonary function tests ( PFT ) . METHODS Eighty-two postmenopausal women who were having natural or surgically initiated menopause and had no risk factor that could affect the respiratory system were included into this prospect i ve , r and omized study . Twenty-five women who refused to use HT were assessed as the control group ( Group I ) . Nineteen women who accepted using HT and who were having surgically initiated menopause were given continuous estrogen ( Group II ) , 23 were given continuous estrogen and progesterone in combination ( Group III ) and 15 were given cyclic estrogen and progesterone combination ( Group IV ) . Forced expiratory volume ( FEV1 ) , forced vital capacity ( FVC ) , FEV1/FVC , forced expiratory flow rate over 25 - 75 % of the forced vital capacity volume and peak expiratory flow rate were assessed at the beginning of the treatment and in the third month in order to evaluate the effects of HT regimens on the women 's PFT . RESULTS A statistically significant increase was observed only in the FEV1 and FVC parameters of Group III after three months of therapy ( P<0.05 ) . The comparison between pre- and posttherapy FEV1 and FVC values showed an increase in the Group IV , but the difference was not statistically significant , while there was no difference between basal and third month FEV1 and FVC values of the group receiving estrogen only . CONCLUSIONS It was seen that particularly continuous combined HT regimen positively affected the FEV1 and FVC parameters of the postmenopausal women Background and Objective The highest level of scientific evidence available for each therapy for menopausal symptoms was sought , for example , systematic review s of r and omised controlled trials ( RCTs ) . Results There is reasonable evidence that some symptoms are modified by lifestyle , for example , cessation of smoking , exercise , reduction of alcohol , diet and alleviation of psychosocial stress . No complementary medicine , for example , phytoestrogens , black cohosh , herbal or homeopathic medicines or complementary therapies , for example , acupuncture , yoga , chiropractic manipulation , reflexology or magnetic devices have a greater effect than the usual placebo effect seen in quality blinded RCTs . Some have potential side-effects . So-called ' bioidentical hormones ' have no evidence -base and potential for harm . None of the above therapies have evidence of efficacy and long-term safety . Selective serotonin and noradrenaline re-uptake inhibitors ameliorate vasomotor symptoms and sometimes menopausal depression better than placebo . The most effective therapy for menopausal ( oestrogen ) deficiency symptoms is oestrogen which is the main component of hormone replacement therapies ( HRT ) . Compared with placebo HRT is highly effective in relieving hot flushes , night sweats , dry vagina and dyspareunia . It also improved joint pains , sexuality and sleeplessness and reduced subsequent fractures in RCTs . The increased risk of oral HRT for thromboembolism is small around menopause , for those without thrombotic risk factors , and is not elevated with non-oral routes . Cardiovascular disease may be reduced when HRT is initiated near menopause . Breast cancer risk increases after several years with the use of oral HRT containing progestogens at an annual rate of 8/10 000 ( < 0.1 % ) . No increase in breast cancer risk was seen with oestrogen-only HRT OBJECTIVE Hormone therapy ( HT ) has been suggested to improve vascular function and inflammation in menopausal women , although not consistently . We aim ed to investigate the effects of HT on endothelial function and inflammation , especially sCD40L , in early menopausal women , and the effect of common estrogen receptor ( ER ) polymorphisms on vascular responses to HT . STUDY DESIGN Eighty-four early menopausal women ( <3 years in menopause ) with menopausal complaints eligible for HT . Forty women received transdermal 17β-estradiol plus cyclical micronized progesterone for 3 months while 44 did not ( controls ) . MAIN OUTCOME MEASURES Brachial artery flow-mediated dilation ( FMD ) and vascular inflammation markers ( sICAM , sP-Selectin and sCD40L ) . Genetic polymorphisms of ERα ( PvuII 454 - 397T > C and XbaI 454 - 351A > G ) and ERβ ( AluI 1730A > G ) were also assessed . RESULTS The two groups did not differ at baseline . Following HT , vasomotor complaints ' severity , blood pressure , LDL , sCD40L , sICAM and sP-Selectin decreased and FMD increased compared to controls ( P<0.05 for all ) . ERβ AluI A allele presence was the most important independent predictor of  HT-induced increase in FMD while ERα XbaI A allele was the only independent predictor of decrease in sCD40L . CONCLUSIONS Short-term HT in early menopausal women improved endothelial function and inflammation . Specific ER polymorphisms that were found to be main determinants of HT-induced effects on endothelium could identify subgroups of women who may benefit the most from HT OBJECTIVES To compare the effects of daily ingestion of dietary soy supplementation , low-dose hormone therapy ( HT ) and placebo on psychological , somatic and urogenital symptoms in postmenopausal women . STUDY DESIGN A double-blind , r and omized , controlled trial . Sixty healthy , symptomatic , postmenopausal women of 40 - 60 years of age were allocated to use dietary soy supplementation ( containing 90 mg of isoflavone ) or HT ( 1 mg estradiol and 0.5 mg norethisterone acetate ) or placebo . MAIN OUTCOME MEASURES the Menopause Rating Scale ( MRS ) was used to assess menopausal symptoms at baseline and after 16 weeks of treatment . Intention-to-treat analyses were performed using the chi-square test , Fisher 's exact test , the Kruskal-Wallis non-parametric test and analysis of variance ( ANOVA ) . RESULTS No statistically significant differences were found between the groups with respect to baseline clinical and sociodemographic characteristics . The psychological , somatic and urogenital symptoms analyzed in the MRS improved during treatment in all the groups , except for urogenital symptoms in the placebo group in which no significant changes were detected . Comparison between groups revealed a statistically significant improvement in somatic symptoms ( hot flashes and muscle pain ) in the users of HT ( -45.6 % ) and dietary soy supplementation ( -49.8 % ) . Urogenital symptoms ( vaginal dryness ) improved significantly in HT users ( -38.6 % ) and in users of the dietary soy supplementation ( -31.2 % ) . There was no statistically significant difference between the groups with respect to overall MRS score or to scores obtained in the psychological symptoms subscale . CONCLUSION Dietary soy supplementation may constitute an effective alternative therapy for somatic and urogenital symptoms of the menopause OBJECTIVES To examine whether significant depressive symptoms in postmenopausal women increases the risk of subsequent mild cognitive impairment ( MCI ) and dementia . DESIGN Prospect i ve cohort study . SETTING Thirty nine of the 40 Women 's Health Initiative ( WHI ) clinical centers that participated in a r and omized clinical trial of hormone therapy . PARTICIPANTS Six thous and three hundred seventy-six postmenopausal women without cognitive impairment aged 65 to 79 at baseline . MEASUREMENTS Depressive disorders were assessed using an eight-item Burnam algorithm and followed annually for a mean period of 5.4 years . A central adjudication committee classified the presence of MCI and probable dementia based on an extensive neuropsychiatric examination . RESULTS Eight percent of postmenopausal women in this sample reported depressive symptoms above a 0.06 cut point on the Burnam algorithm . Depressive disorder at baseline was associated with greater risk of incident MCI ( hazard ratio (HR)=1.98 , 95 % confidence interval (CI)=1.33 - 2.94 ) , probable dementia ( HR=2.03 , 95 % CI=1.15 - 3.60 ) , and MCI or probable dementia ( HR=1.92 , 95 % CI=1.35 - 2.73 ) after controlling for sociodemographic characteristics , lifestyle and vascular risk factors , cardiovascular and cerebrovascular disease , antidepressant use , and current and past hormone therapy status . Assignment to hormone therapy and baseline cognitive function did not affect these relationships . Women without depression who endorsed a remote history of depression had a higher risk of developing dementia . CONCLUSION Clinical ly significant depressive symptoms in women aged 65 and older are independently associated with greater incidence of MCI and probable dementia The aim of this study was to examine the association of exercise frequency and calcium intake ( CI ) with change in regional and total bone mineral density ( BMD ) in a group of postmenopausal women completing 4 years of progressive strength training . One hundred sixty-seven calcium-supplemented ( 800 mg/day ) sedentary women ( 56.1±4.5 years ) r and omized to a progressive strength training exercise program or to control were followed for 4 years . Fifty-four percent of the women were using hormone therapy ( HT ) at baseline . At 1 year , controls were permitted to begin the exercise program ( crossovers ) . The final sample included 23 controls , 55 crossovers , and 89 r and omized exercisers . Exercisers were instructed to complete two sets of six to eight repetitions of exercises at 70–80 % of one repetition maximum , three times weekly . BMD was measured at baseline and thereafter annually using dual-energy X-ray absorptiometry . Four-year percentage exercise frequency ( ExFreq ) averaged 26.8%±20.1 % for crossovers ( including the first year at 0 % ) , and 50.4%±26.7 % for exercisers . Four-year total CI averaged 1,635±367 mg/day and supplemental calcium intake , 711±174 mg/day . In adjusted multiple linear regression models , ExFreq was positively and significantly related to changes in femur trochanter ( FT ) and neck ( FN ) , lumbar spine ( LS ) , and total body ( TB ) BMD . Among HT  users , FT BMD increased 1.5 % , and FN and LS BMD , 1.2 % ( p < 0.01 ) for each st and ard deviation ( SD ) of percentage ExFreq ( 29.5 % or 0.9 days/week ) . HT non-users gained 1.9 % and 2.3 % BMD at FT and FN , respectively , ( p < 0.05 ) for every SD of CI . The significant , positive , association between BMD change and ExFreq supports the long-term usefulness of strength training exercise for the prevention of osteoporosis in postmenopausal women , especially HT users . The positive relationship of CI to change in BMD among postmenopausal women not using HT  has clinical implication s in light of recent evidence of an increased health risk associated with HT CONTEXT Physical activity can reduce the risk of  hip fractures in older women , although the required type and duration of activity have not been determined . Walking is the most common activity among older adults , and evidence suggests that it can increase femoral bone density and reduce fracture risk . OBJECTIVE To assess the relationship of walking , leisure-time activity , and risk of hip fracture among postmenopausal women . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve analysis begun in 1986 with 12 years of follow-up in the Nurses ' Health Study cohort of registered nurses within 11 US states . A total of 61,200 postmenopausal women ( aged 40 - 77 years and 98 % white ) without diagnosis of cancer , heart disease , stroke , or osteoporosis at baseline . MAIN OUTCOME MEASURES Incident hip fracture result ing from low or moderate trauma , analyzed by intensity and duration of leisure-time activity  and by  time spent walking , sitting , and st and ing  , measured at baseline and up date d throughout follow-up . RESULTS From 1986 to 1998 , 415 incident hip fracture cases were identified . After controlling for age , body mass index , use of postmenopausal hormones , smoking , and dietary intakes in proportional hazards models , risk of hip fracture was lowered by 6 % ( 95 % confidence interval [ CI ] , 4%-9 % ; P<.001 ) for each increase of 3 metabolic equivalent (MET)-hours per week of activity ( equivalent to 1 h/wk of walking at an average pace ) . Active women with at least 24 MET-h/wk had a 55 % lower risk of hip fracture ( relative risk [ RR ] , 0.45 ; 95 % CI , 0.32 - 0.63 ) compared with sedentary women with less than 3 MET-h/wk . Even women with a lower risk of hip fracture due to higher body weight experienced a further reduction in risk with higher levels of activity . Risk of hip fracture decreased linearly with increasing level of activity among women not taking postmenopausal hormones ( P<.001 ) , but not among women taking hormones ( P = .24 ) . Among women who did no other exercise , walking for at least 4 h/wk was associated with a 41 % lower risk of hip fracture ( RR , 0.59 ; 95 % CI , 0.37 - 0.94 ) compared with less than 1 h/wk . More time spent st and ing was also independently associated with lower risks . CONCLUSION Moderate levels of activity , including walking , are associated with substantially lower risk of hip fracture in postmenopausal women Background The public health burden of osteoporosis is high , principally because of increased risk of fractures and associated morbidity , h and icap and mortality . Osteoporotic fracture prevention is therefore an important public health goal . General practitioners ( GPs ) play a key role in the management of osteoporosis , both in ensuring timely diagnosis and in providing treatment . Little information is available on st and ards of care for postmenopausal women with osteoporosis in general practice . Objectives The primary objective of this study was to describe risk factors and treatment in postmenopausal women with osteoporosis . Secondary objectives were to evaluate treatment compliance and to assess the impact of osteoporosis on quality of life . Methods This observational , cross-sectional , pharmacoepidemiological study was performed in a primary -care setting in France . A r and om sample of GPs recruited postmenopausal women with a diagnosis of osteoporosis who had been followed by the investigator for at least 2 years . At inclusion , investigators completed a question naire providing information on patient age , osteoporosis duration , risk factors and treatment history . The first three patients recruited by each investigator completed a question naire providing information on sociodemographic features , osteoporosis treatments and quality of life . Treatment compliance was quantified using the Test d’Evaluation de l’Observance and quality of life evaluated using the 12-item Short Form Health Survey ( SF-12 ) . Results Overall , 389 physicians included 3097 patients , of whom 1053 completed the patient question naire . Risk factors for osteoporotic fracture were identified in 2148 patients ( 69.4 % ) , most frequently personal or maternal antecedents of osteoporotic fracture and a low body mass index . Of these , 946 ( 44.0 % ) presented more than one risk factor . At the time of diagnosis , 629 patients ( 59.7 % ) presented fractures , which involved the vertebrae in 51.7 % of cases , the wrist in 40.5 % and the hip in 5.4 % . Older patients were more likely to have fractures at the time of diagnosis and to have multiple fractures . After diagnosis , at least one new fracture occurred in 201 patients ( 19.2 % ) . Multivariate logistic regression analysis identified age > 70 years , diagnosis at least 10 years previously , diagnosis based on the presence of a fracture , biochemical and haematological evaluation at the time of diagnosis , and a change in osteoporosis treatment in the previous 2 years as being significantly associated with incident fracture risk . At inclusion , 1019 patients ( 97.4 % ) were receiving treatment for osteoporosis , most frequently weekly bisphosphonates ( 71.6 % of treatments ) . Most patients ( 81.0 % ) had been treated for at least 1 year . Treatment compliance was high in 61 % of patients and low in < 5 % . Patient variables associated with high compliance were being retired , prescription of bisphosphonates and , among the bisphosphonate users , prescription of weekly formulations . SF-12 quality -of-life scores were low , ranging from 38.6 ( energy/vitality ) to 65.1 ( social functioning ) out of a possible maximum score of 100 . Baseline variables associated with SF-12 physical component summary scores included age , height loss since menopause , diagnosis following a fracture , fracture incidence since diagnosis , time since diagnosis and treatment with bisphosphonates . Conclusions In this study of postmenopausal osteoporosis in the French primary healthcare setting , many women with osteoporosis were diagnosed following a fracture . Although most were treated with bone-consolidating drugs , compliance was suboptimal in a significant minority . Osteoporotic fracture was associated with reduced quality of life The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered This study of 94 postmenopausal female smokers evaluated the effect of nicotine replacement therapy ( NRT ) and hormone therapy ( HT ) on change in weight , energy intake , and physical activity during 2 weeks of smoking abstinence . Women , stratified by current use of HT  , were r and omized to nicotine or placebo patch . After 2 weeks of abstinence , women on nicotine patch had significantly larger increases in total caloric and fat intake than women on placebo patch and a trend toward larger increases in carbohydrates ( total and sweet ) . Conversely , the nicotine group had less weight gain , 0.47 kg , than the placebo group , 1.02 kg ( F=10.31 , p=0.002 ) . No effects were observed for hormone therapy . It appears that in short-term smoking abstinence , postmenopausal women on NRT gain less weight than do women on placebo , in spite of consuming more calories . This may be beneficial in the critical first 1 - 2 weeks of tobacco cessation , especially in light of postmenopausal weight gain Osteoporosis is characterized by low bone mass and architectural changes in bone that render the skeleton brittle and susceptible to fracture [ 1 ] . As the elderly population grows , the worldwide annual incidence of hip fractures is projected to increase from 1.7 million in 1990 to 6.3 million by 2050 , placing great economic strain on health care systems [ 2 ] . Currently , a 50-year-old woman is estimated to have a risk as high as 40 % for sustaining a fracture related to osteoporosis at some point in the future [ 3 ] . The age-adjusted risk for fracture seems to be increasing , and this risk may be an underestimate for the future [ 4 ] . Bone loss after menopause , which results in low bone density , is an important determinant of risk for fracture , although other factors ( such as advanced age , hip geometry , and falls and injuries ) also contribute [ 5 , 6 ] . Bone loss is most rapid during the first few years after menopause , but evidence suggests that the rate of loss also becomes accelerated in advanced old age [ 7 , 8 ] . One strategy to reduce the number of fractures in postmenopausal women is to begin treatment for osteoporosis only in patients who are at high risk for fracture , including those with osteoporosis or previous fragility fractures .  Pharmacologic therapy in women with osteoporosis with or without fractures reduces the incidence of fracture by about 50 % [ 9 , 10 ] . However , half of women who would have sustained fractures without treatment still do so with treatment . Thus , preventing rather than treating osteoporosis is a more appealing clinical objective because it can avoid the increased risk for fracture . There may also be an advantage in terms of preserving the normal microarchitecture of bone . Preventing bone loss associated with menopause and aging and maintaining normal microarchitecture provide important opportunities for the prevention of osteoporosis and fractures . Estrogen is effective in preventing bone loss in early and late postmenopausal women , but it must be taken over the long term to decrease the incidence of vertebral and hip fractures [ 11 ] . Estrogen also relieves menopausal symptoms and , in epidemiologic cohort studies , seemed to protect against cardiovascular disease . However , most women who begin estrogen therapy do not continue it for more than a year , in part because of such side effects as breast tenderness , headache , fluid retention , and withdrawal bleeding [ 12 , 13 ] . Although the benefits of estrogen therapy outweigh the risks in most women , concern about risk for breast cancer is sufficiently great that many women avoid estrogen therapy [ 14 , 15 ] . Alendronate sodium ( monosodium 4-amino , 1-hydroxybutylidene-1 , 1-bisphosphonate ) is a potent and selective inhibitor of osteoclast-mediated bone resorption . Studies in animals with low bone mineral density have shown that alendronate therapy is associated with increased bone mass of normal quality and increased bone strength [ 16 ] . Alendronate treatment of osteoporosis in postmenopausal women induces progressive increases in bone density and a reduction in the incidence of new fractures of the vertebrae , hip , and forearm in osteoporotic women [ 9 , 10 ] . We performed a 3-year r and omized , double-blind , placebo-controlled , dose-ranging study to evaluate the efficacy of alendronate therapy in preventing bone loss in healthy women who had recently experienced menopause . Methods Study Participants Healthy women aged 40 to 59 years who had experienced menopause 6 to 36 months before enrollment were eligible to participate in this study . Women were excluded if their spine bone mineral density was more than 2 SDs above or below normal peak bone mineral density or if they had a history of nontraumatic spine or hip fracture . Women with disorders of bone and mineral metabolism were also excluded , as were those with recent ( within 1 year of study entry ) major upper gastrointestinal diseases ( such as peptic ulcer , esophageal disease , and malabsorption ) . Other exclusion criteria were previous treatment with bisphosphonates or fluoride ( > 1 mg/d ) or treatment within the 12 months before enrollment with estrogen , progestin , calcitonin , glucocorticoids , anticonvulsant agents , phosphate-binding antacids , or excessive vitamin A or vitamin D. Women who regularly used ( > four times per week ) any medication that had the potential to cause gastrointestinal irritation ( such as aspirin ) , who smoked more than 20 cigarettes per day , or who drank three or more alcoholic beverages per day were also excluded . Four hundred forty-seven women met the inclusion criteria and were enrolled at 15 centers throughout the world . The target sample size of 250 women completing the study was selected to detect a difference in bone density of 2.4 % between an individual alendronate dosage and placebo at a P value of 0.05 or less , with 95 % power using an SD of 3.3 % that was obtained from 1-year bone density data in placebo recipients [ 17 ] . All centers conducted the study with appropriate approval from the institutional review boards , and all participants gave informed consent . Treatment Participants were r and omly assigned ( in allocation blocks of five ) to one of five regimens : placebo for 3 years ; alendronate at 1 , 5 , or 10 mg/d for 3 years ; or alendronate at 20 mg/d for 2 years followed by placebo for 1 year ( 20/0 mg/d ) . In all groups , double-blinding was maintained for all 3 years . Alendronate and placebo tablets were identical in size , shape , and color . The women were instructed to take the study drug daily at least 1 hour before breakfast or , as a less desirable alternative , at least 2 hours after a meal and 1 hour before the next meal . All participants also received a daily supplement of calcium carbonate ( Os-Cal 500 , Smith-Kline Beecham Consumer Br and s , LP , Pittsburgh , Pennsylvania , or the equivalent ) unless dietary calcium intake exceeded 1000 mg/d . This supplement was usually taken with the evening meal . After beginning therapy , each participant was seen at months 1 and 3 and every 3 months thereafter . Eight participants ( four in the placebo group and four in the 1-mg/d group ) lost more than 6 % of their spine bone density at 24 months relative to their baseline measurements and were therefore design ated fast bone losers . Seven of these participants completed the study ; from month 24 to the end of the study , they received 5 mg of open-label alendronate per day . The other patient discontinued therapy at month 24 . Bone Mineral Density Bone mineral density of the spine , proximal femur , total body , and forearm was measured every 6 months by dual-energy x-ray absorptiometry with a Hologic QDR-1000 , 1000/W , or 2000 densitometer ( Waltham , Massachusetts ) or a Lunar DPX-L densitometer ( Madison , Wisconsin ) . One bone density quality assurance center ( Oregon Osteoporosis Center ) that remained blinded to treatment allocation was responsible for the quality control of all participant and phantom calibration scans [ 18 ] . Factors to correct for machine calibration drift were applied as necessary . The primary end point was bone mineral density of the lumbar spine ; the other most important end points were bone mineral density of the femoral neck , trochanter , and total body . Bone mineral density of the total body , total hip , and forearm was measured at the centers that had densitometers capable of performing these measurements ( 11 centers measured bone mineral density of the total body ; 10 centers measured bone mineral density of the total hip and forearm ) . Biochemical Markers and Indices of Mineral Metabolism Fasting serum and urine sample s ( second morning void ) were obtained at all clinic visits except those in months 27 and 33 . The resorption markers included urine deoxypyridinoline , measured by high-pressure liquid chromatography , and ( in a subgroup of 268 participants ) urine N-telopeptide cross-links of type I collagen ( Ostex , Seattle , Washington ) . Each of these markers was expressed as a ratio to urine creatinine . Serum osteocalcin levels , measured by radioimmunoassay ( INCSTAR , Stillwater , Nebraska ) , and serum bone-specific alkaline phosphatase levels were used to assess the rate of bone formation . Levels of serum calcium , phosphorus , intact parathyroid hormone ( measured by immunoradiometric assay ) , and 1,25 dihydroxyvitamin D ( measured by competitive binding assay ) were also determined to assess the effects of treatment on mineral metabolism .  N-telopeptide  levels were measured by Medical Research Laboratories ( Highl and Heights , Kentucky ) . All other assays were done at Corning-Nichols Institute ( San Juan Capistrano , California ) . Safety Evaluations At each visit , vital signs were measured and any new or worsening symptoms were recorded . Physical examinations were performed at the baseline , month 3 , and yearly visits . St and ard laboratory safety evaluations ( including evaluations of hematologic , renal , and liver function ) were performed at every visit . Investigators reported any unfavorable or unintended clinical or laboratory events as adverse experiences . After 3 years of therapy , biopsy specimens of transiliac bone were obtained for histologic and histomorphometric assessment from 55 women who provided specific informed consent for this procedure . These analyses were performed , as previously described , by a single investigator who was blinded to treatment groups [ 19 ] . Statistical Analysis The Tukey trend test [ 20 ] was used to assess the trend in response with increasing alendronate dosages . The 20/0-mg/d group was excluded from this test because of the change in dosage . This test uses the minimum P value , adjusted for multiplicity [ 21 ] , that was obtained from tests of the regression sloped on three dosage scalings . The test is done in a stepwise manner , with the highest dosage eliminated , until the minimum P value exceeds 0.05 . Dose-response relations were examined for the responses of the percentage change in bone density variables , natural logarithm ( fraction of the baseline value ) for biochemical Aim To study the effects of menopausal hormone therapy ( HT ) on health-related quality of life in women after breast cancer . Patients and methods In the Stockholm trial , breast cancer survivors were r and omized to HT ( estradiol and progestogen ) or to a control group ( no treatment ) .  A subgroup of 75 women was studied ( 38 with HT , 37 controls ) . Fifty patients were on concomitant tamoxifen .  Patients completed three question naires ( EORTC QLQ C-30 , EORTC QLQ-BR 23 and the Hospital Anxiety and Depression Scale ( HADS ) ) during 1 year of treatment . Results A significant group-by-time interaction was found for improvement of insomnia in the HT group ( p < 0.001 ) . Within the HT group , but not in the control group , there was significant improvement for HADS anxiety , HADS depression , emotional , cognitive , and social functions and global quality of life . When HT was added to tamoxifen , the increase in global quality of life was significant ( p < 0.01 ) . Conclusion The effects of HT on quality of life in breast cancer survivors have not previously been reported . The present data suggest that this controversial treatment may improve quality of life after breast cancer Hot flushes and night sweats ( HF/NS ) are commonly experienced by mid-aged women during the menopause transition . They affect approximately 70 % of women but are regarded as problematic for 15 - 20 % largely due to physical discomfort , distress , social embarrassment , and sleep disturbance . There is a need for effective and acceptable nonmedical treatments for menopausal symptoms due to the declining use of hormone therapy ( HT ) following publication of the Women 's Health Initiative and other prospect i ve studies which associated HT use with increased risk of stroke and breast cancer . HF/NS are an example of a physiological process embedded within , and moderated by , psychological processes , as evidence d by discrepancies between subjective experiences and physiologically measured symptoms . We describe a cognitive model of menopausal hot flushes that can explain symptom perception , cognitive appraisal , and behavioral reactions to symptoms . Theoretically , the model draws on symptom perception theory , self-regulation theory , and cognitive behavioral theories . The model can be used to identify the variables to target in psychological interventions for HF/NS and to aid underst and ing of possible mediating factors . As part of Phase II intervention development , we describe a cognitive behavioral treatment which links the bio-psycho-social processes specified in the model to components of the intervention BACKGROUND Previous studies demonstrate that postmenopausal women who use estrogen  are somewhat protected from bone loss and fractures compared with nonusers , but the extent to which estrogen users remain at risk for osteoporosis and fractures is uncertain . OBJECTIVE To determine long-term probabilities for incident fractures among postmenopausal estrogen users . METHODS We examined data from the Study of Osteoporotic Fractures , a prospect i ve cohort study with 10 years of follow-up ( 1986 - 1999 ) . This cohort includes 8816 women 65 years and older from community setting s in 4 areas of the United States . MAIN OUTCOME MEASURES Hip , wrist , vertebral , and nonvertebral fractures . RESULTS At baseline , using criteria developed by the World Health Organization , 40 % of continuous estrogen users were osteopenic and 13 % were osteoporotic at the hip or spine . Although women currently using estrogen lost less bone density than past users or those who never used estrogen , all user groups on average lost bone from the hip and calcaneus . During 10 years of observation , the adjusted probability of nonvertebral fractures was 19.6 % for continuous estrogen users , similar to current partial users and lower than past users and those who never used estrogen ( P<.05 ) . These comparisons were similar for hip , wrist , and vertebral fractures . CONCLUSIONS Although estrogen use is associated with reduced prevalence of low bone density , less bone loss , and lower probabilities for fractures , osteoporosis and fractures are common in older women who used estrogen continuously since menopause .  Estrogen users should be considered in strategies design ed to detect , prevent , and treat osteoporosis Summary We evaluated the Women ’s Health Initiative ( WHI ) hip fracture risk score in 15,648 postmenopausal Danish nurses . The algorithm was well calibrated for Denmark . However , the sensitivity was poor at common decision making thresholds . Obtaining sensitivity better than 80 % led to a low specificity of 61.4 % . Introduction A new score based on data from the WHI has been design ed to predict 5-year risk of hip fracture in postmenopausal women . The performance of the algorithm has not been vali date d in population s with different lifestyle characteristics and ethnicity . The aim of this study was to test the clinical performance of the algorithm in a large Danish cohort of postmenopausal Caucasian women against hip fracture . Methods The Danish Nurse Cohort is a prospect i ve risk factor and hormone therapy ( HT ) study established in 1993 . Participants in the present analysis were 15,648 postmenopausal nurses . The calibration and diagnostic performance of the WHI algorithm was evaluated using fracture events captured in the Danish National Hospital Registry . Results During 5 years of follow-up , 122 participants suffered a hip fracture ( 1.8/1,000 person years ) . The WHI algorithm predicted that 107 hip fractures would occur , indicating an underestimation of the number of fractures by 12 % . To obtain sensitivity better than 80 % , the cut-off value for 5-year risk was set to 0.5 % , which was accompanied by a low positive predictive value of 1.9 % and a low specificity of 61.4 % . The algorithm predicted too many fractures in HT-users ( 12 observed , 22 expected ) and too few in non HT-users ( 107 observed , 81 expected ) . Conclusions While the WHI algorithm was well calibrated on the Danish population , the clinical utility of the WHI algorithm in Danish postmenopausal women was limited by poor sensitivity at common decision-making thresholds and suboptimal in non-HT-users PURPOSE To up date the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment , particularly adjuvant tamoxifen . METHODS ASCO convened the Up date Committee and conducted a systematic review of r and omized clinical trials from January 2009 to June 2013 and analyzed three historical trials . Guideline recommendations were based on the Up date Committee 's review of the evidence . Outcomes of interest included survival , disease recurrence , and adverse events . RESULTS This guideline up date reflects emerging data on duration of tamoxifen treatment . There have been five studies of tamoxifen treatment beyond 5 years of therapy . The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year duration s of tamoxifen use . In addition to modest gains in survival , extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer . RECOMMENDATIONS Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen , and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor ( in sequence ) . If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen , they should be offered 10 years total duration of tamoxifen . If women are postmenopausal and have received 5 years of adjuvant tamoxifen  , they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy Summary Minimal-trauma fracture is an important issue in breast cancer survivors , especially rib fracture . The likelihood of fracture is affected by menopausal status and a diagnosis of osteoporosis prior to breast cancer . Most women reported at least one assessment of bone mineral density . Introduction We have investigated the self-reported frequency and pattern of minimal-trauma fracture ( MTF ) in breast cancer ( BC ) survivors at least 5 years from diagnosis , along with the use of  bone mineral density ( BMD ) assessment . Methods This study was carried out within the Bupa Health Foundation Health and Wellbeing After Breast Cancer Study which is a question naire-based prospect i ve cohort study of 1683 women diagnosed with their first invasive breast cancer between 2004 and 2006 and followed for at least 5 years . Results One thous and two hundred and five women , who remained free of recurrence or new breast cancer , completed the fifth annual follow-up . One hundred sixty-four ( 13.6 % ) reported at least one MTF . Rib fracture was the most common ( 52 fractures in 46 women ) . Compared with women who remained pre-/peri-menopausal , either being postmenopausal at diagnosis ( OR 3.53 , 95 % Confidence Interval ( CI ) 1.09–11.44 , p = 0.036 ) or changing from pre- to postmenopausal during follow-up ( OR 3.97 , 95 % CI 1.21–13.10 , p = 0.023 ) was associated with a higher likelihood of fracture , as was having a diagnosis of osteoporosis at the time of diagnosis ( OR 1.74 , 95 % CI 1.00–2.99 , p = 0.047 ) . Most women ( 64.9 % ) reported at least one BMD assessment . Conclusions Overall MTF is a problem for breast cancer survivors , with rib fracture a particular issue for women in our study . Both pre-existing osteoporosis and being postmenopausal are risk factors for subsequent MTF in women treated for breast cancer . Clinicians need to be mindful of fracture prevention medication in these groups The sum of evidence -based nutrition has to be more than a Cochrane-type meta- analysis of r and omised controlled trials ( RCTs ) . Most of the evidence base in nutrition is observational , especially cohort studies . RCTs of diet change through to disease outcome are uncommon and the change has usually been addition or removal of only a single food component . Trials with whole diets through to disease outcome are rare and dietary changes made by individuals are unlikely to be an exact copy of the prescription . It is hard to even imagine a trial in which half ( r and omised ) of a large group of middle-aged people agree to avoid vegetables for 5 y and be followed up to see who will develop cancer . Most of the USA 's health cl aims , permitted by the Food and Drug Administration , are not supported by RCTs . But where controlled trials of nutritional change and disease outcome have been achieved , they must be review ed very carefully . Two Cochrane review s on diet and cardiovascular disease ( CVD ) , published in the widely read British Medical Journal ( BMJ ) , were criticised after their publication and the conclusions have not been subsequently adopted by expert committees . The first of these review s was ‘ Dietary fat and prevention of CVD : a systematic review ’ . The second was ‘ Systematic review of long term effects of advice to reduce dietary salt in adults ’ . A critique of these two Cochrane review s is presented here as a contribution to our discussion of the potential of Cochrane methodology to the reliability of knowledge about diet and disease OBJECTIVE This investigation examined whether raloxifene , a selective estrogen receptor modulator , affects the risk for Alzheimer 's disease . METHOD The Multiple Outcomes of Raloxifene Evaluation was a r and omized , placebo-controlled trial among postmenopausal women with osteoporosis . The effect of raloxifene ( 60 or 120 mg/day ) on vertebral fractures was the primary outcome . Development of mild cognitive impairment and dementia was a secondary outcome . Women were given clinical and cognitive evaluations at baseline and annually . After 3 years , among the 5,386 women enrolled at participating sites , those who had clinical symptoms of dementia or scored in the lowest 10th percentile on cognitive screening were evaluated by a blinded dementia specialist and had brain scans and laboratory tests  to evaluate dementia etiology . Dementia was diagnosed by a blinded adjudication committee . RESULTS Of the 5,386 women , 5,153 ( 95.7 % ) were classified as cognitively normal , 181 ( 3.4 % ) had mild cognitive impairment , and 52 ( 1.0 % ) had dementia , 36 with Alzheimer 's disease . Compared to those taking placebo , women receiving 120 mg/day of raloxifene had a 33 % lower risk of mild cognitive impairment ( relative risk , 0.67 ; 95 % confidence interval [ CI ] , 0.46 - 0.98 ) and somewhat lower risks of Alzheimer 's disease ( relative risk=0.52 , 95 % CI=0.22 - 1.21 ) and any cognitive impairment ( relative risk=0.73 , 95 % CI=0.53 - 1.01 ) . Risks of mild cognitive impairment , Alzheimer 's disease , and any impairment were not significantly different in the group taking 60 mg/day of raloxifene . CONCLUSIONS Raloxifene at a dose of 120 mg/day , but not 60 mg/day , result ed in reduced risk of cognitive impairment in postmenopausal women PURPOSE To determine if estrogen plus progestin reduces the incidence of fractures or height loss in postmenopausal women with coronary disease . SUBJECTS AND METHODS We enrolled 2,763 postmenopausal women with coronary disease and with an intact uterus into the Heart Estrogen/progestin Replacement Study , a r and omized double-blind , placebo-controlled secondary prevention trial of cardiovascular disease . Radiographically documented clinical fractures were a prespecified secondary endpoint . Height loss was used as a surrogate for vertebral fractures . The average age of the women was 66.7 + /- 6.7 years , and fewer than 15 % of the women had osteoporosis based on their bone density . Women were r and omly assigned to either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1,380 ) or placebo ( n = 1,383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 64 % at the end of the study . RESULTS During 10,554 person years of follow-up , 286 women experienced a fracture : 138 in the treatment group ( 26.3 per 1,000 person years ) and 148 in the placebo group ( 28.0 per 1,000 person years ) ; relative hazard , 0.94 ; 95 % confidence interval 0.8 to 1.2 , P = 0.61 ) . These included 58 wrist fractures ( 1.01 ; 0.6 to 1.7 ) ; 27 hip fractures ( 1.09 ; 0.5 to 2.3 ) ; 32 spine fractures ( 0.69 ; 0.3 to 1.4 ) , and 192 other fractures ( 0.91 ; 0.7 to 1.2 ) . There was no difference in average height loss between the treatment and placebo groups or in the percent of women who lost more than 2 cm in height : 10.6 % in the treatment group and 12.1 % in the placebo group . CONCLUSIONS There was no evidence of a reduction in the incidence of fractures or rate of height loss in older women not selected for osteoporosis . R and omized studies are needed to clarify the effect of hormone replacement therapy on fracture risk among women with and without osteoporosis Deciding about hormone therapy ( HT ) use is particularly complex for women with mobility impairments . While HT controls menopausal symptoms , the potential increased risk of blood clots result ing from physical inactivity can contraindicate HT use . These women , therefore , may benefit from interventions to help them tailor st and ard information about HT . We r and omly assigned women to receive either a tailored decision support intervention or st and ard menopausal information . Both groups ( n = 176 ) significantly decreased their decisional conflict and uncertainty and increased knowledge after receiving the treatment material s. We interpret the findings in the context of limited medical information about HT for women with disabilities Objective : To examine whether the effect of postmenopausal hormone therapy ( HT ) on brain volumes in women aged 65–79 years differs depending on type 2 diabetes status during postintervention follow-up of a r and omized controlled clinical trial . Methods : The Women 's Health Initiative r and omized clinical trials assigned women to HT ( 0.625 mg/day conjugated equine estrogens with or without 2.5 mg/day medroxyprogesterone acetate ) or placebo for an average of 5.6 years . A total of 1,402 trial participants underwent brain MRI  2.4 years after the trials ; these were repeated in 699 women 4.7 years later . General linear models were used to assess the interaction between diabetes status and HT assignment on brain volumes . Results : Women with diabetes at baseline or during follow-up who had been assigned to HT compared to placebo had mean decrement in total brain volume of −18.6 mL ( 95 % confidence interval [ CI ] −29.6 , −7.6 ) . For women without diabetes , this mean decrement was −0.4 ( 95 % CI −3.8 , 3.0 ) ( interaction p = 0.002 ) . This interaction was evident for total gray matter ( p < 0.001 ) and hippocampal ( p = 0.006 ) volumes . It was not evident for changes in brain volumes over follow-up or for ischemic lesion volumes and was not influenced by diabetes duration or oral medications . Conclusions : For women aged 65 years or older who are at increased risk for brain atrophy due to type 2 diabetes , prescription of postmenopausal HT is associated with lower gray matter ( total and hippocampal ) volumes . Interactions with diabetes and insulin resistance may explain divergent findings on how estrogen influences brain volume among older women Objective : The aim of this study was to evaluate the efficacy of citalopram for climacteric symptoms and to assess the combined effect of citalopram and hormone therapy ( HT ) on climacteric symptoms in women inadequately responsive to HT alone . Design : The study included 100 postmenopausal women who were allocated into one of four groups : ( 1 ) citalopram , ( 2 ) placebo , ( 3 ) citalopram + HT , or ( 4 ) placebo + HT . The women who were unable or unwilling to take HT  were r and omly placed in groups 1 and 2 . The women who were inadequately responsive to HT  were r and omly placed in groups 3 and 4 . The initial dose of citalopram was 10 mg/day in groups 1 and 3 . After 1 week , the dose was increased to 20 mg/day . After starting the medication , follow-up visits took place during the fourth and eighth weeks of treatment . During the first and eighth weeks , women completed two question naires : a modified Kupperman index and the Menopause-Specific Quality of Life Question naire . Results : Mean hot flash scores significantly improved in all groups ( P < 0.05 ) . The reduction rates were 37 % in group 1 , 13 % in group 2 , 50 % in group 3 , and 14 % in group 4 . Psychosocial complaints and mean values on the Kupperman index significantly decreased in all groups ( P < 0.05 ) . Physical well-being significantly improved in groups 1 , 3 , and 4 ( P < 0.05 ) . The decrease in all scores was significantly greater in groups 1 and 3 compared to groups 2 and 4 ( P < 0.01 ) . Conclusion : Citalopram is an effective alternative treatment option for patients who do not want to take HT for the alleviation of climacteric symptoms . Adjuvant treatment with a selective serotonin reuptake inhibitor increases the effectiveness of HT  for the treatment of climacteric symptoms in women who had responded inadequately to HT INTRODUCTION Sexual dysfunction is more prevalent in postmenopausal women . AIMS To prospect ively evaluate and compare the effects of hormone therapy ( HT ) regimens , oral and vaginal estradiol , estradiol + drospirenone and tibolone , on  sexual function in healthy postmenopausal women . METHODS The study included 169 consecutive healthy postmenopausal women , and the women were divided into two groups : 111 women received HT , and 58 women received no treatment and served as a control group . As an HT , 23 women with surgically induced menopause received oral 17-beta estradiol . The rest of the women with natural menopause were prospect ively r and omized : 22 received oral 17-beta estradiol + drospirenone daily , 42 received oral tibolone , and 24 received vaginal 17-beta estradiol .  Sexual function was evaluated with a detailed 19-item question naire , the female sexual function index , including sexual desire , arousal , lubrication , orgasm , satisfaction , and pain . MAIN OUTCOME MEASURES The differences in sexual function were compared before and 6 months after the treatment in all women . RESULTS Total sexual function score increased from 19.81 + /- 7.15 to 22.9 + /- 6.44 in the HT group and decreased from 21.6 + /- 8.69 to 17.6 + /- 5.7 in the control group , revealing a significant difference from baseline to post-treatment between the two groups ( P = 0.000 ) . The highest improvement in total score and arousal was achieved with the oral 17-beta estradiol ( P = 0.000 and P = 0.000 , respectively ) . The highest improvement in lubrication was achieved with the oral and vaginal 17-beta estradiol groups ( P = 0.000 ) . The highest improvement in orgasm was achieved with the tibolone group ( P = 0.000 ) . The highest improvement in pain was achieved with the oral and vaginal 17-beta estradiol groups ( P = 0.000 ) . CONCLUSIONS HT provided significant improvement in sexual function compared to women receiving no treatment , and therefore , HT regimens should be suggested for improvement in sexual functioning of postmenopausal women In postmenopausal women , the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1 - 3 % per year leading to an increase in fracture incidence compared to that seen during tamoxifen use . The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy ( average 7 - 8 % per annum ) . Pre-treatment with tamoxifen for 2 - 5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors , particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor . However , skeletal status should still be assessed at the commencement of aromatase inhibitor therapy . The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors . These patients are considered to be at high risk of clinical ly important bone loss and should have a baseline dual energy X-ray absorptiometry ( DXA ) assessment of bone mineral density ( BMD ) . R and omised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting . Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels .  Bisphosphonates , along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss . Due to the rate of bone loss associated with breast cancer treatments , and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk , the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis . Management recommendations have been summarised in two algorithms , one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy Following the results of the Women 's Health Initiative , many women now decline estrogen replacement at the time of menopause and seek natural remedies that would treat menopausal symptoms and prevent bone loss and other long-term consequences of estrogen deficiency , but without adverse effects on the breast , uterus , and cardiovascular system . The results of most soy studies in this population have had limitations because of poor design , small sample size , or short duration . This report describes the study rationale , design , and procedures of the Soy Phytoestrogens As Replacement Estrogen ( SPARE ) study , which was design ed to determine the efficacy of soy isoflavones in preventing spinal bone loss and menopausal symptoms in the initial years of menopause . Women ages 45 to 60 without osteoporosis and within 5 years from menopause were r and omized to receive soy isoflavones 200 mg daily or placebo for 2 years . Participants have yearly measurements of spine and hip bone density , urinary phytoestrogens , and serum lipids , thyroid stimulating hormone , and estradiol . Menopausal symptoms , mood changes , depression , and quality of life are assessed annually . The SPARE study recruited 283 women , 66.1 % were Hispanic white . With a large cohort , long duration , and large isoflavone dose , this trial will provide important , relevant , and currently unavailable information on the benefits of purified soy isoflavones in the prevention of bone loss and menopausal symptoms in the first 5 years of menopause . Given the high proportion of Hispanics participating in the study , the results of this trial will also be applicable to this minority group OBJECTIVE To reexamine the mortality experience of a cohort of long-term users of hormone replacement therapy ( HRT )  in comparison with that reported previously for the same cohort of women , paying particular attention to cardiovascular mortality , deaths from breast and endometrial cancer , and deaths attributed to suicide or suspected suicide . DESIGN Longitudinal cohort of 4544 long-term users of HRT amongst whom mortality is being monitored prospect ively in comparison with expected rates in the female population of Engl and and Wales ( taking account of age and calendar period ) . SUBJECTS 4544 women , all of whom were recruited from specialist menopause clinics around Britain and had taken at least one year 's continuous HRT at the time of recruitment to the study . MAIN OUTCOME MEASURES All cause mortality , cardiovascular mortality , deaths from female cancers , deaths attributed to suicide or suspected suicide . RESULTS Overall mortality ( based on 236 deaths over the entire study period from recruitment to December 1988 ) remained significantly lower than expected on the basis of national rates ( relative risk ( RR ) 0.56 , 95 % confidence limits ( CL ) 0.47 - 0.66 ) . When specific causes were considered , the only mortality ratios greater than unity were for injury , poisoning and violence ( 1.54 , 95 % CL 1.02 - 2.06 ) , and for suicide and suspected suicide ( ' suicide ' ) ( 2.40 , 95 % CL 1.68 - 3.11 ) . Comparison of the ratios for the 112 additional deaths with those obtained in our previous analysis revealed that one of the few ratios to show any increase was that for breast cancer mortality . This rose from a significant deficit of 0.55 ( 95 % CL 0.28 - 0.96 ) in the earlier period to 1.00 ( 95 % CL 0.55 - 1.45 ) in the later period . There was also a suggestion of an increase in breast cancer risk with increasing duration since first use of HRT . Most of the other cause-specific ratios were very similar over the two periods . The ratio of death from all circulatory diseases was notably lower in the later analysis ( RR 0.37 , 95 % CL 0.15 - 0.58 ) than in the earlier analysis ( 0.51 , 95 % CL 0.36 - 0.69 ) , as were all of the subcategories of cardiovascular death . The mortality ratio for cancer of the ovary and uterine adnexa fell from 1.12 in the previous analysis to 0.63 ( 95 % CL 0 - 1.41 ) . The mortality ratio for ' suicide ' also decreased , but was only slightly lower in the later period . As before , however , there was evidence of a relatively high prevalence of prior psychiatric problems amongst the recent ' suicide ' deaths , suggesting that the excess of deaths from ' suicide ' may be a manifestation of selection . CONCLUSION These data are consistent with a beneficial effect of HRT on cardiovascular diseases , although up date d information comparing progestogen-opposed and -unopposed treatment is not available . The increase in breast cancer mortality contrasts with the pattern for all other specific causes examined ; taken together with the suggestion of an increase in breast cancer mortality with increasing interval since first exposure to HRT , this finding is somewhat worrying Objective The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer . Alternative therapies that are effective in the prevention of menopause , having associated morbidities but no unwanted effects , are of primary interest in the pharmacologic research . The aim of this study was to evaluate the effect of two alternative to estrogens drugs , the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone , on the mammographic appearance of the breast . Design The study group comprised 131 postmenopausal women aged 41 to 67 years . The women were at least 2 years postmenopausal , free of climacteric symptoms , and at the time of entry to the study had not had therapy for at least 9 months . Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone ( n = 56 ) or raloxifene ( n = 48 ) therapy . Women with no risk factors and women who either did not qualify for or denied treatment ( n = 27 ) served as controls . The study duration was 12 months . Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period . Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists . Results No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk . Similarly , no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings . In the tibolone group , 10.7 % of the women showed an increase in breast density in the 12-month reevaluation . The respective figure in the raloxifene group was 6.3 % , whereas no woman in the control group showed an increase in breast density . Differences in the increase in breast density between groups did not , however , reach statistical significance . Accordingly , 10.7 % of women in the tibolone group and 18.8 % of women in the raloxifene group exhibited involutionary changes in the repeat mammogram , whereas 25.9 % of women in the control group revealed a decrease in breast density in the 12-month examination . The percentages were not significantly different between groups . Conclusions Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene . In most patients , these drugs are not likely to interfere with mammogram interpretation . Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography Background . The unexpected results of the Women 's Health Initiative study have decreased the use of conventional hormone therapy ( HT ) , changing physicians ' and patients ' attitudes towards HT and increasing their interest in alternative options . Objective . The present study aim ed to evaluate the effect of isoflavones contained in red clover extracts ( Trifolium pratense ) on menopausal symptoms , lipids and vaginal cytology in menopausal women . Methods . Sixty postmenopausal women aged > 40 years , non-users of HT , with Kupperman index score ⩾15 , were double-blindly r and omized to receive either a commercially available red clover isoflavone supplement ( 80 mg/day ) or placebo for 90 days . Subsequently , after a 7-day washout period , subjects switched to receive the opposite treatment for a further 90 days . Kupperman index score was determined and fasting blood and vaginal cytologic sampling performed at baseline , 90 and 180 days . Results . Fifty-three women ( 88.3 % ) completed the trial . Mean age was 51.3 ± 3.5 years , 69.7 % of the women were aged 50 years or more . There was no significant effect on body mass index , weight or blood pressure after either treatment phase . Baseline Kupperman index score decreased significantly after each treatment phase , with the decrease more pronounced after the isoflavone phase ( baseline : 27.2 ± 7.7 ; after isoflavone : 5.9 ± 3.9 ; after placebo : 20.9 ± 5.3 , p < 0.05 ) . Red clover isoflavone supplementation significantly decreased the rate of menopausal symptoms and had a positive effect on vaginal cytology as expressed by improvement in karyopyknotic , cornification and basal cell maturation indices . Mean total cholesterol , low-density lipoprotein-cholesterol and triglyceride levels also decreased ; however , only the latter was significantly lower compared with placebo . Conclusions . Compared with placebo , red clover isoflavone supplementation in postmenopausal women significantly decreased menopausal symptoms and had a positive effect on vaginal cytology and triglyceride levels Background Patients with high Gleason score , elevated prostate specific antigen ( PSA ) level , and advanced clinical stage are at increased risk for both local and systemic relapse . Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical , metastasis-free and disease-specific survival . No r and omized data is available on the benefits of long-term hormonal therapy ( HT ) in these patients . A prospect i ve study on the efficacy and safety of trimodality treatment consisting of HT , external beam radiation therapy ( EBRT ) , and brachytherapy ( BT ) for high-risk prostate cancer ( PCa ) is strongly required . Methods / Design This is a phase III , multicenter , r and omized controlled trial ( RCT ) of trimodality with BT , EBRT , and HT for high-risk PCa ( TRIP ) that will investigate the impact of adjuvant HT following BT using iodine-125 ( 125I-BT ) and supplemental EBRT with neoadjuvant and concurrent HT .  Prior to the end of September 2012 , a total of 340 patients with high-risk PCa will be enrolled and r and omized to one of two treatment arms . These patients will be recruited from more than 41 institutions , all of which have broad experience with 125I-BT .  Pathological slides will be central ly review ed to confirm patient eligibility . The patients will commonly undergo 6-month HT with combined and rogen blockade ( CAB ) before and during 125I-BT and supplemental EBRT . Those r and omly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist . All participants will be assessed at baseline and every 3 months for the first 30 months , then every 6 months until 84 months from the beginning of CAB.The primary endpoint is biochemical progression-free survival . Secondary endpoints are overall survival , clinical progression-free survival , disease-specific survival , salvage therapy non-adaptive interval , and adverse events . Discussion To our knowledge , there have been no prospect i ve studies documenting the efficacy and safety of trimodality therapy for high-risk PCa . The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach , and to establish an appropriate treatment strategy for high-risk PCa . Trial registration The National Institutes of Health 's consensus conference ( 1 ) defined osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture . Bone strength reflects the integration of two main features : bone density and bone quality .Bone quality refers to architecture , turnover , damage accumulation ( e.g. , microfractures ) , and mineralization . Although osteoporosis can affect any bone , the hip , spine , and wrist are most likely to be affected . Osteoporosis affects an estimated 44 million Americans or 55 % of people 50 years of age or older . Another 34 million Americans are estimated to have low bone mass , meaning that they are at an increased risk for osteoporosis . Osteoporosis can be diagnosed by the occurrence of fragility fracture . In patients without fragility fracture , osteoporosis is often diagnosed by low bone density .  Dual x-ray absorptiometry ( DXA ) is the current gold st and ard test for diagnosing osteoporosis in people without an osteoporotic fracture .  Dual x-ray absorptiometry results are scored as st and ard deviations ( SDs ) from a young healthy norm ( usually female ) and reported as T-scores . For example , a T-score of 2 indicates a bone mineral density that is 2 SDs below the comparative norm . The international reference st and ard for the description of osteoporosis in postmenopausal women and in men age 50 years or older is a femoral neck bone mineral density of 2.5 SD or more below the young female adult mean ( 2 ) . Low bone density , as measured by DXA , is an imperfect predictor of fracture risk , identifying fewer than half the people who go on to have an osteoporotic fracture . Screening guidelines for women are well established ( 3 ) , and the American College of Physicians ( ACP ) recently published guidelines on screening for men ( 4 ) . This guideline presents the available evidence on various pharmacologic treatments to prevent fractures in men and women with low bone density or osteoporosis . Medications used to treat osteoporosis may affect different parts of the skeletal system differently , and efficacy for vertebral fractures does not necessarily imply efficacy for nonvertebral fractures . The target audience for this guideline is all clinicians and the target patient population is all adult men and women with low bone density or osteoporosis . These recommendations are based on the systematic evidence review by MacLean and colleagues ( 5 ) and the Agency for Healthcare Research and Quality sponsored Southern California Evidence -Based Practice Center evidence report ( 6 ) . The drugs currently approved for prevention of osteoporosis include alendronate , ib and ronate , risedronate , zoledronic acid , estrogen , and raloxifene . The drugs currently approved for treatment of osteoporosis include alendronate , ib and ronate , risedronate , calcitonin , teriparatide , zoledronic acid ( in postmenopausal women ) , and raloxifene . Testosterone , pamidronate , and etidronate are not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Methods The literature search done by MacLean and colleagues for the systematic review ( 5 ) included studies from MEDLINE ( 1966 to December 2006 ) , the ACP Journal Club data base , the Cochrane Central Register of Controlled Trials ( no date limits ) , the Cochrane Data base of Systematic Review s ( no date limits ) , Web sites of the United Kingdom National Institute of Health and Clinical Excellence ( no date limits ) , and the United Kingdom Health Technology Assessment Program ( January 1998 to December 2006 ) . The review ers limited their search to English- language publications and human studies . They derived evidence for comparative benefits of various treatments exclusively from r and omized , controlled trials , whereas they included evidence from other types of studies for short- and long-term harms . Two physicians independently abstract ed data about study population s , interventions , follow-up , and outcome ascertainment by using a structured form . For each group within a r and omized trial , a statistician extracted the sample size and number of persons reporting fractures . Two review ers , under the supervision of the statistician , independently abstract ed information about adverse events . The statistician or the principal investigator resolved disagreements . This guideline is based on an evaluation of 76 r and omized , controlled trials , 4 of which were identified in the up date d search , and 24 meta-analyses that were included in the efficacy analyses . The analyses of adverse events included 491 articles , representing 417 r and omized trials , 25 other controlled clinical trials , 11 open-label trials , 31 large observational studies , and 9 case reports of osteonecrosis among bisphosphonate users . MacLean and colleagues ' background article ( 5 ) includes details about the methods used for the systematic evidence review . The ACP rates the evidence and recommendations by using the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) system with minor modifications ( Table 1 ) . In addition , the evidence review ers used predefined criteria to assess the quality of systematic review s and r and omized trials , based on internal and external validity assessment s detailed in the Quality of Reporting of Meta-Analyses ( QUOROM ) statement ( 7 ) . Table 1 . The American College of Physicians ' Guideline Grading System The objective of this guideline is to synthesize the evidence for the following questions : What are the comparative benefits in fracture reduction among and also within the following treatments for low bone density :  bisphosphonates , specifically alendronate , risedronate , etidronate , ib and ronate , pamidronate , and zoledronic acid ; calcitonin ; estrogen for women ; teriparatide ; selective estrogen receptor modulators ( SERMs ) , specifically raloxifene and tamoxifen ; testosterone for men ; vitamins and minerals , specifically vitamin D and calcium ; and the combination of calcium plus vitamin D ? How does fracture reduction result ing from treatments vary among individuals with different risks for fracture as determined by bone mineral density ( borderline , low , or severe ) , previous fractures ( prevention vs. treatment ) , age , sex , glucocorticoid use , and other factors ( such as community-dwelling vs. institutionalized or vitamin Ddeficient vs. not ) ? What are the short- and long-term harms ( adverse effects ) of these therapies , and do these vary by specific sub population s ? Comparative Benefits of Drugs versus Placebo in Fracture Reduction Evidence from 24 meta-analyses ( 830 ) and 35 additional r and omized trials published after the meta-analyses ( 3165 ) described the effect of 9 of the 14 agents ( alendronate , etidronate , risedronate , calcitonin , estrogen , teriparatide , raloxifene , calcium , and vitamin D ) on fracture incidence . For 4 agents ( ib and ronate , pamidronate , zoledronic acid , and tamoxifen ) , the review ers found no meta-analyses and instead gathered the evidence from 14 r and omized trials ( 6679 ) . No studies were found that reported fracture rates for testosterone . Three r and omized trials ( 35 , 80 , 81 ) and 1 meta- analysis ( 82 ) evaluated the combination of calcium plus vitamin D  on fractures .  Bisphosphonates Good- quality evidence showed that alendronate , etidronate , ib and ronate , and risedronate prevent vertebral fractures . In addition , evidence from good- quality studies demonstrated that both alendronate and risedronate prevent nonvertebral and hip fractures . Two large r and omized trials showed that zoledronic acid prevents vertebral and nonvertebral fractures in high-risk population s and reduces the risk for hip fracture ( 67 , 74 ) . Ib and ronate has not been shown to reduce nonvertebral fractures ( 68 ) . Of the 6 fairly small trials that looked at vertebral fractures , 1 demonstrated a statistically significant reduction in fractures with pamidronate relative to placebo ( 0.14 [ 95 % CI , 0.03 to 0.72 ] ) ( 73 ) . However , after these data were pooled , the pooled risk estimate for fractures for pamidronate relative to placebo was not significant ( 0.52 [ CI , 0.21 to 1.24 ] ) ( 6 ) . Calcitonin Fair- quality evidence shows that calcitonin reduces vertebral fractures ( 83 , 84 ) . Good- quality evidence indicates that calcitonin does not reduce nonvertebral fractures ( 13 , 16 ) . Estrogen Good- quality evidence shows that estrogen reduces the incidence of vertebral ( 29 , 85 ) , nonvertebral ( 86 ) , and hip fractures ( 85 ) . Teriparatide Good- quality evidence shows that teriparatide prevents vertebral fractures . The evidence related to teriparatide preventing nonvertebral fractures is mixed ; 1 large r and omized trial showed a reduction in nonvertebral fractures ( 34 ) but 2 small trials did not ( 87 , 88 ) . SERMs Good- quality evidence shows that raloxifene prevents vertebral fractures , but that tamoxifen has no effect on vertebral fractures ( 8991 ) . In addition , both raloxifene and tamoxifen had no effect on hip fractures ( 91 ) . Tamoxifen is not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Testosterone No studies reported fracture rates for testosterone . Calcium and Vitamin D In the studies evaluated by MacLean and colleagues ( 5 ) , the evidence for the effect of calcium alone on reduction of fractures is complex . Most studies of pharmacologic agents for osteoporosis include calcium and vitamin D as part of the treatment regimen . Evidence from 1 meta- analysis ( 27 ) and several r and omized trials ( 35 , 48 , 51 , 92 ) showed no significant difference between calcium and placebo in preventing vertebral , nonvertebral , and hip fractures in postmenopausal women . However , nonadherence to therapy may influence this result , and 1 trial with a prespecified analysis of adherent patients found a reduction in fracture risk ( 48 ) . A recent meta- analysis ( 82 ) concluded that the relative risk ( RR ) for fracture with calcium alone was 0.90 ( CI , 0.80 to 1.00 ) , but it did not include a modestly large trial with negative results ( 35 ) . MacLean and colleagues ( 5 ) UNLABELLED The level of recognition and treatment of osteoporosis is not well characterized in primary care . In data from a large sample of postmenopausal women attending 927 primary care physicians , 29 % of women reported one or more fractures after menopause . The great majority ( 72 % ) were not on any osteoporosis-specific therapy . INTRODUCTION Osteoporosis is often first recognized at the time of a low-trauma fracture . However , by this stage , the risk of subsequent fractures has already risen substantially . Moreover , in many countries , only a small proportion of women , who have already sustained fractures , receive a treatment shown to reduce this increased risk of further fractures . MATERIAL S AND METHODS This project was initiated to examine the prevalence of osteoporotic fractures , risk factors for osteoporosis , and use of antifracture therapy among postmenopausal Australian women . More than 88,000 women from 927 primary care physicians returned over 69,358 surveys . Of these , 57,088 reported the presence of a postmenopausal fracture or risk factors . RESULTS Among these r and omly selected postmenopausal women , 29 % reported having had one or more low-trauma fractures after menopause ( 44 % substantiated in current records ) . One-third of these women reported multiple fractures . The prevalence of all types of fractures , except rib and ankle , increased with age and low body weight . Those who reported fractures were also more likely to report early menopause , corticosteroid use , and a family history of osteoporosis . Moreover , those with vertebral fractures were more likely to record height loss , kyphosis , and back pain . Physical inactivity , low calcium intake , and smoking had no consistent relationship with any fracture outcome . Of the women who reported a fracture after menopause , only 28 % were on any specific therapy for osteoporosis , and 7 % were on calcium alone . Of those who had been told they had osteoporosis by a doctor , 40 % were receiving specific osteoporosis therapy . CONCLUSIONS In this large study of postmenopausal Australian women attending primary care physicians , 29 % reported at least one low-trauma fracture after menopause . Less than one-third of these women were on specific treatment for osteoporosis , and only 40 % were ever told they had osteoporosis . Therefore , osteoporotic fractures are common in postmenopausal Australian women , and few , despite their substantially increased risk of further fractures , are on any specific anti-osteoporotic therapy . These data support the need for more effective education for the community and medical practitioners of the clinical significance of osteoporotic fractures and alternatives for treatment BACKGROUND Postmenopausal oestrogen therapy reduces the risk of osteoporosis and cardiovascular diseases but is associated with an increased risk of endometrial cancer . We have assessed the impact of a regimen of oestrogen with cyclic progestagen on risk of endometrial cancer for postmenopausal women . METHODS We did a population -based case-control study of women aged 45 - 74 years in western Washington State , USA . Cases were identified from a regional cancer registry as having histologically confirmed endometrial cancer during 1985 - 91 . 832 ( 72 % ) of 1154 eligible cases completed interviews . Controls were identified by r and om digit dialling , screened for intact uterus , frequency matched for age and county , and r and omly assigned a reference date within 1985 - 91 . Interviews with 1114 ( 73 % ) of 1526 eligible controls were done . The women provided information about use of hormone replacement therapy , and reproductive and medical history before diagnosis date ( cases ) or reference date ( controls ) . FINDINGS Relative to women who had never used hormones ( for > 6 months ) , women who had taken unopposed oestrogen had a four-fold increase ( 95 % CI 3.1 - 5.1 ) in risk of endometrial cancer . Women who used a combined therapy of oestrogen with cyclic progestagen ( eg . medroxyprogesterone acetate ) had a relative risk of 14 ( 1.0 - 1.9 ) . Among women with fewer than 10 days of added progestagen per month , the relative risk was 3.1 ( 1.7 - 5.7 ) . Whereas that for women with 10 - 21 days of added progestagen was 1.3 ( 0.8 - 2.2 ) . The use of these combined regimens for 5 or more years was associated with risks of 3.7 ( 1.7 - 8.2 ) and 2.5 ( 1.1 - 5.5 ) , respectively , relative to non-users of hormones . INTERPRETATION Postmenopausal women who use combined therapy of oestrogen with cyclic progestagen on a long-term basis have an increased risk of endometrial cancer compared with those who are not on hormone replacement , even when progestagen is added for 10 or more days per month . This increase is much smaller than that associated with unopposed oestrogen , but needs to be confirmed OBJECTIVE This study examined the effect of hormone therapy ( HT ) on the plasma concentration of remnant lipoprotein cholesterol ( RLP-C ) and high-density lipoprotein ( HDL ) sub population s and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease ( CHD ) in postmenopausal women . METHODS Study participants were 256 women who completed the Estrogen Replacement and Atherosclerosis ( ERA ) trial , a placebo-controlled , r and omized trial that examined the effects of 3.2 years of conjugated equine estrogen ( CEE , 0.625 mg/day ) or CEE ( 0.625 mg/day ) plus medroxyprogesterone acetate ( MPA , 2.5mg/day ) on postmenopausal women with established coronary atherosclerosis . Quantitative coronary angiography and plasma RLP-C and HDL sub population s were assessed at baseline and at follow-up . RESULTS Relative to placebo , both CEE and CEE+MPA caused a significant reduction in plasma RLP-C concentrations and a significant increase in alpha1 and alpha2 HDL sub population s. However , in the HT-treated subjects , faster progression of coronary atherosclerosis was observed in women who experienced the greatest reductions in RLP-C and in prebeta1 HDL sub population s. CONCLUSIONS Our data suggest that individual variability in RLP-C and HDL sub population response to HT is a predictor of CHD progression . Lipoprotein response to HT may be an indirect marker of susceptibility to other harmful effect of HT in postmenopausal women with established CHD or an indication of formation of dysfunctional lipoproteins Background Awareness of the risks associated with hormone therapy for menopausal symptoms has sparked a global decline in this treatment . Alternative treatments to relieve menopausal symptoms are therefore required . The applied relaxation ( AR ) technique has proven to be successful for symptom amelioration , but requires participation in 12 weekly classes . The purpose of this study was to determine the effectiveness of a modified relaxation version ( MR ) of AR for treatment of hot flashes , night sweats , and sleep disturbances . Methods We conducted a12-week , r and omized , parallel , open-label , controlled trial in perimenopausal and postmenopausal women visiting the menopausal clinic . Participants were r and omly assigned to an MR or AR group . The MR group ( n=36 ) received a single session of ( MR ) training and the AR group ( n=35 ) received conventional 12-week training . Participants were instructed to practice the techniques daily at home for 12 weeks . The main outcome was the measure on the severity scale and frequency of hot flashes , night sweats , and sleep disturbances . Results All participants completed the study .  Total severity scores in both groups decreased after 12 weeks , but there was no difference between the groups ( P=0.93 ) . The severity score for hot flashes in the MR group decreased more than in the AR group ( P=0.02 ) . The severity scores for night sweats and sleep disturbances decreased in both groups . The frequency of hot flashes , night sweats , and sleep disturbances were also decreased in both groups . Conclusion A shorter , modified version of the AR was equally effective or slightly better than the conventional AR for the relief of hot flashes , night sweats , and sleep disturbances in perimenopausal and postmenopausal women . Recommendations for future research include confirmatory studies and trials with larger sample Summary In this prospect i ve study in 2,137 perimenopausal and early postmenopausal women who were followed over a 13.1-year period of time , we observed no association between bone mineral density measured at the beginning of menopause and the subsequent risk of breast cancer . Introduction This study aim ed to investigate the relationship between BMD and the risk of breast cancer ( BC ) in young postmenopausal women . Methods As part of a clinical research program , 2,137 women who were perimenopausal or within their 5 first postmenopausal years were scanned  between 1988–1990 and review ed on average 13.1 years after their initial examination . Ninety-eight incident BC cases were recorded throughout the follow-up . Results Women with incident BC significantly differed from those who had never had BC with regard to age at menarche , age of birth of 1st child , familial history of BC and postmenopausal hormone therapy ( PHT ) use . There was no significant difference between the two groups for baseline DXA of the spine . There was a trend for BC cases for having lower femoral neck BMD compared to women without BC . However , women with low BMD were more likely to have taken PHT by the end of the study . In Cox multivariate analyses the relationship between BC risk and femoral neck BMD no longer existed . Conclusions There was no relationship between BMD measured within the first postmenopausal years and the risk of BC , which makes unlikely the possibility of using BMD as a predictor factor for BC in early postmenopausal women PURPOSE To assess the long-term contribution of adjuvant chemotherapy ( CT ) and hormonal therapy ( HT ) in patients with locally advanced breast cancer , and to evaluate the impact of time of analysis on the results during accrual and up to 8 years after closure of a r and omized phase III trial . MATERIAL S AND METHODS In a trial using a factorial design , 410 patients were r and omized between radiotherapy ( RT ) alone , RT plus CT , RT plus HT , and RT plus HT plus CT .  RESULTS CT and HT each produced a significant prolongation of the time to locoregional tumor recurrence and to distant progression of disease , with the combined treatments providing the greatest therapeutic effect . At the time of trial closure , a significant improvement of survival was observed in patients who received CT ( P = .004 ) ; however , with a longer follow-up duration , this effect disappeared ( P > .05 ) . HT did not initially appear to improve survival ( P = .16 ) ; however , in the latest analysis with a long-term follow-up duration , a significant improvement of survival was seen ( P = .02 ) . A consistent 25 % reduction in the death hazards ratio has been seen at all evaluations since trial closure in patients who received HT . The best survival results were observed in patients who received RT , HT , and CT ( P = .02 ) , with a reduction of 35 % in the death hazards ratio . CONCLUSION An improvement in survival attributable to HT has been shown in patients with locally advanced breast cancer . The greatest therapeutic effect was seen in the treatment group that received both CT and HT . The improvement obtained with HT became apparent only after long-term follow-up evaluation Objective To develop and vali date an up date d version of the QFracture algorithm for estimating the risk of a patient sustaining an osteoporotic fracture or hip fracture in a primary care population . Design Prospect i ve open cohort study using routinely collected data from 420 general practice s in the United Kingdom to develop up date d QFracture scores and 207 practice s to vali date scores . Cox ’s proportional hazards model was used in the derivation cohort to derive risk equations using several explanatory variables . We calculated measures of calibration and discrimination using the validation cohort . Participants 3 142 673 patients in derivation cohort and 1 583 373 in validation cohort , aged 30 - 100 years , who contributed 23 608 337 and 11 732 106 person years of observation , respectively . We identified 59 772 incident diagnoses of osteoporotic fracture in the derivation cohort and 28 685 in the validation cohort . Outcomes Incident diagnosis of osteoporotic fracture ( vertebral , distal radius , proximal humerus , or hip ) and incident hip fracture recorded in general practice records or linked cause of death records . Results We found significant independent associations with overall fracture risk in women for age , body mass index , ethnic origin , alcohol intake , smoking status , chronic obstructive pulmonary disease or asthma , any cancer , cardiovascular disease , dementia , diagnosis or treatment for epilepsy , history of falls , chronic liver disease , Parkinson ’s disease , rheumatoid arthritis or systemic lupus erythematosus , chronic renal disease , type 1 diabetes , type 2 diabetes , previous fracture , endocrine disorders , gastrointestinal malabsorption , any antidepressants , corticosteroids , unopposed hormone replacement therapy , and parental history of osteoporosis . Risk factors for hip fracture in women were similar except for gastrointestinal malabsorption and parental history of hip fracture . Risk factors for men were largely the same as those for women but also included care home residence . The up date d hip fracture algorithm explained 71.7 % ( 95 % confidence interval 71.1 % to 72.3 % ) of the variation in women and 70.4 % ( 69.3 % to 71.5 % ) in men . D statistic values for hip fracture were high for women ( 3.26 , 3.21 to 3.31 ) and men ( 3.15 , 3.06 to 3.24 ) , and higher than for osteoporotic fracture . Values for the area under the receiver operating characteristics curves for hip fracture were 0.89 for women and 0.88 for men , compared with 0.79 and 0.71 for osteoporotic fracture , respectively . The up date d algorithms performed better than the 2009 algorithms . Conclusions Two QFracture algorithms were up date d to predict risk of osteoporotic and hip fracture in primary care population s to include ethnic origin , all classes of antidepressants , chronic obstructive pulmonary disease , epilepsy , dementia , Parkinson ’s disease , cancer , systemic lupus erythematosus , chronic renal disease , type 1 diabetes , previous fragility fracture , and care home residence . These up date d algorithms showed improved performance compared with previous QFracture algorithms reported in 2009 Background Diabetes has long been recognised as a strong , independent risk factor for cardiovascular disease , a problem which accounts for approximately 70 % of all mortality in people with diabetes . Prospect i ve studies show that compared to their non-diabetic counterparts , the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four . The two biggest trials in type 2 diabetes , the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) and the University Group Diabetes Program ( UGDP ) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control . Theoretical benefits of the peroxisome proliferator activated receptor gamma ( PPAR-gamma ) activator rosiglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus . Objectives To assess the effects of rosiglitazone in the treatment of type 2 diabetes . Search methods Studies were obtained from computerised search es of MEDLINE , EMBASE and The Cochrane Library . Selection criteria Studies were included if they were r and omised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks . Data collection and analysis Two authors independently assessed trial quality and extracted data . Pooling of studies by means of fixed-effects meta- analysis could be performed for adverse events only . Main results Eighteen trials which r and omised 3888 people to rosiglitazone treatment were identified . Longest duration of therapy was four years with a median of 26 weeks . Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide evidence that patient-oriented outcomes like mortality , morbidity , adverse effects , costs and health-related quality of life are positively influenced by this compound . Metabolic control measured by glycosylated haemoglobin A1c ( HbA1c ) as a surrogate endpoint did not demonstrate clinical ly relevant differences to other oral antidiabetic drugs . Occurrence of oedema was significantly raised ( OR 2.27 , 95 % confidence interval ( CI ) 1.83 to 2.81 ) . The single large RCT ( ADOPT - A Diabetes Outcomes Progression Trial ) indicated increased cardiovascular risk . New data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues . Authors ' conclusions New studies should focus on patient-oriented outcomes to clarify the benefit-risk ratio of rosiglitazone therapy . Safety data and adverse events of all investigations ( published and unpublished ) should be made available to the public The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins . As body composition and body fat distribution in particular are independent predictors of cardiovascular disease , we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured . Sixty-two early postmenopausal women were followed up for 2 years in a prospect i ve , r and omized , placebo-controlled study . We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause ( P less than .05 ) , and that this effect was independent of the effect on serum lipids and lipoproteins . The therapy reduced postmenopausal bone loss significantly ( P less than .001 ) , whereas it did not have a statistically significant influence on total body fat mass or total lean body mass . The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition , in particular abdominal fat Context Some data suggest that low- grade inflammation may play a role in the development of colorectal cancer . Contribution In this 10-year prospect i ve study involving 27913 healthy women age 45 years or older , elevated C-reactive protein ( CRP ) levels at baseline were not associated with a higher likelihood of colorectal cancer . Caution s A single baseline CRP measurement may be an imperfect marker of inflammation . The investigators relied on a woman 's report of cancer rather than an ongoing surveillance protocol for colorectal lesions . Implication s Low- grade inflammation may not be associated with in-creased colorectal cancer risk . The Editors C-reactive  protein ( CRP ) , a marker of inflammation , is consistently associated with increased risk for cardiovascular disease ( 1 ) . A recent epidemiologic study has raised the hypothesis that CRP levels might also be associated with incident colon cancer ( 2 ) . This latter hypothesis is supported by clinical observations of an increased risk for colorectal cancer in patients with chronic , relapsing and remitting inflammatory disordersulcerative colitis and Crohn diseasecollectively known as inflammatory bowel diseases ( 3 , 4 ) . Reduced risk for colorectal adenomas and cancer associated with long-term use of aspirin and other nonsteroidal anti-inflammatory drugs ( NSAIDs ) in observational studies and some clinical trials also supports this hypothesis ( 5 ) . Moreover , CRP levels in patients with colorectal cancer are correlated with tumor stage ( 6 - 10 ) . However , colorectal cancer associated with inflammatory bowel diseases accounts for only 1 % to 2 % of all cases of colorectal cancer in the general population ( 3 ) . In addition , the mechanisms by which NSAIDs may reduce the risk for colorectal neoplasia are still under debate and may not necessarily reflect disease inflammatory pathways ( 11 ) . Furthermore , abundant evidence suggests that inflammation is part of the host response to cancer ( 12 , 13 ) ; thus , the elevations in CRP levels observed in patients with colorectal cancer may be a result rather than a cause of disease . Because of the public health importance of this issue , we evaluated whether CRP levels predict  colorectal cancer  risk among 27913 participants in the Women 's Health Study for whom CRP was measured at baseline ; the maximum duration of follow-up was 10.8 years . Methods Study Cohort Beginning in 1993 , 39876 female U.S. health professionals age 45 years or older who were free of cancer and cardiovascular disease were enrolled into the Women 's Health Study , a r and omized , double-blind , placebo-controlled , 22 factorial trial evaluating the balance of benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease ( 14 ) . Upon study enrollment , all participants completed a baseline question naire about their medical history and lifestyle characteristics , including potential risk factors for colorectal cancer . Before r and omization , 28345 women ( 71 % of those r and omly assigned ) also provided baseline blood specimens , sent via overnight courier , using a kit that contained a gel-filled freezer pack as a coolant . Upon arrival at our laboratory , the sample s were subjected to centrifugation ; separated into plasma , leukocytes , and erythrocytes ; and stored in liquid nitrogen . Baseline characteristics among women who did and did not provide blood specimens were largely similar ( mean age , 54.7 years vs. 54.4 years ; body mass index 25 kg/m2 , 48.4 % vs. 51.1 % ; family history of colorectal cancer , 10.6 % vs. 10.5 % ; current use of postmenopausal hormones , 43.5 % vs. 37.5 % ; ever use of oral contraceptives , 69.6 % vs. 69.4 % ; aspirin use before the trial , 11.7 % vs. 10.8 % ; current use of multivitamin supplements , 29.4 % vs. 28.6 % ; history of benign colon polyps , 2.5 % vs. 2.5 % ; and median alcohol intake , 1.1 g/d vs. 0.9 g/d ) . The following were the exceptions : Women who provided blood specimens were more physically active ( median , 598.6 kcal/wk vs. 526.0 kcal/wk ) but were less likely to be current smokers ( 11.7 % vs. 16.8 % ) . Of the 28345 sample s received , 27939 usable sample s were measured for plasma CRP by a vali date d high-sensitivity assay ( Denka Seiken Co. , Tokyo , Japan ) in a core laboratory facility for ongoing st and ardization programs on the CRP measurement ( 15 ) . The current analysis was restricted to 27913 women after the additional exclusion of 21 women with prer and omization cancer reported after r and omization and confirmed by medical record review and 5 women with newly diagnosed nonadenocarcinoma colorectal cancer during follow-up . Ascertainment of Cases of Colorectal Cancer Every 6 months during the first year of follow-up and then annually thereafter , participants were sent question naires asking about newly diagnosed end points , including colon or rectal cancer . Family members or postal authorities reported deaths of participants . Within the past 2 years , morbidity follow-up is 97 % , and mortality follow-up is nearly 100 % . For those who reported a diagnosis of colorectal cancer and for those who are deceased , we sought medical records and other relevant information , which were review ed by an Endpoints Committee consisting of physicians to confirm medical diagnoses . Of the self-reports , medical record review confirmed 96 % . The review ers additionally extracted information on anatomic location and tumor stage at diagnosis ( Duke 's A , spread to submucosa or muscle only ; Duke 's B , spread to pericolic or perirectal tissues , but no lymphatic involvement ; Duke 's C , lymph node involvement or metastasis ) . The current analysis included only confirmed incident cases of colorectal adenocarcinoma . Statistical Analysis We first compared the distribution of baseline risk factors for colorectal cancer by category of plasma CRP level to assess their potential for confounding . Participants were categorized into CRP levels of less than 1 , 1 to 3 , and greater than 3 mg/L , the cutoff points proposed in clinical guidelines for cardiovascular disease ( 16 ) and previously used in this cohort to define cardiovascular disease risk ( 15 ) . For the analysis of total cancer of the colon and rectum , we also categorized women into quartiles of CRP based on the CRP distribution among never users or among ever users of postmenopausal hormones at baseline ( postmenopausal hormone use elevates CRP level [ 17 - 19 ] ) . We calculated person-years for each participant from the date of r and omization to the date of diagnosis of confirmed cancer , death , or 20 February 2004 , whichever occurred first . A Cox proportional hazards regression model , which treats disease outcome as a r and om variable that would change over time , was used to calculate the hazard ratios and 95 % CIs . We first estimated the crude hazard ratios according to category of CRP and then additionally adjusted for age ( in years ) or age and r and omized treatment assignment ( aspirin vs. placebo , vitamin E vs. placebo ) to control for potential confounding by the effects of these treatments . We further performed a multivariate analysis that additionally adjusted for postmenopausal hormone use ( never , past , current ) ; body mass index ( < 23 , 23 to < 25 , 25 to < 27 , 27 to < 30 , 30 kg/m2 ) ; family history of colorectal cancer in first-degree relatives ( yes or no ) ; physical activity ( total kcal/wk in quartiles ) ; smoking status ( never , past , current ) ;  aspirin use before the trial ( yes or no ) ; alcohol consumption ( 0 , > 0 to < 15 , 15 g/d ) ; oral contraceptive use ( never or ever ) ; menopausal status ( premenopausal , postmenopausal , uncertain/unknown ) ; and multivitamin supplement use ( never , past , current ) at baseline . We also conducted an analysis that additionally adjusted for history of self-reported colon polyps at baseline ( yes or no ) . Of the 27913 women in the current analysis , 1817 participants who had missing values for 1 or more covariates were dropped from multivariate analyses . Furthermore , we performed an analysis according to tumor location ( proximal colon , distal colon , and rectum ) and tumor stage at diagnosis ( Duke 's A , B , and C ) . Tests for trend were performed by using the median value for each CRP category as a continuous variable . The assumption of proportional hazards over time was tested by using log likelihood ratio tests to compare models with or without interaction terms between CRP and the logarithm of follow-up time in regression models . There was no indication that the proportionality assumption was violated . Additional analyses excluded incident cases diagnosed within 1 , 2 , and 5 years of follow-up , with further adjustment for symptomatic examination ( yes or no ) and regular screening ( yes or no ) by colonoscopy or sigmoidoscopy , which were asked on the 12-month follow-up question naire to address the potential effect of screening . We conducted analyses stratified by level of other risk factors for colorectal cancer to evaluate whether the association between baseline plasma CRP level and colon cancer risk may exist in subgroups . Tests for interaction between CRP and level of other risk factors in relation to colorectal cancer risk were carried out by using the median value for each CRP category as a continuous variable , an indicator variable for risk factor , and a product term of these 2 variables . The Wald test was used to assess the statistical significance of the interaction term . All P values were 2-sided . All analyses were performed by using SAS software , version 8 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding Source The National Institutes of Health , the Doris Duke Foundation , and the Donald W. Reynolds Foundation sponsored the study . The sponsors did not participate in the design and conduct of the study ; in the collection , analysis , and interpretation of the data ; or in the preparation , review , or approval of the manuscript . The authors had full access to the data files of the study . Results Through 20 February 2004 , 169 incident cases of invasive colorectal adenocarcinoma were confirmed : 70 cases of IMPORTANCE The use of menopausal hormone therapy ( HT ) continues in clinical practice , but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use . OBJECTIVE To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women 's Health Initiative ( WHI ) r and omized clinical trials . DESIGN , SETTING , AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010 . INTERVENTIONS A total of 16,608 women with a uterus were r and omized to conjugated equine estrogens ( 0.625 mg/d [ estrogen ] ) plus medroxyprogesterone acetate ( 2.5 mg/d [ progestin ] ) ( E + P ) or placebo with a median intervention duration of 5.6 years , and 10,739 women with prior hysterectomy were r and omized to conjugated equine estrogens alone ( 0.625 mg/d ) or placebo with a median intervention duration of 7.2 years . MAIN OUTCOMES AND MEASURES Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials . RESULTS In the E + P trial , hazard ratios ( HRs ) for the influence of  combined HT  on breast cancer were lower than 1 for 2 years ( HR , 0.71 ; 95 % CI , 0.47 - 1.08 ) and steadily increased throughout intervention , becoming significantly increased for the entire intervention phase ( HR , 1.24 ; 95 % CI , 1.01 - 1.53 ) . In the early postintervention phase ( within 2.75 years from intervention ) , there was a sharp decrease in breast cancer incidence in the combined HT group , though the HR remained higher than 1 ( HR , 1.23 ; 95 % CI , 0.90 - 1.70 ) . During the late postintervention phase ( requiring patient re-consent ) , the HR for breast cancer risk remained higher than 1 through 5.5 years ( median ) of additional follow-up ( HR , 1.37 ; 95 % CI , 1.06 - 1.77 ) . In the estrogen alone trial , the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase ( HR , 0.79 ; 95 % CI , 0.61 - 1.02 ) and remained lower than 1 in the early postintervention phase ( HR , 0.55 ; 95 % CI , 0.34 - 0.89 ) , but risk reduction was not observed during the late postintervention follow-up ( HR , 1.17 ; 95 % CI , 0.73 - 1.87 ) . Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials . CONCLUSIONS AND RELEVANCE In the E + P trial , the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase , but a higher breast cancer risk remained during the late postintervention follow-up . In the estrogen alone trial , the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up Aims : A study was undertaken to explore how menopausal women are affected by awareness of potential risk of osteoporosis . Methods : A qualitative interview study , including analysis of in-depth interviews with 17 women who independently gave views on risk , out of 24 women interviewed about their menopausal symptoms . The women were selected on the basis of a survey including 1261 women chosen at r and om , to cover a broad spectrum of Danish women , their menopausal experiences , and contact with the healthcare system . The study was part of a larger project targeting menopause . Results : Awareness of osteoporosis risk caused a feeling of uncertainty and worry in some women . Only women reacting in this way seemed to act in order to prevent future fractures . The affected women were puzzled to realize that risk-reducing medication could introduce new hazards . Most of the women had heard about osteoporosis related to menopause as culturally embedded knowledge . Conclusions : Making individual women uncertain and worried must be considered a potentially serious side effect of health promotion . The findings raise the question of whether introducing healthy people to the threat of future diseases is ethically justifiable . As hormonal treatment is no longer recommended for long-term use , it is suggested that the strong link between osteoporosis and menopause should be toned down when counselling menopausal women OBJECTIVES Early age at natural menopause has been associated with increased all-cause mortality in several studies , although the literature is not consistent . This relation has not been examined among African American women . STUDY DESIGN Data were from the Black Women 's Health Study , a follow-up study of African-American women enrolled in 1995 . Among 11,212 women who were naturally menopausal at entry to the study or during follow-up through 2008 , we assessed the relation of age at natural menopause to all-cause and cause-specific mortality . At baseline and biennially , participants reported on reproductive and medical history , including gynecologic surgeries and exogenous hormone use .  Mortality data were obtained from the National Death Index . Multivariable Cox proportional hazard models were used to estimate mortality rate ratios ( MRR ) and 95 % confidence intervals ( CI ) for categories of age at menopause . RESULTS Of 692 deaths identified during 91,829 person years of follow-up , 261 were due to cancer , 199 to cardiovascular diseases and 232 to other causes . Natural menopause before age 40 was associated with increased all-cause mortality ( MRR=1.34 , 95 % CI 0.96 - 1.84 , relative to menopause at 50 - 54 years ; P-trend=0.04 ) and with the subcategories of death considered - cancer , cardiovascular disease , and all other causes . The associations were present among never and ever users of postmenopausal female hormones and among never and ever smokers . CONCLUSIONS In this large prospect i ve cohort of African-American women , natural menopause before age 40 was associated with a higher rate of all-cause and cause-specific mortality . These findings provide support for the theory that natural menopause before age 40 may be a marker of accelerated somatic aging OBJECTIVE To investigate the efficacy of soy isoflavone on climacteric symptoms in postmenopausal women . DESIGN In this double-blind , r and omized , placebo-controlled study , a total of 80 women ( mean age = 55.1 years ) , who reported 5 or more hot flush episodes per day , were r and omized to receive either 250 mg of st and ardized soy extract ( Glycine max AT ) a total of 100mg/day of isoflavone ( n = 40 ) or placebo ( n = 40 ) . Exclusion criteria included : contra-indication for hormone therapy ( HT ) , chronic gastrointestinal diseases , and users of HT within the preceding 6-months . For 10-months , climacteric symptoms were evaluated using a score card and the menopausal Kupperman index . Compliance and safety were also assessed . At baseline and the end of the study , lipid and hormonal profiles , as well as vaginal , mammographic and ultrasonographic parameters were measured . The t-test , Wilcoxon test and ANOVA were used in the statistical analysis . RESULTS At baseline , the mean number of hot flushes was 9.6 + /- 3.9 per day in the isoflavone group and 10.1+/-4.9 in the placebo group ( p>0.05 ) . After 10 months , there was a significant reduction in frequency of hot flushes among isoflavone users when compared to those on placebo ( 3.1 + /- 2.3 and 5.9 + /- 4.3 , respectively ) ( p<0.001 ) . Kupperman index mean values showed a significant reduction in both groups . However , soy isoflavone was significantly superior to placebo , in reducing hot flush severity ( 69.9 % and 33.7 % , respectively ) ( p<0.001 ) . Endometrial thickness , mammography , vaginal cytology , lipids and hormonal profile did not change in both groups . No serious adverse event related to isoflavone treatment was reported . CONCLUSIONS The soy isoflavone extract exerted favorable effects on vasomotor symptoms and good compliance , providing a safe and effective alternative therapeutic for postmenopausal women Objective To develop and vali date two new fracture risk algorithms ( QFractureScores ) for estimating the individual risk of osteoporotic fracture or hip fracture over 10 years . Design Prospect i ve open cohort study with routinely collected data from 357 general practice s to develop the scores and from 178 practice s to vali date the scores . Setting General practice s in Engl and and Wales . Participants 1 183 663 women and 1 174 232 men aged 30 - 85 in the derivation cohort , who contributed 7 898 208 and 8 049 306 person years of observation , respectively . There were 24 350 incident diagnoses of osteoporotic fracture in women and 7934 in men , and 9302 incident diagnoses of hip fracture in women and 5424 in men . Main outcome measures First ( incident ) diagnosis of osteoporotic fracture ( vertebral , distal radius , or hip ) and incident hip fracture recorded in general practice records . Results Use of hormone replacement therapy ( HRT ) , age , body mass index ( BMI ) , smoking status , recorded alcohol use , parental history of osteoporosis , rheumatoid arthritis , cardiovascular disease , type 2 diabetes , asthma , tricyclic antidepressants , corticosteroids , history of falls , menopausal symptoms , chronic liver disease , gastrointestinal malabsorption , and other endocrine disorders were significantly and independently associated with  risk of osteoporotic fracture in women . Some variables were significantly associated with risk of osteoporotic fracture but not with risk of hip fracture . The predictors for men for osteoporotic and hip fracture were age , BMI , smoking status , recorded alcohol use , rheumatoid arthritis , cardiovascular disease , type 2 diabetes , asthma , tricyclic antidepressants , corticosteroids , history of falls , and liver disease . The hip fracture algorithm had the best performance among men and women . It explained 63.94 % of the variation in women and 63.19 % of the variation in men . The D statistic values for discrimination were highest for hip fracture in women ( 2.73 ) and men ( 2.68 ) and were over twice the magnitude of the corresponding values for osteoporotic fracture . The ROC statistics for hip fracture were also high : 0.89 in women and 0.86 for men versus 0.79 and 0.69 , respectively , for the osteoporotic fracture outcome . The algorithms were well calibrated with predicted risks closely matching observed risks . The QFractureScore for hip fracture also had good performance for discrimination and calibration compared with the FRAX ( fracture risk assessment ) algorithm . Conclusions These new algorithms can predict risk of fracture in primary care population s in the UK without laboratory measurements and are therefore suitable for use in both clinical setting s and for self assessment ( www.qfracture.org ) . QFractureScores could be used to identify patients at high risk of fracture who might benefit from interventions to reduce their risk Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures . Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [ 1 - 4 ] . However , only about 10 % of American women elect to receive replacement therapy because of attitudes of physicians and patients , the undesirability of menstrual bleeding , and unresolved questions about the relation of the use of estrogen to breast cancer [ 5 ] . Moreover , the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued , yet the incidence of some adverse effects increases with the duration of estrogen use . Safer alternatives to estrogen use have been sought . Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss , and prospect i ve studies have yielded conflicting results [ 6 - 17 ] . Moreover , some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [ 18 ] . We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo . The study had a three-arm , r and omized , parallel design . The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians , whereas the placebo and calcium groups were double blinded . Methods Healthy , white women between 6 months and 6 years after a natural menopause were recruited to participate in the study . The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory ; written informed consent was obtained from each participant . Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign . All participants had a history and physical examination . Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use , gastrointestinal disease , or any chronic illness . Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements . Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm ( breast or uterus ) , undiagnosed vaginal bleeding , thrombophlebitis or thromboembolism , and acute liver disease .  Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded : gallbladder disease , history of liver disease , first-degree relatives with breast cancer , and hypertension . Calcium urolithiasis was also an exclusion factor . Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study . One hundred eighteen women entered the study . The women were r and omly assigned to three groups : 1 ) hormonal replacement [ estrogen-progesterone-calcium carbonate ] , 2 ) calcium carbonate , or 3 ) placebo . Assignment to the groups was based on computer-generated r and om numbers provided by the statistician , with stratification for years postmenopause . The women in the hormonal replacement group took conjugated equine estrogens ( Premarin , Wyeth-Ayerst Laboratories , Inc. ; Philadelphia , Pennsylvania ) , 0.625 mg daily for 25 days of the month along with medroxyprogesterone ( Provera , Upjohn ; Kalamazoo , Michigan ) , 10 mg from days 16 to 25 . All women received 400 IU of vitamin D daily in the form of a multivitamin , and calcium supplementation ( as Caltrate , Lederle ; Clifton , New Jersey ) was provided to the two treatment groups . The duration of the study was 2.9 1.1 years ( mean SD ) . A 7-day dietary history was review ed with a nutritionist every 2 months ; calcium was provided as calcium carbonate , 600 mg ( Caltrate ) , and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium ( the mean + 2 SD found by Heaney and colleagues [ 7 ] to result in zero calcium balance in estrogen-deprived women ) . The calcium supplements were taken with meals in divided doses . The placebo appeared identical to the calcium carbonate tablets . No patients took antacids or histamine-2 blockers . All women had a baseline mammogram . Measurements Routine laboratory studies included a complete blood count , urinalysis , and serum fasting calcium , phosphorus , urea nitrogen , creatinine , alkaline phosphatase , cholesterol , and aminotransferase measurements [ 19 , 20 ] . In addition , follicle-stimulating hormone , estradiol , parathyroid hormone , osteocalcin , free thyroxine , and bone alkaline phosphatase were measured , and a urine specimen was collected after an overnight fast for hydroxyproline , calcium , and creatinine determinations , following a 3-day low-hydroxyproline diet [ 21 - 23 ] . Total body calcium was measured annually in the participants , using the delayed neutron activation method at Brookhaven National Laboratory [ 24 , 25 ] . This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 ( natural abundance of 0.187 % ) in the body . The Brookhaven National Laboratory whole-body counter was up grade d in 1987 to use 32 NaI ( T1 ) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [ 25 ] . The activated isotope , Calcium-49 , decays with a half-life of 8.72 minutes , emitting a 3.08 MeV characteristic line . More than 99.5 % of the body calcium is contained in the bone [ 26 ] . The method provides total body calcium with a coefficient of variation of about 1.5 % when no substantial change in the body weight occurs during the period of repeated studies . The measurements were made annually . The bone mineral density of the distal radius site was measured using a Lunar Radiation ( Madison , Wisconsin ) single-photon absorptiometer ( SP2 ) .  Bone mineral density of the spine ( L2-L4 ) and femur ( neck , trochanter , and Ward triangle ) was measured using a Lunar Radiation DP4 dual-photon absorptiometer . The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1 . All scans were analyzed using the same software version , which corrects for source decay . Instruments were calibrated daily , and the radioactive source was changed annually . Each measurement was done every 6 months . The coefficient of variation of these measurements was 2 % , except for the Ward triangle ( 2.5 % ) . Activity was measured using  activity monitors  ( large-scale integrated monitors ) , which were worn about the waist [ 27 ] . The average of 2 weekdays and 1 weekend day was used as an activity score . Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise . Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons : It measures mass rather than density per unit area ; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique ; it is more precise than the other measurements ; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton . The rate of change in bone mineral was calculated for each woman at each of the sites used in the study . St and ard linear regression procedures were used to estimate the rate of bone mineral change for each woman , and the regression intercept was used as the best estimate of the baseline value . Because some women terminated their participation in the study before others , the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [ 28 ] . Analyses of covariance were done using body mass index , activity scores , cigarette smoking , calcium intake , age , and years postmenopause as covariates . The data reported in this article are based on all women who provided at least three observations for a particular skeletal site . We considered other criteria , such as using data only from women who had participated in the study for at least 2 years , and all data analyses were done for this subgroup as well . The results of these analyses were invariably similar to those reported here and therefore are not presented separately . The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages ; separate analyses were carried out for each . The two indices were similar . Evidence from recent research is substantial that estrogen replacement therapy is effective , whereas the efficacy of calcium supplements is question able . Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy , and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown . A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions . We used two a priori contrasts : the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo . All P values reported are two-tailed . Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1 . Analysis of variance showed no significant differences in the baseline variables . The initial and final activity scores did not differ significantly . Table 1 . Baseline Values for Patient Characteristics , Bone Mineral Measurements , and Chemical Variables The range of initial daily calcium intake in the overall study group was 150 to 1263 mg ; in the calcium augmentation group , it was 222 to Over the last 40 years , there has been increasing epidemiological evidence that post-menopausal treatment with sex steroids in physiological doses may reduce the relative risk of cardiovascular disease ( CVD ) . These findings have been supported by biological studies showing favourable changes in cardiovascular risk factors with estrogen supplementation . The impact of the so-called ' healthy user ' bias has been eagerly debated , and the results of the first and only r and omized long-term clinical trial of HRT for primary prevention have therefore been long awaited . The dramatic decision to halt the Women 's Health Initiative ( WHI ) study before completion came unexpectedly as the consequence of not only an increased risk of breast cancer but also increased occurrence of cardiovascular events with HRT . Due to the superior design of the study , the results from the WHI study have had an enormous impact on the clinical recommendations of HRT to post-menopausal women , concurrent with a degradation of evidence from observational studies . It is not very likely that other long-term r and omized clinical trials ( RCTs ) will be completed and epidemiology has certainly been disreputed-so is this ' time out ' for HRT studies Objective Pueraria lobata ( PL ) is used as a traditional Chinese herbal remedy for menopausal symptoms , as well as an ingredient in preparations for conditions affecting menopausal women , such as osteoporosis , coronary heart disease , and some hormone-dependent cancers . The scientific basis for its action may be its action as a phytoestrogen . Design To examine the effects of PL in comparison with hormone replacement therapy ( HRT ) on lipid profile , sex hormone levels , bone turnover markers , and indices of cognitive function . For the study , 127 community-living , postmenopausal women aged 50 to 65 years were r and omized to receive HRT ( n = 43 ) , PL ( equivalent to 100 mg isoflavone ; n = 45 ) , or no treatment ( n = 39 ) for 3 months . The following measurements were carried out at baseline and after 3 months for all participants : menopausal symptoms question naire ; neuropsychological tests covering memory , attention , motor speed , and word-finding ability ; quality of life ( SF36 ) ; lipid profile ; urinary deoxypyridinoline ; dietary phytoestrogen intake and urinary phytoestrogen ; estradiol ; follicle-stimulating hormone ; and luteinizing hormone . Results Only participants in the HRT group showed a mean reduction in cholesterol and low-density lipoprotein cholesterol that was significantly different from that of the control group . No significant changes in lipid profile or follicle-stimulating hormone and luteinizing hormone were observed in the PL group compared with the controls . However , both the HRT and PL groups showed an improvement in Mini-Mental State Examination score and attention span compared with the case of participants receiving no treatment . HRT and PL had different effects on cognitive function ;  HRT improved delayed recall , whereas flexible thinking seemed improved in the PL group . Conclusions This study was unable to demonstrate a scientific basis for the use of PL for improving the health of postmenopausal women in general . However , the effect of PL on cognitive function deserves further study Data from the Third National Health and Nutrition Examination Survey ( 1 ) indicate that 11 % of U.S. women have a history of clinical gallbladder diseasethat is , either previous cholecystectomy or self-reported history of gallstones . Factors associated with gallbladder disease , at least in some studies , include older age , female sex , white ethnicity/race , obesity , rapid weight loss , and , among women , greater parity , use of oral estrogencontaining contraceptives , and postmenopausal estrogen therapy ( 2 ) . These associations , in general , have been based on observational data and may partly reflect the effects of ascertainment and recall bias , as well as confounding . While some observational studies suggest that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold ( 3 ) , such an association has not been reported consistently ( 2 , 3 ) . The effect of combined estrogen plus progestin therapy has been less well studied , and no recent clinical trial data exist on the relation of such therapy to the risk for biliary tract surgery among postmenopausal women . To determine whether estrogen plus progestin therapy is associated with the risk for biliary tract surgery among postmenopausal women , we analyzed data from the Heart and Estrogen/progestin Replacement Study ( HERS ) , the first large r and omized , double-blind trial of estrogen plus progestin therapy for the secondary prevention of coronary heart disease ( 4 ) . Gallbladder disease events , including biliary tract surgery , were among several prespecified secondary outcomes of interest . Methods Participants Between 1 February 1993 and 1 October 1994 , 2763 postmenopausal women with coronary artery disease were recruited from 20 clinical centers across the United States for participation in HERS , a r and omized , double-blind study of the effect of combined , continuous estrogenprogestin therapy ( conjugated equine estrogens , 0.625 mg/d , and medroxyprogesterone acetate , 2.5 mg/d ) on recurrent coronary heart disease events . Baseline data , which were collected at the visits for initial screening and r and om allocation , included demographic characteristics , medical history , risk factors for coronary heart disease , physical examination , and laboratory data . Women were not eligible to enroll in HERS if they had used any estrogen or female hormones within the previous 3 months , including pills , suppositories , injections , vaginal creams , or transdermal patches . We excluded 510 women from these analyses who reported at enrollment a history of surgical gallbladder removal . We did include , however , 123 women with a self-reported history of gallstones who had not undergone cholecystectomy . After these exclusions , data from 2253 participants were available for analysis . Measurements Baseline data included participant age , years of education , number of pregnancies , ethnicity/race ( white , African American , or other ) , past use of postmenopausal estrogen therapy , history of cigarette smoking , history of alcohol consumption , and diabetes mellitus . Data were also obtained on use of lipid-lowering medications and antihypertensive medications , including thiazide diuretics .  Participants who stated that they had smoked at least 100 cigarettes in their life were considered to have a history of smoking . Participants were asked , Has a doctor told you that you had diabetes , sugar diabetes , or high blood sugar ? Those who answered yes were classified as having a history of diabetes . Women with a history of gestational diabetes only were classified as not having diabetes mellitus . Participants were weighed without shoes or outdoor clothing on a st and ard balance-beam scale to the nearest 0.1 kg . Height was measured to the nearest 0.1 cm by using the height rod of a st and ard beam scale or , where available , a wall-mounted stadiometer . We calculated the body mass index as weight (kg)/height ( m2 ) . At baseline , year 1 , and the end of the study , serum lipid and lipoprotein levels were obtained from all participants and were measured at the Johns Hopkins Lipoprotein Analytical Laboratory , Baltimore , Maryl and , which is certified by the U.S. Centers for Disease Control and Prevention for the measurement of serum lipids and lipoproteins . Ascertainment of End Points Participants were determined to have incident gallbladder disease by physician adjudicators who were blinded to the r and omization status [ active hormone treatment or placebo ] . Symptomatic nonsurgical biliary tract disease was defined as a hospital admission for acute cholecystitis , choledocholithiasis , or gallstone pancreatitis and was established on the basis of 1 ) reported symptoms in combination with elevated levels on liver function testing and gallstones with dilated biliary ducts on abdominal ultrasonography or 2 ) nuclear medicine scan diagnostic of acute gallbladder disease . Incident biliary tract surgery , which included  cholecystectomy , sphincterotomy , or bile duct exploration  , was established by review of operative reports and discharge summaries . All biliary tract surgeries were cholecystectomies with the exception of 12 sphincterotomies and 2 stent insertions . Nonsurgical and surgical gallbladder disease events were considered separate end points and are mutually exclusive . The main HERS results , reported in 1998 ( 4 ) , were based on the near-final data available at that time . We present the up date d and final results for incident biliary tract events ( 5 ) . Statistical Analysis We used unpaired two-tailed t-tests to compare the age , level of education , number of pregnancies , body mass index , alcohol consumption , serum lipid level , and lipoprotein levels of the women r and omly assigned to receive postmenopausal hormone therapy or placebo .  Using chi-square tests , we compared the hormone therapy and placebo groups according to ethnicity/race , history of lipid-lowering medication use , pre study postmenopausal estrogen use , thiazide diuretic use , cigarette smoking , ascorbic acid supplement use , history of gallbladder disease , and diabetes mellitus . The treatment groups were divided fairly equally with respect to baseline variables , except for statin use . To analyze the association between postmenopausal hormone therapy and incident gallbladder disease events , we used unadjusted and statin useadjusted proportional hazards models . All risk estimates were derived solely from proportional hazards models . We also estimated KaplanMeier curves for time to occurrence of biliary tract surgery , according to treatment assignment . The number of participants needed to be treated for a new case of biliary tract surgery to occur was calculated by using the incidence rates per person-year of observation . For predictor variables other than treatment assignment , we calculated the hazard ratio and 95 % CI by using proportional hazards regression models to estimate the risk for incident biliary tract surgery . We used simple regression models that controlled only for treatment assignment ; we also used multivariable regression models that included variables with a previously reported association with gallbladder disease . Our model-fitting methods relied primarily on biological criteria ; we began by including factors previously reported to be associated with gallbladder disease . Although the risk for type I errors is always present when c and i date predictors are many relative to the number of outcomes , our model-building process accounted for this possibility when we considered the statistical significance of the result ing multivariable model . Results were confirmed by using stepwise and backwards selection methods . We identified one statistically significant interaction between postmenopausal hormone treatment and smoking . Adjustment for this interaction did not substantially affect the hazard ratios for other variables entered in the multivariable models . We performed these analyses by using SAS software ( 6 ) . A correlation between outcomes at each clinical center could potentially affect the SEs for the relative hazard estimates . Therefore , to control for such potential clustering by center , we used STATA software ( 7 ) to generate robust SEs for the proportional hazards models ( 8) . Because site-specific practice patterns could confound the relation of statin use to biliary tract surgery , we also examined statistical models that included clinical center as a fixed effect . We calculated the number of participants needed to be treated to result in one additional biliary tract surgery  by using the reciprocal of the absolute risk increase . However , because the 95 % CI for the absolute risk increase included zero , the CI for the number needed to treat for harm ( NNTH ) included . We use a method described by Altman ( 9 ) to present the CI in these circumstances . The CI around the NNTH will therefore range from an NNTH to to a number needed to treat for benefit ( NNTB ) . Role of the Funding Source Wyeth-Ayerst Research funded HERS . The study was design ed and carried out by the HERS investigators , including scientists from Wyeth-Ayerst Research . Investigators at the HERS Coordinating Center at the University of California , San Francisco , collected the outcome data , supervised the adjudication of outcome events , and analyzed the data . Results Gallbladder disease was particularly prevalent among this cohort of postmenopausal women with coronary artery disease . Twenty-three percent of women reported a history of cholelithiasis or cholecystectomy at baseline ( 10 ) . With the exception of statin use , which was more prevalent among women assigned to receive placebo ( P = 0.01 ) , the distribution of baseline variables was similar in both treatment groups ( Table 1 ) . Approximately 23 % of the HERS participants had a history of pre-enrollment hormone use ; the type and duration did not differ between the treatment groups . Table 1 . Selected Baseline Characteristics of Postmenopausal Women Receiving Hormone Therapy or Placebo  in the Heart and Estrogen/progestin Replacement Study ( HERS ) A Raloxifene , a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis , has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled , r and omized clinical trial in postmenopausal women with osteoporosis . This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial . Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board . A total of 7,705 women were enrolled in the 4-year trial ; 2,576 received placebo , 2,557 raloxifene 60mg/day , and 2,572 raloxifene 120mg/day . Women were a mean of 66.5-years old at trial entry , 19 years postmenopause , and osteoporotic ( low bone mineral density and /or prevalent vertebral fractures ) . As of 1 November 1999 , 61 invasive breast cancers had been reported and were confirmed by the adjudication board , result ing in a 72 % risk reduction with raloxifene ( relative risk ( RR ) 0.28 , 95 % confidence interval ( CI ) 0.17 , 0.46 ) . These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer . Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84 % ( RR 0.16 , 95 % CI 0.09 , 0.30 ) . Raloxifene was generally safe and well-tolerated , however , thromboembolic disease occurred more frequently with raloxifene compared with placebo ( p=0.003 ) . We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment , through prevention of new cancers or suppression of sub clinical tumors , or both . Additional r and omized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis , at risk for cardiovascular disease , and at high risk for breast cancer This manuscript describes the study design and rationalle for the Kronos Early Estrogen Prevention Study ( KEEPS ) and the KEEPS Cognitive and Affective ancillary study ( KEEPS Cog ) . KEEPS is a multicenter , r and omized , double-blinded , placebo-controlled trial , design ed to test the hypothesis that low-dose hormone therapy ( HT ) initiated in recently postmenopausal women will reduce the progression of sub clinical atherosclerosis as measured by carotid artery intima-media thickness ( CIMT ) and coronary artery calcification ( CAC ) over four years . The KEEPS Cog ancillary study was design ed to assess potential estrogenic treatment effects on cognition and mood . We present the KEEPS trial in the context of issues raised by the Women 's Health Initiative ( WHI ) and the Women 's Health Initiative Memory Study ( WHIMS ) . Here we also describe the most recent results and ongoing HT-related research studies design ed to address similar issues . This article is part of a Special Issue entitled Hormone Therapy Objective : The aim of this study was to investigate whether tapering down of combined estrogen plus progestogen therapy ( EPT ) reduced the recurrence of hot flashes and resumption of therapy compared with abrupt discontinuation . A secondary aim was to evaluate whether health-related quality of life ( HRQoL ) was affected after discontinuation of EPT and to investigate the possible factors predicting resumption of EPT . Methods : Eighty-one postmenopausal women undergoing EPT because of hot flashes were r and omized to tapering down or abrupt discontinuation of EPT .  Vasomotor symptoms were recorded in self-registered diaries , and resumption of hormone therapy ( HT ) was asked for at every follow-up . The Psychological General Well-being Index was used to assess HRQoL. Results : Neither the number nor the severity of hot flashes or HRQoL or frequency of resumption of HT differed between the two modes of discontinuation of EPT during up to 12 months of follow-up . About every other woman had resumed HT within 1 year . Women who resumed HT after 4 or 12 months reported more deteriorated HRQoL and more severe hot flashes after discontinuation of therapy than did women who did not resume HT . Conclusions : Women who initiate EPT  because of hot flashes may experience recurrence of vasomotor symptoms and impaired HRQoL after discontinuation of EPT regardless of the discontinuation method used , abrupt or taper down . Because , in addition to severity of flashes , decreased well-being was the main predictor of the risk to resume HT , it seems important to also discuss quality of life in parallel with efforts to discontinue HT OBJECTIVE The main purpose in organizing this survey was to collect information relevant to The North American Menopause Society 's ( NAMS ) educational mission and to document women 's knowledge of , and attitudes toward , menopause . DESIGN During June-July 1997 , The Gallup Organization conducted 750 telephone interviews with a r and omly selected sample of women 45 - 60 years of age from across the United States . Women were asked about their sources of information on menopause , what changes in health they anticipated as a result of menopause , why they used hormone therapy , and their attitudes toward menopause as a natural or a medical event . RESULTS Women are more likely to believe that depression and irritability are associated with menopause than heart disease , but only a few associate menopause with an increasing vulnerability to either memory loss or Alzheimer 's disease . Relief of physical symptoms of menopause was mentioned as the reason for starting hormone therapy more often than to protect against osteoporosis ( 25 % relative to 15 % ) , or to prevent stroke or a heart attack ( 10 % ) , or to reduce the risk of developing Alzheimer 's disease ( 2 % ) . The single main source of women 's information on menopause was a health professional ( 49 % ) . The majority of women who were already menopausal or experiencing menstrual changes expressed an attitude toward menopause that was either neutral ( 42 % ) or positive ( 36 % ) . CONCLUSIONS Women are divided in their views of menopause , some seeing it as a medical condition requiring medical treatment , whereas others see it as a natural transition to be managed by " natural " means . Providing women with accurate , up-to- date information and enhancing communication between healthcare providers and menopausal women remain the challenges for NAMS CONTEXT Postmenopausal women have a greater risk than men of developing Alzheimer disease , but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent . On July 8 , 2002 , the study drugs , estrogen plus progestin , in the Women 's Health Initiative ( WHI ) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy . OBJECTIVE To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo . DESIGN , SETTING , AND PARTICIPANTS The Women 's Health Initiative Memory Study ( WHIMS ) , a r and omized , double-blind , placebo-controlled clinical trial , began enrolling participants from the Women 's Health Initiative ( WHI ) estrogen plus progestin trial in May 1996 . Of the 4894 eligible participants of the WHI study , 4532 ( 92.6 % ) postmenopausal women free of probable dementia , aged 65 years or older , and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS . INTERVENTION Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate ( n = 2229 ) , or a matching placebo ( n = 2303 ) . MAIN OUTCOME MEASURES Incidence of probable dementia ( primary outcome ) and mild cognitive impairment ( secondary outcome ) were identified through a structured clinical assessment . RESULTS The mean ( SD ) time between the date of r and omization into WHI and the last Modified Mini-Mental State Examination ( 3MSE ) for all WHIMS participants was 4.05 ( 1.19 ) years . Overall , 61 women were diagnosed with probable dementia , 40 ( 66 % ) in the estrogen plus progestin group compared with 21 ( 34 % ) in the placebo group . The hazard ratio ( HR ) for probable dementia was 2.05 ( 95 % confidence interval [ CI ] , 1.21 - 3.48 ; 45 vs 22 per 10 000 person-years ; P = .01 ) . This increased risk would result in an additional 23 cases of dementia per 10 000 women per year . Alzheimer disease was the most common classification of dementia in both study groups . Treatment effects on mild cognitive impairment did not differ between groups ( HR , 1.07 ; 95 % CI , 0.74 - 1.55 ; 63 vs 59 cases per 10 000 person-years ; P = .72 ) . CONCLUSIONS Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older . In addition , estrogen plus progestin therapy did not prevent mild cognitive impairment in these women . These findings , coupled with previously reported WHI data , support the conclusion that the risks of estrogen plus progestin outweigh the benefits PURPOSE To compare , by a secondary analysis , the therapeutic benefits of and rogen suppression in protocol prostate cancer patients with relapse after radiotherapy ( RT ) for locally advanced disease who , in the Phase III trial beginning in 1987 , were assigned to receive or not receive a short course of neoadjuvant maximal and rogen suppression before definitive RT . METHODS AND MATERIAL S Between 1987 and 1991 , 456 patients were entered in the Radiation Therapy Oncology Group trail 86 - 10 and r and omized to receive ( Arm I ) or not to receive ( Arm II ) neoadjuvant hormonal therapy ( HT ) , which was 4 months of goserelin ( 3.6 mg every 4 weeks ) and flutamide ( 250 mg t.i.d . ) before and during RT for bulky T2-T4 tumors . The overall and disease-specific survival after both r and omization and salvage HT for patients with relapse was evaluated , as well as the duration of response in those patients undergoing salvage HT . The outcomes in patients who had received neoadjuvant HT vs. those who had not were compared . The median follow-up after r and omization for all alive patients was 9.0 years and was 5.5 years for alive patients after beginning salvage HT . RESULTS Fewer patients received  salvage HT  on Arm I than on Arm II ( 45 % vs. 63 % , p < 0.001 ) . The outcomes by r and omized treatment arm ( I vs. II ) from the time of beginning salvage HT were similar . At 5 years after salvage HT , the overall survival rates were 41 % and 41 % and the disease-specific survival rates were 50 % and 50 % . At 8 years after r and omization , the overall survival rates were 47 % and 44 % and the disease-specific survival rates were 55 % and 56 % . CONCLUSION Although a 4-month course of neoadjuvant and concurrent maximum and rogen suppression and RT ( compared with RT alone ) significantly increases the freedom from relapse rate and freedom from receiving salvage HT , it does not compromise the long-term beneficial effect of subsequent salvage HT , if needed for relapse . These findings with long follow-up in patients treated for locally advanced disease diagnosed 9 - 14 years previously should help allay concerns of the possible development of " resistance " to and rogen suppression when 4-month courses of neoadjuvant HT are used before primary treatment Summary Background Given concerns over the use of hormone replacement therapy ( HRT ) , women are seeking natural alternatives to cope with the symptoms and effects of menopause . The bone sparing effects of soy protein and its isoflavones is well established in animal studies , while 5 previous human studies on soy and bone have yielded variable outcomes due in part to their short duration of study . Progesterone has been suggested as a bone – trophic hormone , but the effect of long – term , low dose transdermal progesterone is unknown . Aim The aim of the study was to compare for the first time the long – term effects of soymilk , with or without isoflavones with natural transdermal progesterone , or the combination , on bone mineral density in the lumbar spine and hip . Methods Postmenopausal , Caucasian women with established osteoporosis or at least 3 risk – factors for osteoporosis , were r and omly assigned , double – blind to one of four treatment – groups : soymilk containing isoflavones  ( soy+ , n = 23 ) ,  transdermal progesterone ( TPD+ , n = 22 ) , or the combination of soy+ and TDP+,(n = 22 )  or placebo ( isoflavone – poor soymilk , soy÷ and progesterone – free – cream TDP÷ , n = 22 ) . All subjects received comparable intakes of calcium , minerals and vitamins . Bone mineral content ( BMC ) and density ( BMD ) were measured in lumbar spine and hip by using dual – energy X-ray absorptiometry ( DEXA ) at baseline and after 2 years . Findings The percentage change in lumbar spine BMD and BMC respectively , did not differ from zero in the soy+ group ( + 1.1 % , + 2.0 % ) and TDP+ group ( ÷1.1 % , + 0.4 % ) but significant bone loss occurred in the control group ( ÷4.2%,÷4.3 % ) and the combined treatment group ( ÷2.8 % , ÷2.4 % ) . No significant changes occurred for femoral neck BMD or BMC .InterpretationDaily intake of two glasses of soymilk containing 76 mg isoflavones  prevents lumbar spine bone loss in postmenopausal women . Transdermal progesterone had bone – sparing effects but when combined with soy milk a negative interaction between the two treatments occurs result ing in bone – loss to a greater extent than either treatment alone BACKGROUND Perimenopausal and menopausal women are more likely to complain of memory loss than are premenopausal women , although the association between menopause and cognitive loss remains controversial . Recently published studies on the risks of hormone therapy have left many women and their physicians seeking effective nonhormonal treatments for menopausal symptoms , including cognitive loss . OBJECTIVE This study investigated the efficacy of the cholinesterase agent donepezil in the treatment of menopause-related cognitive loss . METHODS Community-dwelling women in natural menopause were recruited for a r and omized , double-blind , placebo-controlled study of donepezil . To qualify for enrollment , the Brief Cognitive Rating Scale was used to determine cognitive symptoms , and women with depression were excluded . Subjects were r and omized to receive either donepezil , commencing at 5 mg/d , or placebo . At week 6 of r and omization , the dosage of donepezil was increased to 10 mg/d . Treatment continued throughout the 26-week study . The primary outcome measure was the overall change in neurocognitive test results over time . Outcome variables of test scores were analyzed before and after receipt of donepezil or placebo . RESULTS A total of 28 women aged 46 to 60 years were enrolled . Fourteen women were r and omized to receive active drug , 14 to placebo .  Two women dropped out of the placebo group . There were no statistically significant differences between treatment groups in post-/pre-dose mean score ratios . No interactions were statistically significant . The P values for tests of equal variances did not reveal a difference in the means . Subjective measures did show some trends toward improvement in memory and cognition . CONCLUSION Donepezil was no more effective than placebo in treating the symptoms of menopause- related memory and cognitive loss UNLABELLED The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption . Women with highest remodeling had greatest loss of bone mass and estimated bone strength , whereas those with low remodeling lost less bone and maintained estimated bone strength . INTRODUCTION Bone loss from the inner ( endocortical ) surface contributes to bone fragility , whereas deposition of bone on the outer ( periosteal ) surface is believed to be an adaptive response to maintain resistance to bending . MATERIAL S AND METHODS To test this hypothesis , changes in bone mass and estimated indices of bone geometry and strength of the one-third distal radius , bone turnover markers , and fracture incidence were measured annually in 821 women 30 - 89 years of age for 7.1 + /- 2.5 years . The analyses were made in 151 premenopausal women , 33 perimenopausal women , 279 postmenopausal women , and 72 postmenopausal women receiving hormone replacement therapy ( HRT ) .  RESULTS In premenopausal women , periosteal apposition increased the radius width , partly off setting endocortical resorption ; therefore , the estimated cortical thickness decreased . Outward displacement of the thinner cortex maintained bone mass and cortical area and increased estimated bending strength . Estimated endocortical resorption accelerated during perimenopause , whereas periosteal apposition decreased . Further cortical thinning occurred , but estimated bending strength was maintained by modest outward cortical displacement . Endocortical resorption accelerated further during the postmenopausal years , whereas periosteal apposition declined further ; cortices thinned , but because outward displacement was minimal , estimated cortical area and bending strength now decreased . Women with highest remodeling had the greatest loss of bone mass and strength . Women with low remodeling lost less bone and maintained estimated bone strength . In  HRT-treated women , loss of bone strength was partly prevented . These structural indices predicted incident fractures ; a 1 SD lower section modulus doubled fracture risk . CONCLUSIONS Periosteal apposition does not increase after menopause to compensate for bone loss ; it decreases . Bone fragility of osteoporosis is a consequence of reduced periosteal bone formation and increased endocortical resorption . Underst and ing the mechanisms of the age-related decline in periosteal apposition will identify new therapeutic targets . On the basis of our results , it may be speculated that the stimulation of periosteal apposition will increase bone width and improve skeletal strength OBJECTIVE Decision-making at menopause remains a challenge for women and their health care providers as the paradigm for hormone therapy continues to evolve . The role of decision-support for this process remains to be defined . METHODS A r and omized controlled trial of a computer-based hormone therapy ( HT ) decision-aid versus a control intervention consisting of a printed pamphlet among 177 post-menopausal women receiving care in a Veterans Affairs Medical Center . RESULTS Participants found the computer-based decision-aid  easy to use and retained risk information incorporated from emerging scientific data . There was no difference between groups with respect to the primary outcomes of knowledge , satisfaction with decision , decisional conflict or HT use . A trend was reported towards decreased decisional conflict in the evidence in decision-making ( p=0.07 ) and factors of uncertainty ( p=0.06 ) domains among the subset of participants who were on HT at baseline and used the computer-based decision-aid . CONCLUSION The computer-based decision-aid was able to effectively incorporate emerging scientific information but was no more effective than a printed pamphlet control with regard to improving decision-process outcomes . PRACTICE IMPLICATION S The incremental benefit of a complex versus simpler decision-aid for post-menopausal women remains to be established prior to widespread dissemination of interactive computer-based HT decision-aids CONTEXT Despite decades of use and considerable research , the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain . OBJECTIVE To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled disease prevention trial ( the estrogen-alone component of the Women 's Health Initiative [ WHI ] ) conducted in 40 US clinical centers beginning in 1993 . Enrolled were 10 739 postmenopausal women , aged 50 - 79 years , with prior hysterectomy , including 23 % of minority race/ethnicity . INTERVENTION Women were r and omly assigned to receive either 0.625 mg/d of conjugated equine estrogen ( CEE ) or placebo . MAIN OUTCOME MEASURES The primary outcome was coronary heart disease ( CHD ) incidence ( nonfatal myocardial infa rct ion or CHD death ) . Invasive breast cancer incidence was the primary safety outcome . A global index of risks and benefits , including these primary outcomes plus stroke , pulmonary embolism ( PE ) , colorectal cancer , hip fracture , and deaths from other causes , was used for summarizing overall effects . RESULTS In February 2004 , after review ing data through November 30 , 2003 , the National Institutes of Health ( NIH ) decided to end the intervention phase of the trial early . Estimated hazard ratios ( HRs ) ( 95 % confidence intervals [ CIs ] ) for CEE vs placebo for the major clinical outcomes available through February 29 , 2004 ( average follow-up 6.8 years ) , were : CHD , 0.91 ( 0.75 - 1.12 ) with 376 cases ; breast cancer , 0.77 ( 0.59 - 1.01 ) with 218 cases ; stroke , 1.39 ( 1.10 - 1.77 ) with 276 cases ; PE , 1.34 ( 0.87 - 2.06 ) with 85 cases ; colorectal cancer , 1.08 ( 0.75 - 1.55 ) with 119 cases ; and hip fracture , 0.61 ( 0.41 - 0.91 ) with 102 cases . Corresponding results for composite outcomes were : total cardiovascular disease , 1.12 ( 1.01 - 1.24 ) ; total cancer , 0.93 ( 0.81 - 1.07 ) ; total fractures , 0.70 ( 0.63 - 0.79 ) ; total mortality , 1.04 ( 0.88 - 1.22 ) , and the global index , 1.01 ( 0.91 - 1.12 ) . For the outcomes significantly affected by CEE , there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years . The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years . CONCLUSIONS The use of CEE increases the risk of stroke , decreases the risk of hip fracture , and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years . A possible reduction in breast cancer risk requires further investigation . The burden of incident disease events was equivalent in the CEE and placebo groups , indicating no overall benefit . Thus , CEE should not be recommended for chronic disease prevention in postmenopausal women INTRODUCTION Women in the menopausal stage of life usually have climacteric symptoms of  hot flashes ,  back pain , sleeplessness , night sweats and increased risk of cardiovascular disorders . Although physical exercises have been documented to favourably alleviate some of these problems , there 's a paucity of knowledge of their effects on menopausal women in Nigeria . OBJECTIVES This study investigated the effect of a twelve-week Endurance Exercise Programme ( EEP ) on quality of life(QOL ) and menopausal symptoms in these women . METHODS Participants were purposively recruited and assigned into perimenopausal and postmenopausal groups based on history of thier last menstrual period and from each of these groups r and omized into : perimenopausal exercise group ( PEMEG ) , postmenopausal exercise group ( POMEG ) , perimenopausal control group ( PEMCG ) postmenopausal control group ( POMCG ) .  Quality of life ( QOL ) , Menopausal symptoms - Back Pain ( BP ) and hot flashes ( HF ) among other variables , were evaluated at baseline and 4 weekly intervals . EEP consisted of a 10-station circuit of muscular and cardiovascular endurance , flexibility , coordination , abdominal and pelvic floor muscle exercises . RESULTS One hundred and seventy five menopausal women , mean age 52.3 + /- 4.1 years . Significant changes occurred between baseline and end of 12th week mean values of PEMEG for QOL : 565.9 + /- 108.8 vs 725.0 + /- 42.9 and BP 4.42 + /- 1.7 vs 1.00 + /- 0.0 . ( p= 0.000 ) . Also , in POMEG : QOL 558.3 + /- 127.7 vs 736.5 + /- 44.8 ; and BP 5.37 + /- 1.48 vs 1.88 + /- 1.18 ( p=0.000 ) . Significant changes in QOL and BP did not occur in the control groups . CONCLUSION Routine participation in endurance exercise programme is recommended for menopausal women for improved QOL OBJECTIVE In some women , hot flashes and other symptoms attributed to menopause persist for many years after the cessation of menses . The frequency and severity of such symptoms and response to hormone therapy in older women have not been well documented . METHODS We used data from the Heart and Estrogen/Progestin Replacement Study , a blinded , clinical trial among 2763 women with documented coronary disease and a uterus who were r and omized to receive either conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg in one tablet or placebo .  Participants were queried at baseline and annually regarding menopausal symptoms . Breast symptoms were self‐reported , and uterine bleeding was recorded on a daily diary . RESULTS Symptoms associated with menopause were relatively common among Heart and Estrogen/Progestin Replacement Study participants , whose average age was 67 years and who averaged 18 years since menopause . At baseline , 16 % of women reported frequent hot flashes , 26 % vaginal dryness , 10 % genital irritation , 55 % trouble sleeping , and 53 % early awakening . Women assigned to hormone therapy reported less frequent hot flashes , vaginal dryness , and trouble sleeping compared with women assigned to placebo , but more frequent vaginal discharge , genital irritation , uterine bleeding , and breast symptoms . The reporting of breast symptoms among women in the hormone group decreased from 40 % at 1 year to 13 % by the 4th year . Uterine bleeding was reported by 31 % and spotting by an additional 33 % of women in the hormone group during the 1st year of treatment ; by the 4th year , these proportions had fallen to 11 % and 20 % , respectively . CONCLUSION Symptoms typically attributed to menopause are common in elderly women .  Postmenopausal hormone therapy  reduces hot flashes , trouble sleeping , and vaginal dryness , but at st and ard doses in elderly women is associated with vaginal discharge , genital irritation , uterine bleeding , and breast symptoms OBJECTIVE To determine the effects of 9 months of hormone replacement therapy ( HRT ) on cognitive performance in women aged 75 years and older . METHODS A 9-month r and omized , double-blinded , placebo-controlled parallel trial . Fifty-two elderly postmenopausal women ( age range 75 - 91 years ) without known contraindications to HRT or evidence of dementia or depression were enrolled . Participants were r and omly assigned in a 1:2 ratio to placebo or conjugated estrogens at 0.625 mg/d plus trimonthly medroxyprogesterone acetate at 5 mg/d for 13 days ( HRT ) . Main outcome measures were change from baseline and rate of change from baseline for the following psychometric tests : Verbal Fluency Test , Weschler Paired Associate Learning and 20 min Delayed Recall , Trailmaking A and B Tests , Cancellation R and om Letter and R and om Form Tests . RESULTS At baseline , women in the HRT group reported a younger age of onset of menopause and a higher prevalence of hysterectomy , but otherwise did not differ from women in the placebo group . After 9 months of treatment , there were no significant group differences for any of the cognitive performance measures . The lack of an observed group-by-time difference for all cognitive tests remained after controlling for age of onset of menopause , education , and previous hysterectomy . CONCLUSIONS Although conclusions are limited by small sample size and the relatively short duration of treatment , results suggest that 9 months of estrogen replacement in combination with trimonthly progestin does not improve cognitive performance in women over 75 years who do not have dementia or depression It is well known that a family history of breast cancer is an important risk factor for the disease . A critical issue is how to advise patients with a family history of breast cancer about perimenopausal and postmenopausal use of hormone replacement therapy ( HRT ) . Hoskins and colleagues [ 1 ] have provided guidelines on assessment and counseling of women with such a history , including a recommendation that they avoid exogenous estrogens . A considerable body of literature has discussed the association of HRT and risk for breast cancer . Interpretation of available data is not consistent : Two meta-analyses [ 2 , 3 ] found a positive association , and two others [ 4 , 5 ] found no association . More recent studies have not clarified the issue [ 6 - 8 ] . Findings on increased risk in women with a family history of breast cancer have been more consistent . A meta- analysis [ 3 ] of five studies that had examined the issue suggested that the risk for breast cancer associated with HRT  was elevated among women without a family history of breast cancer ( relative risk [ RR ] , 1.5 [ 95 % CI , 1.2 to 1.7 ] ) but was even greater among women with a family history ( RR , 3.4 [ CI , 2.0 to 6.0 ] ) . Of the studies not included in the meta- analysis , some [ 9 - 12 ] but not all [ 6 , 7 , 13 ] reported similar observations . Beyond the issue of the effects of HRT on the incidence of breast cancer , further consideration of the concomitant effect of HRT on risk for death is warranted . A recent report from the Nurses ' Health Study [ 8 ] suggests that hormonal therapy lasting at least 5 years is associated with a 45 % increase in the rate of death from breast cancer . Analytic epidemiologic studies suggest that women who receive HRT have a significantly lower risk for death , primarily because of protection against cardiovascular disease [ 14 - 17 ] . Thus , it is important to examine all-cause mortality when considering the risks and benefits of HRT use [ 18 ] , especially among women with a family history of breast cancer . As part of the Iowa Women 's Health Study , a prospect i ve cohort study of 41 837 women who were 55 to 69 years of age at baseline in 1986 , data were collected on self-reported family history of breast cancer in first-degree relatives and on history of HRT use . These data were used to examine the risks for postmenopausal breast cancer , case fatality , and total mortality . Methods The Iowa Women 's Health Study Cohort Participants in the Iowa Women 's Health Study were selected from a r and om sample of all women between 55 and 69 years of age who had a valid Iowa driver 's license in 1985 [ 19 ] . This sampling frame comprised approximately 94 % of female Iowa residents in that age range . The primary purpose of the study was to examine the association of obesity and body fat distribution with the incidence of cancer and mortality rate . A total of 41 837 women returned a mailed question naire ( response rate , 42.7 % ) . Three follow-up question naires mailed in October 1987 , August 1989 , and June 1992 were used to collect information on incident self-reported disease and each participant 's current residence . Only minor demographic differences were seen at baseline between respondents and nonrespondents [ 20 ] . Nonrespondents have subsequently been found to have a higher 5-year incidence of cancer and rate of death ( primarily death from diseases related to smoking ) [ 21 ] . The incidence of breast cancer , however , was similar among respondents and nonrespondents ( RR , 1.01 [ CI , 0.9 to 1.1 ] ) . Self-reported items on the baseline question naire included education level ; marital status ; smoking history ; usual alcohol intake during the past year ; physical activity ; reproductive history ; and history of various medical conditions , including diabetes and heart disease . We asked women whether they had menstruated in the past year and asked them to state the age at which and the reason why their periods had stopped ( natural menopause , surgery , medication , or other ) . We asked them whether they had ever used pills , other than birth control pills , which contain estrogen or other female hormones and how long they had used them . Response categories for duration of use were one month or less , 2 - 6 months , 7 - 12 months , 13 months-2 years , 3 - 5 years , or more than 5 years . Participants were asked whether their mothers , sisters , or daughters had ever had breast cancer . No information was collected on the number of relatives in a given category or on the age of relatives . For exclusion purpose s , we ascertained the presence of prevalent cancer by asking participants whether they had ever been told by a physician that they had any form of cancer , excluding skin cancer . Participants reported their current height and weight and their weight at 18 years of age . A paper measuring tape was sent so that a friend , spouse , or relative could measure the circumferences of the waist ( 1 inch above the umbilicus ) and the hips ( maximum ) . The height , weight , and circumference measurements obtained by this protocol are valid and reliable [ 22 ] . Anthropometric values were used to derive current body mass index ( weight in kg/height in m2 ) , body mass index at 18 years of age ( based on their current height ) , and the ratio of waist circumference to hip circumference . The second follow-up survey included questions on use of mammography , including whether the participants had ever undergone mammography and the length of time since the last mammography had been done . Cohort Follow-up Cases of breast cancer ( codes 500 to 509 of the International Classification of Diseases for Oncology , Second Edition ) among Iowa residents were ascertained through the State Health Registry of Iowa , which is part of the National Cancer Institute 's Surveillance , Epidemiology , and End Results Program ( SEER ) [ 23 ] . Each year , registry cases and cohort members were matched by a computer according to social security number , name , maiden name , and date of birth . Primary tumor site , date of diagnosis , nonspecific extent of disease , and tumor size were obtained for each incident cancer case from 1986 through 1993 . Information on deaths was obtained from the State Health Registry of Iowa for Iowa residents and from the National Death Index for women who did not respond to the three follow-up surveys . Causes of death were coded according to the International Classification of Diseases , Ninth Revision [ 24 ] . Data Analysis Participants with the following baseline characteristics were excluded from the analysis : premenopausal status ( n = 569 ) , total or partial mastectomy ( n = 1870 ) , history of any cancer other than skin cancer ( n = 2293 ) , and unknown family history of breast cancer ( n = 1186 ) . After women with these characteristics were excluded , 35 919 women remained in the at-risk cohort for analysis . Women were considered to be at risk for breast cancer from January 1986 through 31 December 1993 or until one of the following censoring events occurred : diagnosis of breast cancer , death , relocation to an area other than Iowa , or other loss to follow-up . Person-years of follow-up for the mortality analyses were calculated from completion of the 1986 baseline question naire until death or the end of 1993 . Characteristics of the women were collapsed into natural categories or quartiles . Use of HRT was categorized by status ( current , former , and never ) at baseline and by duration ( 5 years or > 5 years ) . To describe the association of family history , HRT , and other variables with the incidence of breast cancer  and total mortality rate , we computed age-adjusted rates and 95 % CIs [ 25 ] ; multivariate-adjusted relative risks and 95 % CIs were derived through proportional hazards regression models by using the SAS program PHREG ( SAS Institute , Cary , North Carolina ) [ 26 ] . Multiplicative interactions were evaluated by comparing the 2 log likelihoods of models with and without the cross-product ( interaction ) terms within the context of proportional hazards regression . Results Risk Factors and Incidence of Breast Cancer After 8 years and more than 275 000 person-years of observation , 1085 cases of postmenopausal breast cancer were documented . The association of accepted risk factors [ 27 ] with incidence of breast cancer was evident in this cohort . Early age at menarche , late age at first birth , high waist-to-hip ratio , high body mass index , education , and alcohol intake were associated with increased risk ; high body mass index at 18 years of age was associated with decreased risk ( Table 1 ) . All subsequent analyses of the incidence of breast cancer include adjustment for these risk factors in addition to current age , type of menopause , and age at menopause . Table 1 . Multivariate-Adjusted Relative Risks for Potential Risk Factors for Breast Cancer among 35 919 Postmenopausal Women *  Hormone Replacement Therapy and Incidence of Breast Cancer by Family History A family history of breast cancer in mothers or sisters was reported by 12.2 % of the cohort at risk . Approximately 38 % of the cohort at risk reported having ever received HRT . The frequency of reported use did not differ by family history : 38.3 % of women without a family history and 37.7 % of women with a family history ( P > 0.2 ) . Duration of use was similar ( P > 0.2 ) . After adjustment for the risk factors listed in Table 1 , the relative risks for breast cancer among women who had formerly received HRT for 5 years or less or for more than 5 years were 1.04 and 0.89 , respectively . The multivariate adjusted relative risks for current short-term ( 5 years ) and long-term ( > 5 years ) users of HRT were 1.34 ( CI , 0.98 to 1.82 ) and 1.17 ( CI , 0.90 to 1.51 ) , respectively . The age-adjusted incidence rates of breast cancer associated with HRT use by family history of breast cancer are shown in Table 2 . Among women without a family history of breast cancer , the rate of breast cancer in those who were currently receiving HRT and had been receiving it for at least 5 years was 41 cases per 10 000 person-years , a rate not significantly greater than the 36 CONTEXT Polycystic ovary syndrome ( PCOS ) is associated with the metabolic syndrome and , consequently , with a potentially increased risk of cardiovascular disease ( CVD ) and related mortality later in life . Studies regarding CVD and mortality in PCOS women well into the postmenopausal age are lacking . OBJECTIVE Our objective was to examine whether postmenopausal PCOS women differ from controls regarding cardiovascular risk factors , myocardial infa rct ion ( MI ) , stroke and mortality . DESIGN AND SETTING We conducted , at a university hospital , a prospect i ve study of 35 PCOS women ( 61 - 79 yr ) and 120 age-matched controls . The study was performed 21 yr after the initial study . PARTICIPANTS Twenty-five PCOS women ( Rotterdam criteria ) and 68 controls participated in all examinations . Data on morbidity were based on 32 of 34 PCOS women and on 95 of 119 controls . INTERVENTIONS INTERVENTIONS included reexamination , interviews , and data from the National Board of Health and Welfare and from the Hospital Discharge Registry . MAIN OUTCOME MEASURES Blood pressure , glucose , insulin , triglycerides , total cholesterol , high- and low-density lipoprotein , apolipoprotein A1 and B , fibrinogen , and plasminogen activator inhibitor antigen were studied . Incidences of MI , stroke , hypertension , diabetes , cancer , cause of death , and age at death were recorded . RESULTS PCOS women had a higher prevalence of hypertension ( P = 0.008 ) and higher triglyceride levels ( P = 0.012 ) than controls . MI , stroke , diabetes , cancer , and mortality prevalence was similar in the two cohorts with similar body mass index . CONCLUSIONS The well-described cardiovascular/metabolic risk profile in pre- and perimenopausal PCOS women does not entail an evident increase in cardiovascular events during the postmenopausal period BACKGROUND AND AIM OF THE STUDY The aim of this study is to report the prevalence of menopausal symptoms by severity among the Finnish female population and the association of their symptoms with lifestyle ( smoking , use of alcohol , physical activity ) and body mass index ( BMI ) . MATERIAL AND METHODS Health 2000 is a nationally representative population -based study of Finnish adults . Data were collected by home interview , three self-administered question naires and a clinical examination by a physician . This study included women aged 45 - 64 years ( n=1427 ) . All symptoms included menopause-specific symptoms . Both univariate analysis and a factor analysis based on symptom factors were performed by menopausal group . Multiple regression analysis included each symptom factor as a dependent variable and confounding and lifestyle factors ( age , education , smoking , alcohol use , physical activity , BMI , use of hormonal replacement therapy ( HRT ) and chronic disease status ) . RESULTS Over one-third ( 38 % ) of the premenopausal , half of the perimenopausal , and 54 % of both postmenopausal and hysterectomized women reported bothersome symptoms . The difference between pre- and perimenopausal women was largest and statistically most significant in the case of back pain and hot flushes . Physically active women reported fewer somatic symptoms than did women with a sedentary lifestyle . Smoking was not related to vasomotor symptoms . CONCLUSION Bothersome symptoms are common in midlife , regardless of menopausal status . Inverse association between physical activity and menopausal symptoms needs to be confirmed in r and omized trials Background With the exception of sexual functioning and weight , social and behavioural effects of postmenopausal hormone therapy ( HT ) have not been reported from trials . This paper reports such results from the EPHT-trial in Estonia . Methods A r and omized trial , with a blind and non-blind sub-trial in Estonia . From 1999–2001 , 1778 women were recruited . The mean follow-up was 3.6 years . Women 's experiences were asked in the first and final study year by mailed question naires ( 74 and 81 % response rates ) . Comparisons of the groups were made by cross-tabulation and logistic regression , adjusting for age . Results There were no differences between the HT and non-HT groups in regard to being employed , the extent of social involvement or marital status or opinions on aging . There was no difference in the frequency of free-time exercise , or overweight . Some of the indicators suggested less sexual inactivity , but the differences were small . Conclusion In a trial setting , postmenopausal hormone therapy did not influence work or social involvement or health behaviour . Trial registration IS RCT IMPORTANCE Controversy exists about the frequency women should undergo screening mammography and whether screening interval should vary according to risk factors beyond age . OBJECTIVE To compare the benefits and harms of screening mammography frequencies according to age , breast density , and postmenopausal hormone therapy ( HT ) use . DESIGN Prospect i ve cohort . SETTING Data collected January 1994 to December 2008 from mammography facilities in community practice that participate in the Breast Cancer Surveillance Consortium ( BCSC ) mammography registries . PARTICIPANTS Data were collected prospect ively on 11,474 women with breast cancer and 922,624 without breast cancer who underwent mammography at facilities that participate in the BCSC . MAIN OUTCOMES AND MEASURES We used logistic regression to calculate the odds of advanced stage ( IIb , III , or IV ) and large tumors ( > 20 mm in diameter ) and 10-year cumulative probability of a false-positive mammography result by screening frequency , age , breast density , and HT use . The main predictor was screening mammography interval . RESULTS Mammography biennially vs annually for women aged 50 to 74 years does not increase risk of tumors with advanced stage or large size regardless of women 's breast density or HT use . Among women aged 40 to 49 years with extremely dense breasts , biennial mammography vs annual is associated with increased risk of advanced-stage cancer ( odds ratio [ OR ] , 1.89 ; 95 % CI , 1.06 - 3.39 ) and large tumors ( OR , 2.39 ; 95 % CI , 1.37 - 4.18 ) . Cumulative probability of a false-positive mammography result was high among women undergoing annual mammography with extremely dense breasts who were either aged 40 to 49 years ( 65.5 % ) or used estrogen plus progestogen ( 65.8 % ) and was lower among women aged 50 to 74 years who underwent biennial or triennial mammography with scattered fibrogl and ular densities ( 30.7 % and 21.9 % , respectively ) or fatty breasts ( 17.4 % and 12.1 % , respectively ) . CONCLUSIONS AND RELEVANCE Women aged 50 to 74 years , even those with high breast density or HT use , who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of false-positive results than those who undergo annual mammography . When deciding whether to undergo mammography , women aged 40 to 49 years who have extremely dense breasts should be informed that annual mammography may minimize their risk of advanced-stage disease but the cumulative risk of false-positive results is high UNLABELLED Most hip fractures occur in subjects without osteoporosis and are associated with a fall . Conventional menopausal hormone therapy ( HT ) improves postural balance , which might explain the rapid reduction in hip fracture risk . It is unclear whether tibolone improves postural balance , which might determine its effects on peripheral fracture risk . OBJECTIVE To study the short-term effects of low-dose tibolone therapy on postural balance in elderly women . METHODS Eighty healthy women ( 70 evaluable ) , aged 60 years or more , were recruited through advertising in the local media . They were r and omly allocated to receive either tibolone ( 1.25 mg/d ) or placebo for 6 months . Postural balance was assessed as sway velocity , using a force platform . RESULT ( S ) Baseline characteristics , including serum estradiol values and postural balance , were similar in the two study groups . On average , the overall dosing compliance was very high , over 97 % in both groups . After 6 months , sway velocity had decreased ( improved ) by 7.6 % ( -0.97 cm/s ; P=0.16 vs. baseline ) in the tibolone arm and by 2.5 % ( -0.30 cm/s ; P=0.59 vs. baseline ) in the placebo group . The difference 0.67 cm/s was not statistically significant ( 95 % CI -2.44 , 1.10 ; P=0.45 ) . Adjustments for age , serum estradiol level and variable value at baseline , revealed similar results . CONCLUSIONS Short-term treatment with tibolone ( 1.25 mg/d ) , compared to placebo , did not significantly affect postural balance function in elderly women Background Postmenopausal hormone therapy may have long-term effects on cognitive function depending on women 's age . Methods Postintervention follow-up was conducted with annual cognitive assessment s of two r and omized controlled clinical trial cohorts , beginning an average of 6 - 7 years after study medications were terminated : 1,376 women who had enrolled in the Women 's Health Initiative when aged 50 - 54 years and 2,880 who had enrolled when aged 65 - 79 years . Women had been r and omly assigned to 0.625mg/d conjugated equine estrogens ( CEE ) for those with prior hysterectomy ( mean 7.1 years ) , CEE with 2.5mg/d medroxyprogesterone acetate for those without prior hysterectomy ( mean 5.4 years ) , or matching placebos . Results Hormone therapy , when prescribed to women aged 50 - 54 years , had no significant long-term posttreatment effects on cognitive function and on changes in cognitive function . When prescribed to older women , it was associated with long-term mean ( SE ) relative decrements ( st and ard deviation units ) in global cognitive function of 0.081 ( 0.029 ) , working memory of 0.070 ( 0.025 ) , and executive function of 0.054 ( 0.023 ) , all p < .05 . These decrements were relatively stable over time . Findings did not vary depending on the hormone therapy regimen , prior use , or years from last menstrual period . Mean intervention effects were small ; however , the largest were comparable in magnitude to those seen during the trial 's active intervention phase . Conclusions CEE-based hormone therapy delivered near the time of menopause provides neither cognitive benefit nor detriment . If administered in older women , it results in small decrements in several cognitive domains that remain for many years OBJECTIVES To compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis and to assess the efficacy of either bisphosphonate in combination with hormone replacement therapy ( HRT ) . PATIENTS AND METHODS In this pragmatic study , the main efficacy criterion was the mean annual change in bone mineral density ( BMD ) . Patients who had a past or current history of etidronate or alendronate treatment for postmenopausal osteoporosis with at least 18 months follow-up and an evaluation in 1999 were eligible . Recruitment was in an outpatient clinic with a special focus on metabolic bone diseases . Osteoporosis was defined as at least one low-energy fracture or as a  lumbar spine  or femoral neck BMD decrease to at least 2.5 SD below the mean in young women . HRT  was not an exclusion criterion provided treatment duration was longer than 1 year . Etidronate was given cyclically ( 14-day courses in a dosage of 400 mg/d separated by 76-day intervals with calcium and vitamin D supplementation ) and alendronate was given daily in a dosage of 10 mg/d . RESULTS Of the 99 patients who met our inclusion criteria , 53 received etidronate ( including 23 on HRT ) and 46 alendronate ( 18 on HRT ) . Repeat BMD measurements were obtained in 88 patients , including 11 who stopped their bisphosphonate therapy within the first year of use because of adverse events . Lumbar spine BMD ( mean + /- SD ) increased significantly both in the etidronate group ( + 2.1 % + /- 0.7%/year ) and in the alendronate group ( + 5.3 % + /- 0.9%/year ) . The increase was significantly greater with alendronate ( P < 0.01 ) . The lumbar spine BMD increase was largest in the patients on alendronate and HRT ( + 6.5 % + /- 1.4%/year ) and was smallest ( and nonsignificant ) in the patients on etidronate without HRT ( + 1.2 % + /- 0.8 % ) . Femoral neck BMD showed no significant changes in any group . In the intention-to-treat analysis , fractures occurred in 12 etidronate patients ( 22.6 % ) and six ( 13.0 % ) alendronate patients ( nonsignificant ) . Adverse events requiring bisphosphonate discontinuation before the scheduled date of the follow-up BMD measurement occurred in one patient ( 1.9 % ) in the etidronate group ( generalized osteomalacia ) and in ten patients ( 21.7 % ) in the alendronate group ( upper or lower gastrointestinal tract symptoms in six and four patients , respectively ; P < 0.01 ) . CONCLUSION Both etidronate and alendronate significantly increased lumbar BMD , but the effect was significantly more marked with alendronate . Conversely , adverse effects , most notably gastrointestinal symptoms , were more common with alendronate , so that premature treatment discontinuation because of adverse events were more common in the alendronate group . Both differences should be taken into account when selecting the best drug for a patient with postmenopausal osteoporosis Background Cardiovascular disease is the leading cause of death for adults in Australia . In recent years there has been a shift in health service delivery from institutional to community‐based care for chronic conditions , including cardiovascular disease . The general practice setting is seen to offer greater flexibility , higher levels of efficiency and more client focused healthcare delivery than is possible in the acute care sector . It has been suggested that practice nurses represent a useful adjunct to current models of cardiovascular disease management . To date , significant descriptive research has been conducted exploring the demographics , roles , educational needs and issues facing practice nurses . However , there is a need to evaluate the effectiveness of practice nurse interventions in terms of patient outcomes , clinician satisfaction and cost‐effectiveness . Objectives This review seeks to present the best available evidence regarding the efficacy of general practice nurse interventions for cardiac risk factor reduction in healthy adults , as well as those with established cardiovascular disease or known cardiac risk factors . Search Strategy A systematic literature search was performed using Medline ( 1966 ‐ 2005 ) , CINAHL ( 1982 −2005 ) , Cochrane Controlled Trials Register ( Issue 4 , 2005 ) and the Joanna Briggs Institute Evidence Library . In addition , the reference lists of retrieved papers , conference proceedings and the Internet , were scrutinised for additional trials . Selection Criteria This review considered any English language r and omised trials that investigated interventions conducted by the practice nurse for cardiovascular disease management or reduction of cardiac risk factors . Interventions conducted by specialist cardiac nurses in general practice were excluded . Outcomes measured included blood pressure , smoking cessation , total cholesterol , exercise , body weight/body mass index and cost‐effectiveness . Results Eighteen trials , reported in 33 papers , were included in the review . Ten trials investigated multifaceted interventions , while the remaining eight trials reported targeted interventions . Of the trials that reported multifaceted interventions , three trials investigated risk reduction in those with established cardiovascular disease , four trials focused on those with known cardiovascular disease risk factors and three trials included the general community . The eight trials which examined the efficacy of targeted interventions focused upon dietary intake ( two trials ) , smoking cessation ( three trials ) , weight reduction ( one trial ) and physical activity ( two trials ) . The effect of both the multifaceted and targeted interventions on patient outcomes was variable . However , both the multifaceted and targeted interventions demonstrated similar outcome trends for specific variables . Improvements were demonstrated by most studies in blood pressure , cholesterol level , dietary intake and physical activity . The variation in outcome measures and contradictory findings between some studies makes it difficult to draw definitive conclusions . Conclusions While interventions to reduce cardiovascular disease risk factors have produced variable results , they offer significant potential to assist patients in modifying their personal risk profile and should be developed . The public health importance of these changes is dependant upon the sustainability of the change and its effect on the health outcomes of these individuals . Further well‐ design ed research is required to establish the effectiveness of practice nurse interventions for cardiovascular disease management and risk factor reduction in terms of patient outcomes and cost‐effectiveness Osteoporosis is a major public health issue leading to significant morbidity , loss of independence and excess loss of life . It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis ( 1 , 2 ) . This is associated with almost 1.5 million fractures annually , including 300,000 hip fractures ( 2 , 3 ) . A review of the evidence by Cumming in 1990 ( 4 ) and subsequently published r and omized clinical trials have shown that calcium and /or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women ( 5–9 ) . However , there are a limited number of calcium and /or vitamin D trials ( 10–13 ) and observational studies [ review of evidence by Cumming and Nevitt ( 14 ) and Kanis ( 15 ) ] , to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures . It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence ( 16–21 ) . To address these major health concerns of postmenopausal women , the Calcium-Vitamin D ( CaD ) trial of the Women ’s Health Initiative ( WHI ) was design ed to test the primary hypothesis that women who are r and omized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily , a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo . The objective of this paper is IMPORTANCE Postmenopausal hormone therapy with conjugated equine estrogens ( CEEs ) may adversely affect older women ’s cognitive function . It is not known whether this extends to younger women . OBJECTIVE To test whether prescribing CEE-based hormone therapy to postmenopausal women aged 50 to 55 years has longer-term effects on cognitive function . DESIGN Trained , masked staff assessed participants with an annual telephone-administered cognitive battery that included measures of global and domain-specific cognitive functions . Cognitive testing was conducted an average of 7.2 years after the trials ended , when women had a mean age of 67.2 years , and repeated 1 year later . Enrollment occurred from 1996 through 1999 . SETTING Forty academic research centers . PARTICIPANTS The study population comprised 1326 postmenopausal women , who had begun treatment in 2 r and omized placebo-controlled clinical trials of hormone therapy when aged 50 to 55 years . INTERVENTION The clinical trials in which the women had participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate over a mean of 7.0 years . MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function . Secondary outcomes were verbal memory , attention , executive function , verbal fluency , and working memory . RESULTS Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo : mean ( 95 % CI ) intervention effect of 0.02 ( −0.08 to 0.12 ) st and ard deviation units ( P = .66 ) . Similarly , no overall differences were found for any individual cognitive domain ( all P > .15 ) . Prespecified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy : mean treatment effects of −0.17 ( −0.33 to −0.02 ) and −0.25 ( −0.42 to −0.08 ) , respectively ; however , this may be a chance finding . CONCLUSIONS AND RELEVANCE CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50 to 55 years . We are not able to address whether initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects cognitive function , either in the short or longer term . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01124773 BACKGROUND Vinorelbine ( VRL ) has been shown to be active in hormone-refractory prostate cancer ( HRPC ) in phase II studies , alone or in combination . Its moderate toxicity profile is well tolerated in elderly patients . PATIENTS AND METHODS Patients with metastatic prostate cancer , progressive after primary hormonal therapy , were r and omised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks , and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression . Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy ( HT ) for all their patients . R and omisation was stratified by centre . Further chemotherapy was allowed after progression . The primary end point was progression-free survival ( PFS ) . The final analysis was performed on a total of 414 patients . Reported results were all based on intention-to-treat analyses . All progressions and responses were review ed by an independent panel . RESULTS PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm , according to the statistical hypothesis of the protocol ( P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10 % ) . The 6-month PFS rates were 33.2 % versus 22.8 % , and the median duration s of PFS were 3.7 versus 2.8 months . In the multivariate Cox analysis , which included age , Karnofsky performance status ( PS ) , haemoglobin , alkaline phosphatase at study entry and number of prior hormonal treatments , the P value was decreased to 0.005 . The prostate-specific antigen ( PSA ) response rate ( > or = 50 % decline sustained for at least 6 weeks ) was significantly higher for VRL plus HT compared with HT ( 30.1 % versus 19.2 % ; P=0.01 ) . Clinical benefit , defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks , and at least stable assessment in the other two , was also more frequently observed in patients who received VRL plus HT versus HT alone ( 30.6 % and 19.2 % ; P=0.008 ) . There was no statistical difference in overall survival . Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression , compared with 28 % of patients in the VRL-based arm . Aminoglutethimide did not seem to result in better efficacy for either arm . VRL plus HT was well tolerated , with a median administered relative dose intensity of 90 % ; grade 4 neutropenia occurred in 6.5 % of patients and non-haematological toxicity was rare . CONCLUSIONS The combination of VRL and hydrocortisone compared with hydrocortisone alone result ed in improved clinical benefit , PFS and PSA response rate . This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids . There was no gain in survival ; however , the combination is well tolerated in this elderly group of patients , who often present cardiac co-morbidities , and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer BACKGROUND Tibolone has estrogenic , progestogenic , and and rogenic effects . Although tibolone prevents bone loss , its effects on fractures , breast cancer , and cardiovascular disease are uncertain . METHODS In this r and omized study , we assigned 4538 women , who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture , to receive once-daily tibolone ( at a dose of 1.25 mg ) or placebo . Annual spine radiographs were used to assess for vertebral fracture . Rates of cardiovascular events and breast cancer were adjudicated by expert panels . RESULTS During a median of 34 months of treatment , the tibolone group , as compared with the placebo group , had a decreased risk of vertebral fracture , with 70 cases versus 126 cases per 1000 person-years ( relative hazard , 0.55 ; 95 % confidence interval [ CI ] , 0.41 to 0.74 ; P<0.001 ) , and a decreased risk of nonvertebral fracture , with 122 cases versus 166 cases per 1000 person-years ( relative hazard , 0.74 ; 95 % CI , 0.58 to 0.93 ; P=0.01 ) . The tibolone group also had a decreased risk of invasive breast cancer ( relative hazard , 0.32 ; 95 % CI , 0.13 to 0.80 ; P=0.02 ) and colon cancer ( relative hazard , 0.31 ; 95 % CI , 0.10 to 0.96 ; P=0.04 ) . However , the tibolone group had an increased risk of stroke ( relative hazard , 2.19 ; 95 % CI , 1.14 to 4.23 ; P=0.02 ) , for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board . There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups . CONCLUSIONS Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis . ( Clinical Trials.gov number , NCT00519857 . Results from epidemiologic studies of  postmenopausal hormone  use and dementia have been conflicting . Investigators from the Women 's Health Initiative Memory Study reported that the incidence of dementia in women aged > /=65 years assigned to hormone use was increased . Here the authors report results from a prospect i ve cohort study of 2,906 dementia-free women ( 1,519 hormone users and 1,387 hormone nonusers ) aged > or = 75 years who were recruited from a Southern California health plan in 1999 and followed through 2003 .  Cognitive status was assessed annually using the Telephone Interview of Cognitive Status-modified , supplemented by the Telephone Dementia Question naire and medical record review . The mean self-reported age at initiation of hormone use was 48.3 years for users of estrogen alone ( n = 1,072 ) and 54.9 years for users of estrogen plus progestin ( n = 447 ) ; self-reported mean duration s of hormone use were 30.5 years and 23.2 years , respectively . There were 283 incident dementia cases identified during follow-up . After adjustment for age , education , and medical history , hazard ratios for incident dementia were 1.34 ( 95 % confidence interval : 0.95 , 1.89 ) in estrogen/progestin users and 1.23 ( 95 % confidence interval : 0.94 , 1.59 ) in estrogen users . These findings do not provide support for an effect of estrogen or estrogen/progestin use in preventing dementia CONTEXT Clinical trials demonstrating increased risk of cardiovascular disease and breast cancer among women r and omized to hormone replacement therapy  have increased interest in other therapies for menopausal symptoms . Dietary supplements containing isoflavones are widely used as alternatives to hormonal therapies for hot flashes , but there is a paucity of data supporting their efficacy . OBJECTIVE To compare the efficacy and safety of 2 dietary supplements derived from red clover with placebo in symptomatic menopausal women . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial of menopausal women , aged 45 to 60 years , who were experiencing at least 35 hot flashes per week . The study was conducted between November 1999 and March 2001 at 3 US medical centers and included women who were recently postmenopausal ( mean [ SD ] , 3.3 [ 4.5 ] years since menopause ) experiencing 8.1 hot flashes per day . Women were excluded if they were vegetarians , consumed soy products more than once per week , or took medications affecting isoflavone absorption . INTERVENTION After a 2-week placebo run-in , 252 participants were r and omly assigned to Promensil ( 82 mg of total isoflavones per day ) , Rimostil ( 57 mg of total isoflavones per day ) , or an identical placebo , and followed-up for 12 weeks . MAIN OUTCOME MEASURE The primary outcome measure was the change in frequency of hot flashes measured by participant daily diaries . Secondary outcome measures included changes in quality of life and adverse events . RESULTS Of 252 participants , 246 ( 98 % ) completed the 12-week protocol . The reductions in mean daily hot flash count at 12 weeks were similar for the Promensil ( 5.1 ) , Rimostil ( 5.4 ) , and placebo ( 5.0 ) groups . In comparison with the placebo group , participants in the Promensil group ( 41 % ; 95 % confidence interval [ CI ] , 29%-51 % ; P = .03 ) , but not in the Rimostil group ( 34 % ; 95 % CI , 22%-46 % ; P = .74 ) reduced hot flashes more rapidly . Quality -of-life improvements and adverse events were comparable in the 3 groups . CONCLUSION Although the study provides some evidence for a biological effect of Promensil , neither supplement had a clinical ly important effect on hot flashes or other symptoms of menopause Context Research ers have not previously reported the efficacy and safety of parathyroid hormone ( 1 - 84 ) ( PTH ) for the primary prevention of osteoporotic fractures .  Contributions Among 2532 postmenopausal women with osteoporosis r and omly assigned to receive PTH or placebo , PTH decreased new vertebral fractures . The magnitude of the effect depended on assumptions about fractures in the one third of patients who withdrew from the trial prematurely . Adverse effects included hypercalciuria , hypercalcemia , and nausea . Caution Endogenous PTH and vitamin D levels could affect patients response to the drug but were not assessed in the study . Implication s Parathyroid hormone ( 1 - 84 ) effectively prevented new vertebral fractures but also increased hypercalciuria , hypercalcemia , and nausea . The Editors Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing patients to an increased risk for fracture ( 1 ) . Optimal treatment for osteoporosis should improve the amount , density , and quality of bone , thereby reducing skeletal fragility and fractures .  Antiresorptive agents , such as bisphosphonates , are commonly used for treating postmenopausal osteoporosis . Although these agents preserve bone architecture , they do not stimulate new bone formation or improve bone architecture . Anabolic or bone-forming agents are an alternative approach to the treatment of osteoporosis . Research ers have shown that parathyroid hormone ( PTH ) and certain peptide fragments of PTH increase bone mass and improve bone quality ( 2 , 3 ) . Teriparatide , a fragment of human PTH composed of its N-terminal 34 amino acids , has been approved for the treatment of postmenopausal women with osteoporosis who are at high risk for bone fracture . However , research ers have studied this agent only in women with prevalent vertebral fractures ( 4 ) , and data demonstrating prevention of the first vertebral fracture are lacking . We conducted the Treatment of Osteoporosis with Parathyroid Hormone ( TOP ) Study to examine the efficacy and safety of PTH ( 1 - 84 ) versus placebo for treating postmenopausal women with osteoporosis . We design ed the study to examine the change in incidence of all vertebral fractures between the treatment groups . We also design ed the study to examine the efficacy of this new bone-forming agent in preventing a first vertebral fracture in women without a vertebral fracture . Methods Study Participants We included postmenopausal women 45 to 54 years of age if bone mineral density ( BMD ) was 3.0 SDs or more ( T-score 3.0 ) below the mean peak bone mass of young adult women at the lumbar spine , femoral neck , or total hip with no prevalent vertebral fracture or if BMD T-score was2.5 and they had 1 to 4 vertebral fractures before enrollment . We included postmenopausal women 55 years of age or older if BMD T-score was2.5 and they had no vertebral fractures or if BMD T-score was2.0 and they had 1 to 4 vertebral fractures . We excluded women if baseline serum calcium level was greater than 2.66 mmol/L ( > 10.7 mg/dL ) or if urinary calciumcreatinine ratio was 1.0 or more . We included women with mild hypercalcemia ( serum calcium , 2.55 to 2.66 mmol/L [ 10.2 to 10.7 mg/dL ] ) and mild hypercalciuria ( 24-hour urine calcium7.6 mmol [ 302 mg ] ) at baseline . We did not measure baseline levels of serum PTH and vitamin D. We excluded women if they had taken bisphosphonates for a total of more than 12 months or for more than 90 days in the 12 months before enrollment . We allowed  previous estrogen therapy  if it had been discontinued for at least 4 weeks before the screening visit . We excluded women who had received PTH ( or a peptide fragment or analogue ) , PTH-related protein , fluoride , or strontium and those who had a history of metabolic bone disease ( other than osteoporosis ) , nephrolithiasis , or clinical ly significant hepatic or renal disorders . We also excluded women who were taking medications known to affect bone mineral metabolism . The ethics review committee for each center approved the study . All women provided written informed consent . An independent data and safety monitoring board review ed the progress and safety of the study . Study Design We conducted a r and omized , double-blind , placebo-controlled , parallel-group study in 168 centers in 9 countries . We r and omly assigned the study drug to blocks of 4 patients by using a computer-generated algorithm and shipped it in blocks of 4 to each study site . Women at each site were sequentially assigned the uniquely numbered , r and omly assigned study drug treatment kits by telephone . Women were stabilized for at least 2 weeks with supplemental calcium , 700 mg/d citrate salt , and vitamin D3 , 400 U/d , and then received 100 g of recombinant human PTH or placebo daily by subcutaneous injection for 18 months with continued calcium and vitamin D3 supplementation . Patients were instructed to administer the injection in the morning in the thigh or abdomen by using an injector pen . Study Conduct and Outcome Measures The primary end point was the occurrence of new or worsened vertebral fractures ( in all women and in women with and without a prevalent fracture ) identified by radiography at baseline , month 18 , or the final study visit . Radiologists assessed vertebral fractures in a blinded manner at a central reading organization by using a semiquantitative 4-point grading scale ( 5 ) . An incident vertebral fracture ( new or worsened ) was identified by a change in grade of 1 or more from baseline . Secondary outcomes included changes in BMD at lumbar spine , hip , whole body , and forearm ( distal one-third radius ) that we measured by using dual-energy x-ray absorptiometry with Hologic ( Hologic Inc. , Bedford , Massachusetts ) or Lunar ( GE Medical Systems , Madison , Wisconsin ) densitometers ( reported as percentage change from baseline to st and ardize instrumental differences in determining absolute BMD ) and stadiometric measurements of height . We measured whole body and forearm BMD only in a subset of approximately 300 women from selected sites with appropriate software . We reported nonvertebral clinical fractures and bone loss ( > 7 % at lumbar spine or > 9 % at total hip or femoral neck ) as adverse events . We did not distinguish between traumatic and fragility nonvertebral fractures . We used quantitative computed tomography ( 6 , 7 ) to evaluate the effects of PTH treatment at month 18 on volumetric cortical and trabecular BMD at lumbar vertebra ( L3 ) and the hip in 122 consenting women from a single center at which the technique was available . We assessed bone turnover markers ( serum bone-specific alkaline phosphatase and urinary N-telopeptides of type I collagen ) in the first 600 r and omly assigned women in the study . We measured bone-specific alkaline phosphatase by using the T and em R-Ostase immunoradiometric assay ( interassay coefficient of variation , 8 % ) ( Hybritech , San Diego , California ) . We measured N-telopeptides of type I collagen by using Osteomark enzyme-linked immunoabsorbent assay kits ( interassay coefficient of variation , 4.0 % ) ( Wampole Laboratories , Princeton , New Jersey ) normalized to urine creatinine concentrations . We made safety assessment s at months 1 , 3 , 6 , 9 , 12 , 15 , and 18 that included physical examinations , vital signs , electrocardiography ( months 1 , 12 , and 18 ) , adverse-event monitoring and central clinical laboratory assessment s consisting of chemistry ( including serum total calcium and creatinine ) , hematology , and urinalysis ( including 24-hour urine collection s and fasting , morning urinary calciumcreatinine ratios ) . Adverse events were reported spontaneously by patients , captured in a patients diary , or reported by a patient in response to an open-ended question from clinical study personnel . We used a central laboratory normal range for serum total calcium level of 2.15 to 2.55 mmol/L ( 8.6 to 10.2 mg/dL ) . We performed an analysis for antibodies to PTH with a vali date d electrochemiluminescent immunoassay by using biotinylated recombinant human PTH ( range , 26.3 to 2632.5 pmol/L ; intra-assay coefficient of variation , 8 % to 16 % ) ( Igen International , Inc. , Gaithersburg , Maryl and ) . We obtained iliac crest bone biopsy specimens at month 12 or 18 from a subset of 40 consenting women after tetracycline double-labeling ( 8) that we examined for abnormal bone structure . We anticipated that women might need to discontinue calcium supplementation and reduce the dosing frequency of the study drug to prevent excessive increases in serum calcium level , urinary calcium level , or both . We conservatively predefined hypercalcemia as a single , unconfirmed , predose serum total calcium value greater than 2.66 mmol/L ( > 10.7 mg/dL ) and hypercalciuria as a 24-hour urinary calcium value of 7.6 mmol or more ( 302 mg ) ( increased to > 9.0 mmol [ > 360 mg ] during the study ) or a fasting urinary calciumcreatinine ratio of 1.0 or more . If a woman developed hypercalcemia or hypercalciuria , we discontinued the daily calcium supplementation ; if either condition continued , we reduced the dosing frequency of the study drug . Statistical Analysis We estimated the sample size for our study by assuming that 67 % of the patients would not have a prevalent fracture ; that the 18-month vertebral fracture incidence for patients with and without a prevalent fracture who received placebo would be 10 % and 2.5 % , respectively ; and that 20 % of the patients in each group would discontinue the study early without a new or worsened fracture .  We expected a sample of 2600 patients ( 1300 per treatment group ) to provide at least 90 % power to detect a significant 60 % or greater reduction in vertebral fracture incidence in the PTH treatment group compared with the placebo group ( 2-sided level of 0.05 ) . We analyzed data by using SAS software , version 8.0 ( SAS Institute , Inc. , Cary , North Carolina ) . We used descriptive statistics to summarize demographic and other baseline variables . We assessed comparability of the treatment groups at baseline by using t-tests for continuous We examined whether estradiol and norethindrone hormone therapy ( HT ) prevented decline in delayed verbal recall in older women with normal to mildly impaired memory functioning . This was a 2-year , r and omized , double-blind , placebo-controlled trial of 142 women aged 61 - 87 , r and omly assigned to receive 1 mg 17-beta estradiol daily and 0.35 mg norethindrone 3 days/week or daily placebo for 2 years . The primary outcome was short-delay verbal recall of the California Verbal Learning Test ( CVLT ) . To look for differences in response to HT by baseline short-delay recall , we examined the primary outcome in participants grouped according to whether their baseline scores were below average for the age group or greater than or equal to this score and according to whether they met criteria for Mild Cognitive Impairment ( MCI ) or not . 133 women completed 1 year of the trial and 128 completed 2 years . Prespecified covariates in all repeated measures analyses of covariance ( RANCOVA ) included age , education , APOE epsilon4 , and prior HT use . RANCOVA showed no overall significant treatment effects at year 1 or year 2 . After testing for an interaction , which was significant ( p=0.02 ) , we found that women in the HT group who scored at or above the average showed significantly less decline than the placebo group in short-delay verbal recall after 1 year , p=0.007 and 2 years , p=0.01 . No treatment effects were found in women below the average in either year . When grouped according to whether the participant met criteria for MCI , the interaction between treatment group and MCI subgroup was not significant . These results suggest that benefits of estrogen exposure may be limited to those with average to above average scores on the delayed verbal recall .  HT dose and formulation may have contributed to these beneficial outcomes . Replication is warranted before recommendations can be made in the clinical setting The profound disparities between the largely positive basic science findings of gonadal steroid action in brain and the adverse outcomes of recent hormone therapy clinical trials in women who are either aged postmenopausal or postmenopausal with Alzheimer 's disease have led to an intense re assessment of gonadal hormone action and the model systems used in basic and clinical science . The power of model systems is their predictive validity for a target population --in this case , menopausal women considering the health benefits and risks of hormone therapy .  Analysis of the model systems used across the basic to clinical research continuum separate into two broad classes : those that use prevention interventions in healthy organisms and those that use hormone interventions in organisms with compromised neurological function . Basic science analyses that led to elucidation of the neurotrophic and neuroprotective effects of estrogen and the underlying mechanisms of action typically used a prevention-based experimental paradigm . This paradigm relies on healthy neurons/brains/animals/humans as the starting foundation followed by exposure to estrogen/hormone followed by exposure to neurodegenerative insult . The prevention paradigm in basic science analyses parallels the analyses of Sherwin and colleagues ( Psychoneuroendocrinology 13 : 345 - 357 , 1988 ) , who investigated the cognitive impact of estrogen therapy in women with surgical- or pharmacological-induced menopause . Observational retrospective and prospect i ve studies are also consistent with the healthy cell bias of estrogen action and a prevention paradigm of estrogen or hormone therapy intervention . For the most part , the epidemiological observational data indicate reduction in the risk of Alzheimer 's disease in women who began  estrogen or hormone therapy  at the time of the menopause . In contrast , studies that fall within the second class , hormone intervention in organisms with compromised neurological function -- that is , a treatment paradigm -- exhibit a mixed profile . In a r and omized double-blind clinical trial of  estrogen therapy in a cohort of women aged 72 or more years and diagnosed with Alzheimer 's disease , estrogen therapy result ed in a modest benefit in the short term ( 2 months ) and adverse progression of disease in the long term ( 12 months ) . In the Women 's Health Initiative Memory Study ( WHIMS ) cohort of women 65 or more years of age , with no indicators of neurological disease but with variable health status , estrogen and hormone therapy for 5 years increased the risk of developing Alzheimer 's disease . These data would suggest that as the continuum of neurological health progresses from healthy to unhealthy , so too do the benefits of estrogen or hormone therapy . If neurons are healthy at the time of estrogen exposure , their response to estrogen is beneficial for both neurological function and survival . In contrast , if neurological health is compromised , estrogen exposure over time exacerbates neurological demise . Based on these and other data , a hypothesis of a healthy cell bias of gonadal hormone action is put forth . The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the domains of scientific inquiry and to access future applications of estrogen and hormone therapeutic interventions BACKGROUND Studies of weight loss and changes in bone mineral density ( BMD ) have primarily been short-term trials in obese subjects . OBJECTIVE We examined the effects of a 5-yr intervention design ed to prevent menopausal weight gain or promote modest weight loss on BMD in premenopausal women participating in the Women 's Healthy Lifestyle Project . DESIGN We enrolled 373 premenopausal women ( age 44 - 50 yr ) and r and omly assigned them to either lifestyle intervention ( 175 women , low-fat dietary modification , weight loss , and physical activity intervention ) or control group ( 198 women ) .  BMD and body weight were measured at baseline , annual follow-up visits ( 18 , 30 , 42 , and 54 months ) , and two postintervention follow-ups ( 66 and 78 months ) . BMD was measured by dual x-ray absorptiometry . RESULTS Over the 54 months of intervention , women in the intervention group lost 0.4 kg , whereas control women gained 2.6 kg ( P = 0.011 ) . The intervention group experienced significantly greater hip bone loss ( -0.20%/yr ) than the control group ( -0.03%/yr ) . During the postintervention , differences in rates of bone loss disappeared . When considering both menopausal status and use of hormone therapy ( HT ) , the annualized BMD changes were lower in women reporting HT use ; nevertheless , among women on HT , those who lost more than 3 % body weight experienced greater total hip BMD loss ( -0.25%/yr ) compared with those who gained weight ( -0.02%/yr ) ( P = 0.025 ) . CONCLUSIONS Women r and omized to a lifestyle intervention aim ed at preventing menopausal weight gain or promoting modest weight loss experienced greater rates of hip bone loss than control women BACKGROUND AND AIMS Oxidative stress has been advocated as a major cause for cardiovascular disease ( CVD ) , and low plasma antioxidant concentrations are associated with endothelial dysfunction , the first step towards atherosclerosis . However , although the antioxidant content in fruits and vegetables may explain at least in part their protective effect against CVD , supplementation with antioxidant vitamins fails to improve endothelial function and reduce CVD risk . The aim of this study was to investigate the impact of a diet rich in antioxidants on endothelial function measured by flow-mediated dilatation ( FMD ) in volunteers at low cardiovascular risk . METHODS AND RESULTS In a crossover trial , 24 subjects ( 13 women , mean age 61 ± 3 years ) , received , in a r and omised order , a 14-day high ( HT ) and a 14-day low ( LT ) antioxidant diets , with a 2-week wash-out ( WO ) in between . Both diets were comparable in daily portions of fruits and vegetables , and in alcohol , fibre and macronutrient intake , but differed in their total antioxidant capacity . Before and after each diet , anthropometrics , blood pressure , fasting plasma glucose , lipid profile , hepatic enzymes , circulating antioxidant concentrations , high sensitivity C-reactive protein ( hs-CRP ) and FMD were assessed . FMD increased significantly during the HT diet compared to the LT ( p < 0.000 ) . FMD values were 2.3 % higher after HT compared with LT ( p < 0.001 ) after adjustment for age , gender and diet order . α-tocopherol increased significantly ( p < 0.05 ) and hs-CRP and of γ-glutamyltranspeptidase decreased significantly ( p < 0.05 and p < 0.01 , respectively ) during the HT diet , compared with the LT diet . CONCLUSIONS A short-term HT diet improves endothelial function in volunteers at low cardiovascular risk , which may further reduce their risk of CVD OBJECTIVES To describe the effects of low dose hormonal replacement therapy ( LD-HRT ) on quality of life in early postmenopausal women , since the postmenopausal estrogen deprivation in mid age women often brings along a series of changes and symptoms , which may greatly affect quality of life . METHODS Fifty normal postmenopausal women were recruited and r and omly treated with LD-HRT , 17beta-estradiol ( 1 mg/day ) and norethisterone acetate ( 0.5 mg/day ) ( LD-HRT ) or calcium supplement ( controls ) . No significant differences in age , age at menopause , the presence of chronic diseases and socio-economic status were present in the two groups . The Women 's Health Question naire ( WHQ ) , a vali date d quality -of-life instrument for perimenopausal and postmenopausal women , was administered at baseline and after 6 and 12 weeks of treatment in both groups . RESULTS At baseline no significant differences in WHQ scores were present in the two groups . In the control group the scores in all different areas showed no significant modification either after 6 and 12 weeks of observation . Conversely , the LD-HRT group showed a significant decrease in the scores of vasomotor symptoms , somatic symptoms , anxiety/fear , depressed mood and sleep problem items . No effects on memory/concentration and menstrual symptoms areas were evident . CONCLUSION Although quality of life is also and may be mainly influenced by socio-economic and cultural factors , LD-HRT definitively can improve not only vasomotor symptoms , but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women CONTEXT Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions , particularly memory . OBJECTIVE The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women . DESIGN This study was a r and omized , double-blind , placebo-controlled clinical trial . SETTING Participants were women from 14 of 40 clinical centers of the Women 's Health Initiative ( WHI ) . PARTICIPANTS Postmenopausal women ( 1416 ) aged 65 yr and older , free of probable dementia , and enrolled in WHI and the WHI Memory Study ( WHIMS ) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr , were studied . INTERVENTION Intervention was conjugated equine estrogen ( CEE ; 0.625 mg ) with 2.5 mg medroxyprogesterone acetate ( MPA ) in one daily tablet ( CEE + MPA ) or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS CEE + MPA had a negative impact on verbal memory ( P < or= 0.01 ) and a trend to a positive impact on figural memory ( P = 0.012 ) over time compared with placebo , but other cognitive domains were not affected . Both effects on memory were evident only after long-term therapy . CEE + MPA did not significantly influence positive affect , negative affect , or depressive symptoms . CONCLUSIONS The effect of CEE + MPA on cognitive function varies across cognitive domains in older women , reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain . Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research Fracture prevention is one of the public health priorities worldwide . Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis , the most common metabolic bone disease . Different effective treatments for osteoporosis are available . Hormone replacement therapy ( HRT ) at different doses rapidly normalizes turnover , preserves bone mineral density ( BMD ) at all skeletal sites , leading to a significant , reduction in vertebral and non-vertebral fractures .  Tibolone , a selective tissue estrogenic activity regulator ( STEAR ) , is effective in the treatment of vasomotor symptoms , vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT . Selective estrogen receptor modulators ( SERMs ) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures . The combination of bazedoxifene and conjugated estrogens , defined as tissue selective estrogen complex ( TSEC ) , is able to reduce climacteric symptoms , reduce bone turnover and preserve BMD . In conclusion , osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms . The use of a st and ard dose of HRT for osteoporosis prevention is based on biology , epidemiology , animal and pre clinical data , observational studies and r and omized , clinical trials . The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover , with compelling scientific evidence Summary The Women 's Health Initiative ( WHI ) double-blind , placebo-controlled clinical trial r and omly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo , with average intervention period of 7.0 years . The trial was design ed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture , and secondarily , total fracture and colorectal cancer . Introduction This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data , with emphasis on fractures , cardiovascular disease , cancer , and total mortality . Methods WHI calcium and vitamin D r and omized clinical trial ( CT ) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation , and these data were contrasted and combined with corresponding data from the WHI prospect i ve observational study ( OS ) . Results Among women not taking personal calcium or vitamin D supplements at baseline , the hazard ratio [ HR ] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 ( 95 % confidence interval ( CI ) , 0.38–1.00 ) . In combined analyses of CT and OS data , the corresponding HR was 0.65 ( 95 % CI , 0.44–0.98 ) . Supplementation effects were not apparent on the risks of myocardial infa rct ion , coronary heart disease , total heart disease , stroke , overall cardiovascular disease , colorectal cancer , or total mortality , while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive . Conclusion Though based primarily on a subset analysis , long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women . Other health benefits and risks of supplementation at doses considered , including an elevation in urinary tract stone formation , appear to be modest and approximately balanced BACKGROUND Bone mass measurements are widely used to diagnose osteoporosis and identify patients at risk for fractures . Recent studies have shown that reduced bone mass is also predictive of all-cause and cardiovascular mortality in healthy postmenopausal women . Among chronic hemodialysis patients reduced bone mass result ing from the combined effects of age-related factors and renal osteodystrophy has been associated with vascular calcification . In this prospect i ve study , we investigated the ability of bone mass measurements to predict mortality in chronic hemodialysis patients . METHODS Eighty eight patients underwent hip bone mass measurements by dual energy x-ray absorptiometry ( DEXA ) and were followed up for a mean of 3.5 years . Eleven patients received renal transplants and were therefore excluded . Forty of the remaining patients died , predominantly due to cardiovascular causes ( 43 % ) . RESULT Cox regression analysis showed patient age , osteoporosis or osteopenia , and baseline average calcium x phosphate product ( Ca x P ) to be independently predictive of increased mortality . Patients with osteopenia or osteoporosis had a 3.3- and 4.3-fold increased risk of death , respectively . A Ca x P of > or=5.0 mmol2/L2 predicted a threefold increased risk of death . Previous renal transplantation predicted a lower mortality . CONCLUSIONS This study has shown for the first time that reduced total hip bone mass is an independent predictor of all-cause mortality among chronic hemodialysis patients . Our findings suggest that reduced bone mass and elevated Ca x P may be involved in the pathogenesis of cardiovascular disease in these patients but further research is required to investigate the possible mechanisms for these associations During the past 30 years , fluoride salts have been studied as agents for the treatment of osteoporosis in postmenopausal women with the expectation that stimulation of osteoblastic proliferation and activity and the subsequent increase in bone formation would be followed by a significant decrease in fracture rates [ 1 - 3 ] . It is widely accepted that fluoride is effective in increasing trabecular bone mass in the spine [ 4 ] . However , discrepant results have been obtained from studies evaluating the effects of fluoride salts on cortical bone mass and , more important , on the quality of the newly synthesized bone and on vertebral and nonvertebral fracture rates [ 5 - 9 ] . These differences are probably related to differences in fluoride dose , formulation , and regimen ; duration of therapy ; and treated population s. Because bone-forming agents such as fluoride are expected to work mainly by increasing bone mineral content without restoring disrupted bone tissue integrity , they may be particularly useful in patients with mild to moderate osteoporosis in whom the microarchitecture of the skeleton is not excessively damaged . To test this hypothesis , we studied the effect of low-dose fluoride ( sodium monofluorophosphate [ MFP ] ) plus calcium in a 4-year , r and omized , double-blind , controlled clinical trial in postmenopausal women with moderately low bone mineral density ( BMD ) of the spine . Methods Patients Our study included white postmenopausal women with lumbar ( L2 to L4 ) BMD of the spine below the 90th percentile of the distribution of BMD of the spine seen in Belgian women with osteoporosis [ 10 , 11 ] . This degree of bone loss corresponded to a T-score of 2.5,in accordance with the operational definition of osteoporosis recently proposed by a World Health Organization study group [ 12 ] . Patients were included in the study regardless of whether they had previously had vertebral or nonvertebral fractures ; most of the patients were thought to be free of vertebral fractures at enrollment . Previous hip fracture was an exclusion criterion . All patients were free of other causes of osteoporosis , such as diseases or medications known to interfere with bone metabolism ; none had been treated with any drug for postmenopausal osteoporosis ; and no such treatment was allowed during the study . Hormone replacement therapy was continued , for ethical reasons , in women for whom it had been prescribed before enrollment for purpose s other than bone therapy . R and omization was not stratified with respect to hormone replacement therapy . Patients with bone diseases other than osteoporosis , renal insufficiency , hypochlorhydria , or severe chronic disorders that could have interfered with the study were excluded . Study Design Patients were r and omly assigned in a blinded manner to one of two therapeutic groups . Every day for 4 years , they received either two chewable tablets that each contained 76 mg of MFP ( 10 mg of equivalent fluoride [ fluoride ion ] ) and 1250 mg of calcium carbonate ( 500 mg of equivalent calcium ) or two chewable tablets that each contained 1250 mg of calcium carbonate alone and were similar in appearance to the MFP-plus-calcium tablets . Total daily dosages , therefore , were 20 mg of equivalent fluoride plus 1000 mg of calcium in the MFP-plus-calcium group and 1000 mg of calcium in the calcium-only group . The two tablets were taken at different meals . We determined compliance at each study visit by asking each patient for the number of days on which she had not taken the tablets and by counting the unused tablets . Compliance was expressed as the percentage of tablets taken ( 100 % if the patient had taken all of the tablets ) . Patients received r and omization numbers sequentially . R and omization was computer generated in blocks of four according to a strict st and ard operating procedure by persons who had no contact with the persons in the center who assigned patients to study groups . The r and omization code was kept at the study sponsor 's facility under secure conditions that were detailed in writing . The clinical research center was given opaque , sealed envelopes , each of which contained the code for one patient . Treatment assignment and other relevant information were thus concealed and were to be revealed only in the case of a medical emergency . Blinding was achieved by using the following procedures . First , the persons who did the visual readings of the spine radiographs saw the codes only after the results were analyzed . Second , the data were analyzed under blinded conditions : that is , a first analysis was done with groups A and B ; the analysts did not know which group had received which treatment . Efficacy Evaluation Criteria The primary end point was the number of patients with new vertebral fractures during the 4-year treatment period , in accordance with recently published guidelines for the evaluation of drugs to be registered in Europe for the prevention or treatment of osteoporosis [ 13 ] . St and ardized lateral radiographs of the thoracic and lumbar spine were obtained at enrollment and at each year of follow-up , for up to 4 years , in a single radiology center . The radiographs were sent to an independent assessor . Films were digitized , and the anterior , middle , and posterior heights of each vertebral body from the fourth thoracic ( T4 ) to the fifth lumbar ( L5 ) were determined ( accuracy of the digitizer , 0.025 mm ) by a computer program . This was done by persons with no knowledge of treatment assignment or film sequence . A new  vertebral fracture ( incident fracture ) was defined as a reduction of at least 20 % and an absolute decrease of at least 4 mm in any height of at least one vertebral body between enrollment and the latest follow-up film . All fractures , including borderline cases , were confirmed by visual reading . This definition was applied to vertebrae that were not fractured at enrollment , whereas fractures present at enrollment were determined on the digitized enrollment radiographs by using the Melton-Riggs 25 % unadjusted algorithm [ 14 ] . The possible progression of such baseline lesions was assessed with the Vertebral Deformity Index obtained for each vertebra ( T5 through L5 ) ; these were then summed to obtain the Spine Deformity Index , a continuous measure of vertebral deformities [ 15 ] . The Spine Deformity Index was also used as a secondary variable in patients with incident or progressing vertebral deformities , in whom it was expressed as the mean change between the last observed value and baseline . Bone mineral density was measured by using dual-energy x-ray absorptiometry on the same densitometer ( Hologic QDR 1000 , Waltham , Massachusetts ) at 6-month intervals at the lumbar spine ( L2 to L4 ) and the nondominant hip ( total hip ) after previously described and vali date d procedures were performed [ 11 , 16 ] . In our h and s , the long-term coefficients of variation of dual-energy x-ray absorptiometry are 0.8 % for BMD of the spine and 1.1 % for BMD of the total hip [ 17 ] . Biochemical determinations of bone remodeling were made at 6-month intervals . Bone formation was assessed by radioimmunoassay of serum bone-specific alkaline phosphatase ( Ostase , Hybritech , San Diego , California ) . For bone resorption , we measured the ratio of urinary hydroxyproline to creatinine on the second fasting urine spot ( 2-hour morning urine ) ( Hypronostikon kit , Organon Technika , Oss Boxtel , the Netherl and s ) . All peripheral ( nonvertebral ) fractures that occurred during the study were recorded independently of the nature and severity of the trauma that may have determined them . Statistical Analysis All analyses were done according to the intention-to-treat approach : that is , all patients who had at least one valid measurement after r and omization were considered in the analysis , whether they were still taking the study drug or not . In the case of drop-out and , thus , discontinuation of therapy with the study medication , the patient was invited to return to the clinic at annual intervals ( for 4 years , if possible ) so that the radiography necessary to record outcome could be done . An exact- significance chi-square test was done to compare the number of patients with new vertebral fractures in the two groups . We calculated 95 % CIs for vertebral fracture rates in each study group and for the difference in rates between the two groups , along with the point estimates of these rates . These rates were also expressed in terms of the number needed to treat for 4 years to prevent one fracture , including values for the lower and upper bounds of the 95 % CIs . Changes in the Spine Deformity Index in patients with incident or progressing vertebral deformities were compared by analysis of variance . Analysis of variance for repeated measurements was used to compare the absolute values for BMD of the spine over the course of the study in the two groups . Analysis of variance for repeated measurements was also done to compare BMD of the total hip and percentage changes in biochemical markers of bone remodeling throughout the study . All P values are two-tailed . All statistical analyses were done with the SPS/WIN 6.2 statistical package ( SPS , Inc. , Chicago , Illinois ) . Role of Study Sponsor The trial was approved by the Ethical Committee of Liege University ( registration no. 90/43 - 1262 of 14 May 1990 ) , and all patients gave full informed consent before inclusion . The Rotta Research Group , which markets MFP and calcium combinations in Germany , Italy , and other countries , provided the drugs and funding for the study . Scientists from the Rotta Research Group were directly involved in the design , monitoring , and data management of the study and agreed to be listed as authors . However , the Rotta Research Group as a corporate entity had no control over the decision to approve or su bmi t the manuscript for publication . Results Two hundred patients were enrolled in the study . The characteristics of the entire patient sample ( 100 patients were assigned to each group ) at enrollment are shown in Table 1 . From a longitudinal prospect i ve study , 160 women with spontaneous menopause and without steroid medication were followed during the transition from pre- to  postmenopause  . After 12 years 152 women were still participating in the study . Blood sample s were drawn every 6 months until 1 year after the menopause and every 12 months thereafter . Measurements of bone mineral density ( BMD ) on the forearm were performed every second year . All women routinely completed a question naire concerning symptoms frequently attributed to the climacteric period . All data were grouped around the onset of the menopause , thereby allowing longitudinal evaluation of the changes in the variables from the premenopausal to the postmenopausal period . The beginning of the perimenopausal period was characterized by transitory elevations of follicle-stimulating hormone ( FSH ) . A significant increase in serum levels of gonadotropins was observed for both FSH and luteinizing hormone ( LH ) from about 5 years before the menopause . Within the 6 month period around the menopause there was a further increase which culminated within the first postmenopausal year for LH and 2 - 3 years postmenopause for FSH . Thereafter , a continuous decrease in LH occurred over the following 8 years . With respect to FSH , there was a slight decline starting about 4 years postmenopause . During the premenopausal period an increasing frequency of inadequate luteal function or anovulation occurred and , in the postmenopausal years , the serum levels of progesterone ( P ) were invariably low . Gradually , the ratio between estrone ( E1 ) and 17-beta-estradiol ( E2 ) increased , reflecting the declining follicular steroidogenesis . A marked decrease in estrogen levels occurred during the 6 month period around the menopause , most pronounced in E2 . During the next 3 years , the levels of E2 and E1 showed an essentially parallel , moderate decline . Around the menopause , serum levels of testosterone ( T ) , delta 4- and rostenedione ( A ) and sex hormone-binding globulin ( SHBG ) showed small but significant decreases . From about 3 years postmenopause , the levels were relatively constant over the following 5 years . A decrease in BMD was observed in the postmenopause , and from about 3 years postmenopause , estradiol correlated positively with BMD . Before , as well as after the menopause , body mass index ( BMI ) showed an inverse correlation with SHBG . Postmenopausal and rostenedione correlated positively with E1 , E2 and T. BMI correlated positively with E1 and E2 . The concentrations of the free fraction of E2 and T are dependent on the levels of SHBG , which in turn has a negative correlation with BMI . The impact of this will influence the severity of symptoms , the degree of bone loss and the need for supplementary therapy * The up date s are underlined for quick reference . INTRODUCTION A critical need exists for efficient , measurable systems of disease management that reconcile conflicts between socioeconomic responsibility and patient welfare . Clinical guidelines have become an important component of these systems because they address elements of care that are effective and that reduce the variability in our approach to patient management . The American Association of Clinical Endo-crinologists ( AACE ) 2001 Medical Guidelines for Clinical Practice for the Prevention and Management of Postmenopausal Osteoporosis address the prevention , diagnosis , and management of postmenopausal osteoporo-sis , a disorder that is recognized as a major public health problem because of its physical and socioeconomic consequences . They are intended to simplify medical decision making and to help physicians and their patients make good decisions about skeletal health and postmenopausal osteoporosis . The specific goals of these guidelines are to reduce the incidence of fractures related to osteoporosis and to achieve the highest quality of life for individual patients by using the most effective and efficient methods of diagnosis and management . In the preparation of this 2001 edition , reports in the peer- review ed literature dealing with prevention , diagnosis , and treatment of postmenopausal osteoporosis , which were published and indexed between 1996 ( the publication date of the previous edition of these guidelines ) and January 2001 , were identified by computer search , review ed , and grade d for clinical relevance and scientific merit . Although cost-effectiveness was carefully considered , variabilities in actual costs could not be accurately determined . Therefore , cost-effectiveness modeling was not undertaken . Whenever possible , recommendations were based on r and omized , prospect i ve , double-blind studies of well-defined patient population s. Studies that used the most relevant clinical endpoint , fracturing , were considered " level 1 " evidence . When level 1 evidence was not available , recommendations were based on cross-sectional studies , investigations that tested smaller or nonr and omized patient population s , or studies that tested secondary or surrogate clinical endpoints for fracture , such as bone mineral density ( BMD ) or bone turnover markers , in treated population s ( level 2 evidence ) . When stronger evidence was not available , review s , editorials , and expert opinions were used ( level 3 evidence ) . We recognize that the process of developing clinical guidelines necessarily results in a narrowing and codifica-tion of clinical choices , which can be inappropriate in some clinical situations . Because the application of objective information to the specific needs of patients is the ultimate responsibility of the practicing physician , clinical practice guidelines are not intended to be rigid or restrictive , nor There is growing and consistent evidence that estrogen use in postmenopausal women is associated with a substantial reduction in the occurrence of cardiovascular disease . However , remarkably little is known about the biological mechanisms by which estrogen therapy may influence risk . Even less information is available on the cardiovascular effects of combined estrogen-progestin use . PEPI was not design ed to test whether estrogen and estrogen-progestin therapy is efficacious in the prevention of cardiovascular disease , as a much larger trial with clinical disease outcomes is needed to answer that question . However , PEPI will provide critical evidence regarding the potential effectiveness of the various estrogen and estrogen/progestin regimens ni altering risk factors for cardiovascular disease in women . Detailed information on factors such as adherence , side effects , and general patient acceptability will also be ascertained . The main results from PEPI will provide the scientific community with information on the basic actions of estrogen and estrogen/progestin therapy  on four biological systems believed to be causally associated with cardiovascular disease occurrence . Further , since the trial is design ed to continue for 3 years , PEPI will be able to provide information on longer term as well as short-term effects on these systems . Finally , the results from PEPI should enable women and their physicians to select an optimal hormonal regimen , i.e. , one that is acceptable , safe , and provides the most beneficial and least deleterious changes in cardiovascular and other risk factors Objective To evaluate the effects of electro-acupuncture ( EA ) and hormone therapy ( HT ) on vasomotor symptoms in women with a history of breast cancer . Methods Forty-five women were r and omized to EA  ( n = 27 ) for 12 weeks or HT ( n = 18 ) for 24 months . The number of and distress caused by hot flushes were registered daily before , during and up to 24 months after start of treatment . Results In 19 women who completed 12 weeks of EA , the median number of hot flushes/24 h decreased from 9.6 ( interquartile range ( IQR ) 6.6–9.9 ) at baseline to 4.3 ( IQR 1.0–7.1 ) at 12 weeks of treatment ( p < 0.001 ) . At 12 months after start of treatment , 14 women with only the initial 12 weeks of EA had a median number of flushes/24 h of 4.9 ( IQR 1.8–7.3 ) , and at 24 months seven women with no other treatment than EA had 2.1 ( IQR 1.6–2.8 ) flushes/24 h. Another five women had a decreased number of flushes after having additional EA . The 18 women with HT had a baseline median number of flushes/24 h of 6.6 ( IQR 4.0–8.9 ) , and 0.0 ( IQR 0.0–1.6 ; p = 0.001 ) at 12 weeks . Conclusion Electro-acupuncture is a possible treatment of vasomotor symptoms for women with breast cancer and should be further studied for this group of women Studies that evaluate the influence of gastric bypass ( RYGP ) on bone mass are limited to short-term follow-up . We analysed changes in bone mineral density ( BMD ) three years after surgery and evaluated the main determinants of the development of bone disease . Prospect i ve study of 59 morbidly obese white women aged 46 ± 8 years . BMD scanning using DEXA and plasma determinations of calcium , parathyroid hormone , 25-hydroxyvitamin D and insulin-like growth factor-I were made prior , at 12 months and 3 years after surgery . In the first postoperative year BMD decreased at femoral neck ( FN ) 10.2 % and in the lumbar spine ( LS ) 3.2 % , in the third year it additionally decreased 2.7 % and 3.1 % , respectively . BMD at both sites remained above the values of women of the same age . In the follow-up , 1.7 % developed osteoporosis at FN and 6.8 % at LS . Patients with bone disease were older , the percentage of women with menopause was greater in this group and had lower initial and final values of lean mass . The percentage of BMD loss at FN remained positively associated with the percentage of lean mass loss [ β 0.304 , p = 0.045 ] , and menopause [ β 0.337 , p = 0.025 ] . Major osteoporotic fracture and hip fracture risk was low even in menopausal patients ( 3.1 % and 0.40 % , respectively ) . After RYGP menopausal women and those with greater lean mass loss are at higher risk of BMD loss but progression to osteoporosis is uncommon and the risk of fracture is low
Women taking HT had a significantly decreased incidence of fracture with long-term use .
Research ers found no strong evidence that HT has a clinical ly meaningful impact on the incidence of colorectal cancer .
AUTHORS ' CONCLUSIONS : Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT , provided they do not have specific contraindications .
HT may be unsuitable for some women , including those at increased risk of cardiovascular disease , increased risk of thromboembolic disease ( such as those with obesity or a history of venous thrombosis ) or increased risk of some types of cancer ( such as breast cancer , in women with a uterus ) .
The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented .
HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia , nor for prevention of deterioration of cognitive function in postmenopausal women .
Although HT is considered effective for the prevention of postmenopausal osteoporosis , it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable .
BACKGROUND : Hormone therapy ( HT ) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease , osteoporosis and  dementia in older women .
This is an up date d version of a Cochrane review first published in 2005 .
OBJECTIVES : To assess effects of long-term HT ( at least 1 year 's duration ) on mortality , cardiovascular outcomes , cancer , gallbladder disease , fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment .