Managing menopause. A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease Postmenopausal Hormone Use and Secondary Prevention of Coronary Events in the Nurses' Health Study: A Prospective, Observational Study Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. 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 Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies? Remnant-like lipoproteins, hormone therapy, and angiographic and clinical outcomes: the Women's Angiographic Vitamin & Estrogen Trial. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. Evidence-based review of therapies at the menopause. HRT and cardiovascular disease. Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy. Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Women and Menopause: Beliefs, Attitudes, and Behaviors. The North American Menopause Society 1997 Menopause Survey DHEA, important source of sex steroids in men and even more in women. Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Synopsis of the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Changes in the Use of Postmenopausal Hormone Therapy after the Publication of Clinical Trial Results Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Dietetic guidelines: diet in secondary prevention of cardiovascular disease. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women. Osteoporosis in menopause. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Menopause hormonal therapy in women with systemic lupus erythematosus. 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 and Alzheimer disease dementia Interleukin-10 concentration and coronary heart disease (CHD) event risk in the estrogen replacement and atherosclerosis (ERA) study. Elevated levels of sE-selectin in post-menopausal females are decreased by hormone replacement therapy to levels observed in pre-menopausal females. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. The effects of a soy rich diet on serum lipids: the Menfis randomized trial. Exercise effects on hip bone mineral density in older, post-menopausal breast cancer survivors are age dependent Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? Menopause and modifiable coronary heart disease risk factors: a population based study. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial Reproductive hormone exposure timing and ischemic heart disease: Complicated answers to a simple question. A double-blind, placebo-controlled trial of donepezil for the treatment of menopause-related cognitive loss. 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. Escitalopram versus ethinyl estradiol and norethindrone acetate for symptomatic peri- and postmenopausal women: impact on depression, vasomotor symptoms, sleep, and quality of life Impact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer. Prognostic role of flow-mediated dilation and cardiac risk factors in post-menopausal women. Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Age at natural menopause in relation to all-cause and cause-specific mortality in a follow-up study of US black women. Abnormal uterine bleeding in pre-menopausal women. Screening for Breast Cancer in Average-Risk Women: A Guidance Statement From the American College of Physicians Ten years post-menopausal hormone replacement therapy--effect on lipoproteins. Influence of exercise on mood in postmenopausal women. The Effects of a Multimodal Intervention Trial to Promote Lifestyle Factors Associated With the Prevention of Cardiovascular Disease in Menopausal and Postmenopausal Australian Women Hormone replacement therapy use and menopausal symptoms among women participating in a behavioral lifestyle intervention. Physical activity for the prevention and treatment of major chronic disease: an overview of systematic reviews Long-Term Prevention with Hormone-Replacement Therapy after the Menopause: Which Women should be Targeted? Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy Menopausal hormone therapy and risks of melanoma and nonmelanoma skin cancers: women's health initiative randomized trials. Prevention of early postmenopausal bone loss with cyclical etidronate Some problems with Cochrane reviews of diet and chronic disease Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women 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. Menopause Is Associated with Accelerated Lung Function Decline Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Cognitive effects of estradiol after menopause Effect of androgens combined with hormone therapy on quality of life in post-menopausal women with sexual dysfunction Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients. Menopause and risk factors for coronary heart disease. Overview of Reviews The prevention of eczema in infants and children: an overview of Cochrane and non-Cochrane reviews. Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence Psychological interventions for needle-related procedural pain and distress in children and adolescents. Menopausal Symptoms in Older Women and the Effects of Treatment With Hormone Therapy Phase III randomized equivalence trial of early breast cancer treatments with or without axillary clearance in post-menopausal patients results after 5 years of follow-up. Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study Effects of estrogen with and without progestin on urinary incontinence. Effects of hormone replacement therapy on muscle performance and balance in post-menopausal women. New findings from non-linear longitudinal modelling of menopausal hormone changes. Usefulness of Pravastatin in Primary Prevention of Cardiovascular Events in Women: Analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA Study) The effect of hormone therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone Therapy trial 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. Cognitive behavioral therapy and physical exercise for climacteric symptoms in breast cancer patients experiencing treatment-induced menopause: design of a multicenter trial C-Reactive Protein Levels Are Not Associated with Increased Risk for Colorectal Cancer in Women Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review Bias due to selective inclusion and reporting of outcomes and analyses in systematic reviews of randomised trials of healthcare interventions. No effect of HRT on health-related quality of life in postmenopausal women with heart disease. Prevalence and treatment of menopausal symptoms among breast cancer survivors. Prevention of cardiovascular risk factor elevations in healthy premenopausal women. Vitamin D and calcium intake and risk of early menopause. Benefits of Soy Isoflavone Therapeutic Regimen on Menopausal Symptoms Is age at menopause increasing across Europe? Results on age at menopause and determinants from two population-based studies Gabapentin vs. low-dose transdermal estradiol for treating post-menopausal women with moderate to very severe hot flushes 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. Adult Weight Change and Risk of Postmenopausal Breast Cancer 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. Women and cardiovascular risk. Investigations for postmenopausal uterine bleeding: special considerations for endometrial volume. Dose-response and withdrawal effects on climacteric symptoms after hormonal replacement therapy. A placebo-controlled therapeutic trial. Fish consumption and the incidence of cerebrovascular disease. Non-hormonal treatment of vulvo-vaginal atrophy-related symptoms in post-menopausal women Relationship of body weight to menarcheal and menopausal age: implications for breast cancer risk. Body mass index and bone loss among postmenopausal women: the 10-year follow-up of the OSTPRE cohort Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? Observational Studies Analyzed Like Randomized Experiments: An Application to Postmenopausal Hormone Therapy and Coronary Heart Disease Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak. Efficacy and safety of DT56a compared to hormone therapy in Greek post-menopausal women Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Comparing the effects of estrogen and an herbal medicine on peripheral blood flow in post-menopausal women with hot flashes: hormone replacement therapy and gui-zhi-fu-ling-wan, a Kampo medicine. Menopause and the risk of coronary heart disease in women. Isoflavone Soy Protein Supplementation and Atherosclerosis Progression in Healthy Postmenopausal Women: A Randomized Controlled Trial Endogenous Sex Hormones and Cardiovascular Disease Incidence in Men Reconciling systematic reviews of exercise-based cardiac rehabilitation and secondary prevention programmes for coronary heart disease Decision-making at menopause: a randomized controlled trial of a computer-based hormone therapy decision-aid. Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo Wasted research when systematic reviews fail to provide a complete and up-to-date evidence synthesis: the example of lung cancer Effect of exemestane on the lipidemic profile of post-menopausal operable breast cancer patients following 5–7 years of adjuvant tamoxifen: preliminary results of the ATENA substudy The endocrine transition around menopause ‐ a five years prospective study with profiles of gonadotropines, estrogens, androgens and SHBG among healthy women Effectiveness of a shared team approach between nurses and doctors for improved risk factor management in survivors of stroke: a cluster randomized controlled trial
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 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 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 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 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 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 BACKGROUND Little is known about the impact of post-menopausal hormone therapy on remnant-like particle ( RLP ) concentrations and about the relationship between RLP concentration and angiographic progression of coronary artery disease and clinical events in women . METHODS RLP cholesterol and triglyceride levels were measured at baseline and 3 months after r and omization in 397 post-menopausal women enrolled in The Women 's Angiographic Vitamin & Estrogen ( WAVE ) trial . Correlates of baseline RLP levels and changes in levels with post-menopausal hormone therapy were determined with multiple linear regression . Coronary angiography was performed at baseline and after a mean of 2.9 years . Changes in minimal and average luminal diameter were modeled with multivariate linear regression , clinical outcomes ( non-fatal myocardial infa rct ion , stroke , or cardiovascular death ) with multiple logistic regression . RESULTS The mean subject age was 65 years , 66 % of subjects were white , 18 % of subjects smoked , most subjects were overweight or obese , and 35 % of subjects had diabetes mellitus .  RLP cholesterol ( 0.277 + /- 0.254 mmol/L ) and triglyceride ( 0.386 + /- 0.552 mmol/L ) levels corresponded approximately to the 90th percentile in women in the Framingham study . RLP levels did not change significantly with hormone therapy . RLP levels at baseline , changes in RLP levels , and on treatment RLP levels did not relate to angiographic changes or clinical outcomes ( non-fatal myocardial infa rct ion , stroke , or cardiovascular death ) . CONCLUSIONS RLP levels were high among post-menopausal women enrolled in the WAVE study , were not affected by hormone therapy , and did not relate to angiographic progression of coronary artery disease or clinical outcomes BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later . However , the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation ( the hormone-timing hypothesis ) has not been tested . METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause ( < 6 years [ early postmenopause ] or ≥10 years [ late postmenopause ] ) and were r and omly assigned to receive either oral 17β-estradiol ( 1 mg per day , plus progesterone [ 45 mg ] vaginal gel administered sequentially [ i.e. , once daily for 10 days of each 30-day cycle ] for women with a uterus ) or placebo ( plus sequential placebo vaginal gel for women with a uterus ) . The primary outcome was the rate of change in carotid-artery intima-media thickness ( CIMT ) , which was measured every 6 months . Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography ( CT ) , which was performed when participants completed the r and omly assigned regimen . RESULTS After a median of 5 years , the effect of estradiol , with or without progesterone , on CIMT progression differed between the early and late postmenopause strata ( P=0.007 for the interaction ) . Among women who were less than 6 years past menopause at the time of r and omization , the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group ( P=0.008 ) . Among women who were 10 or more years past menopause at the time of r and omization , the rates of CIMT progression in the placebo and estradiol groups were similar ( 0.0088 and 0.0100 mm per year , respectively ; P=0.29 ) . CT measures of coronary-artery calcium , total stenosis , and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum . CONCLUSIONS Oral estradiol therapy was associated with less progression of sub clinical atherosclerosis ( measured as CIMT ) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause . Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum . ( Funded by the National Institute on Aging , National Institutes of Health ; ELITE Clinical Trials.gov number , NCT00114517 . ) 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 Hormone replacement therapy ( HRT ) has profound effects on the cardiovascular system , with plausible biological mechanisms explaining both the benefits and harm . Benefits may result from oestrogen action on metabolic risk factors , such as lipids , glucose and insulin metabolism , as well as direct arterial effects , reducing atherogenesis . Harm may arise from inappropriately high starting doses causing transient increases in coagulation activation and adverse vascular remodelling . Observational studies of HRT suggest that there is a beneficial effect on the incidence of coronary heart disease ( CHD ) . Any benefit of HRT seen in r and omized clinical trials appears to be confined to those women within several years of their menopause , and it is clear from the r and omized trials that age at initiation is a crucially important consideration . Women initiating HRT within 10 years of menopause onset may achieve cardiovascular benefit , particularly in terms of primary CHD prevention , whilst avoiding risks of stroke and venous thrombo-embolism BACKGROUND AND OBJECTIVES The incidence of coronary artery disease ( CAD ) is higher in post-menopausal than in pre-menopausal women . Epidemiological studies suggest that hormone replacement therapy ( HRT ) decreases the risk of cardiovascular disease in post-menopausal women .  HRT could modify the cardiovascular risk via several mechanisms , including modifications in the fibrinolytic system and lipoprotein ( a ) levels . Our study was aim ed at investigating some of these modifications . DESIGN AND METHODS In the cross-sectional part of the study we evaluated several components of the fibrinolytic system , coagulation inhibitors and lipid profile in premenopausal ( n=15 ) and post-menopausal women ( n=64 ) with CAD and compared these parameters with those of healthy pre-menopausal ( n=31 ) and post-menopausal women ( n=88 ) . The prospect i ve part of the study analyzed the effect of HRT with transdermal estrogen with or without progestogen in post-menopausal women with CAD . RESULTS Pre- and postmenopausal women with CAD showed significant lower fibrinolytic activity and higher plasminogen activator inhibitor type 1 ( PAI-1 ) levels than their control groups . Lp(a ) levels were higher in premenopausal women with CAD than in healthy premenopausal women . In post-menopausal women with CAD , HRT induced a significant decrease in PAI-1 and Lp(a ) levels . No significant differences were observed in any parameter studied between the groups treated with transdermal estrogen with and without progestogen . INTERPRETATION AND CONCLUSIONS CAD is associated with a decrease in fibrinolytic activity , possibly due to an increase in PAI-1 levels . An increase in fibrinolytic activity and a decrease in PAI-1 and Lp(a ) levels were observed in CAD women receiving transdermal HRT and these changes may have a favorable impact on the risk of new cardiovascular events in post-menopausal CAD women 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 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 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 A major achievement from 500 million years of evolution is the establishment of a high secretion rate of dehydroepi and rosterone ( DHEA ) by the human adrenal gl and s coupled with the indroduction of menopause which stops secretion of estrogens by the ovary . Cessation of estrogen secretion at menopause eliminates the risks of endometrial hyperplasia and cancer which would result from non-opposed estrogen stimulation during the post-menopausal years . In fact , from the time of menopause , DHEA becomes the exclusive and tissue-specific source of sex steroids for all tissues except the uterus . Intracrinology , a term coined in 1988 , describes the local formation , action and inactivation of sex steroids from the inactive sex steroid precursor DHEA . Over the past 25 years most , if not all , the genes encoding the human steroidogenic and steroid-inactivating enzymes have been cloned and sequenced and their enzymatic activity characterized . The problem with DHEA , however , is that its secretion decreases from the age of 30 years and is already decreased , on average , by 60 % at time of menopause . In addition , there is a large variability in the circulating levels of DHEA with some post-menopausal women having barely detectable serum concentrations of the steroid while others have normal values . Since there is no feedback mechanism controlling DHEA secretion within ' normal ' values , women with low DHEA will remain with such a deficit of sex steroids for their remaining lifetime . Since there is no other significant source of sex steroids after menopause , one can reasonably believe that low DHEA is involved , in association with the aging process , in a series of medical problems classically associated with post-menopause , namely osteoporosis , muscle loss , vaginal atrophy , fat accumulation , hot flashes , skin atrophy , type 2 diabetes , memory loss , cognition loss and possibly Alzheimer 's disease . A recent r and omized , placebo-controlled study has shown that all the signs and symptoms of vaginal atrophy , a classical problem recognized to be due to the hormone deficiency of menopause , can be rapidly improved or corrected by local administration of DHEA without systemic exposure to estrogens . In addition , the four domains of sexual dysfucntion are improved . For the other problems of menopause , although similar large scale , r and omized and placebo-controlled studies usually remain to be performed , the available evidence already strongly suggests that they could be improved , corrected or even prevented by exogenous DHEA . In men , the contribution of adrenal DHEA to the total and rogen pool has been measured at 40 % in 65 - 75-year-old men . Such data stress the necessity of blocking both the testicular and adrenal sources of and rogens in order to achieve optimal benefits in prostate cancer therapy . On the other h and , the comparable decrease in serum DHEA levels observed in both sexes has less consequence in men who continue to receive a practically constant supply of testicular sex steroids during their whole life . In fact , in men , the appearance of hormone-deficiency symptoms common to women is observed at a later age and with a lower degree of severity . Consequently , DHEA replacement has shown much more easily measurable beneficial effects in women . Most importantly , despite the non-scientific and unfortunate availability of DHEA as a food supplement in the United States , a situation that discourages rigorous clinical trials on the crucial physiological and therapeutic role of DHEA , no serious adverse event related to DHEA has ever been reported in the world literature ( thous and s of subjects exposed ) or in the monitoring of adverse events by the FDA ( millions of subjects exposed ) , thus indicating , as expected from its known physiology , the excellent safety profile of DHEA . With today 's knowledge , one can reasonably suggest that DHEA offers the promise of a safe and efficient replacement therapy for the multiple problems related to hormone deficiency after menopause without the risks associated with estrogen-based or any other treatments Atherosclerotic cardiovascular disease ( ASCVD ) is the leading cause of death , decreased quality of life , and medical costs in the United States . Nearly 1 in 3 Americans die of heart disease and stroke ( 1 ) . Most ASCVD is preventable through a healthy lifestyle and effective treatment of cholesterol and blood pressure . The 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults from the American College of Cardiology and American Heart Association ( ACC/AHA ) provides an evidence -based approach to reducing ASCVD risk ( 2 ) . Guideline Development Process In 2008 , the National Heart , Lung , and Blood Institute ( NHLBI ) convened the Adult Treatment Panel ( ATP ) IV to up date the 2001 ATP-III cholesterol guidelines using a rigorous systematic process to identify and review r and omized , controlled trials ( RCTs ) with cardiovascular outcomes and meta-analyses of these RCTs . The panel comprised experts and clinicians from the fields of cardiology , epidemiology , primary care , and endocrinology ( 2 ) and received support from the Lifestyle Management and Risk Assessment Work Groups ( 3 , 4 ) . Systematic evidence review s conducted according to principles recommended by the Institute of Medicine ( 5 ) were performed to answer 3 questions relevant to clinical care . Two questions focused on the evidence supporting low-density lipoprotein cholesterol ( LDL-C ) and nonhigh-density lipoprotein cholesterol ( HDL-C ) levels as targets of treatment . One question examined the reduction in ASCVD events and adverse effects for each cholesterol-lowering drug class . The panel synthesized the evidence from these 3 review s as well as from Lifestyle Management and Risk Assessment Work Groups review s ( 3 , 4 ) that addressed 5 additional critical questions . Systematic electronic search es of relevant data bases of the peer- review ed English- language literature published from 1 January 1995 through 1 December 2009 for each critical question were conducted by an NHLBI-selected independent contractor and focused on RCTs and systematic review s and meta-analyses of RCTs assessed as fair to good quality . In addition , RCTs with ASCVD outcomes that included coronary heart disease , stroke , and cardiovascular deaths published after that date were eligible for consideration through July 2013 . Evidence tables were constructed , and the strength of evidence was rated according to the NHLBI ( Table 1 of the Supplement ) . Recommendations were grade d according to criteria from the NHLBI ( Table 2 of the Supplement ) and ACC/AHA ( Table 3 of the Supplement ) . Because of the inherent differences in grading systems and the clinical questions driving the recommendations , alignment between the NHLBI and ACC/AHA formats was imperfect . A complete description of the methods used and results of the evidence review are provided in the guideline ( 2 ) and the NHLBI evidence report ( www.nhlbi.nih.gov/ guidelines /cholesterol/ser/index.htm ) . Supplement . NHLBI and ACC/AHA Criteria for Rating Strength of Evidence To help clinicians estimate ASCVD risk , the risk assessment working group developed the Pooled Cohort Equations using data from 5 NHLBI-sponsored longitudinal , population -based cohorts of African American and non-Hispanic white men and women to estimate risk for a first myocardial infa rct ion , coronary heart disease death , or fatal or nonfatal stroke on the basis of age , sex , race , smoking status , total cholesterol level , HDL-C level , systolic blood pressure , antihypertensive therapy , and diabetes ( 4 , 6 ) . These equations significantly advance ASCVD risk estimation by providing sex- and race-specific estimates and including stroke as an outcome . The earlier Framingham equations calculated only coronary heart disease risk for non-Hispanic whites . The draft recommendations were review ed by 23 experts and representatives of federal agencies identified by the NHLBI . In September 2013 , the recommendations developed by the panel were transitioned to the ACC/AHA and had additional review by 4 experts nominated by the ACC Foundation and the AHA . The governing bodies of the ACC and AHA approved the guideline , which also received endorsement from the American Association of Cardiovascular and Pulmonary Rehabilitation , American Pharmacists Association , American Society for Preventive Cardiology , Association of Black Cardiologists , Preventive Cardiovascular Nurses Association , and WomenHeart : The National Coalition for Women with Heart Disease . Recommendations The guideline focuses on treatment of blood cholesterol to reduce ASCVD risk in adults . Major recommendations are summarized here and in Table 1 . The guideline report provides a complete listing of recommendations and supporting evidence behind each recommendation ( 2 ) . Table 1 . Major Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults * 1 . Encourage Adherence to a Healthy Lifestyle A healthy lifestyle is the foundation for cardiovascular health . The panel endorsed the 2013 ACC/AHA Lifestyle Management Guideline ( 3 ) for a diet that is low in saturated fat , trans fat , and sodium ; emphasizes vegetables , fruits , whole grains , low-fat dairy products , poultry , fish , legumes , nontropical vegetable oils , and nuts ; and limits sweets , sugar-sweetened beverages , and red meats and engage in regular aerobic physical activity . Adults also should maintain a healthy body weight , avoid smoking , and control hypertension and diabetes when present . 2 . Statin Therapy Is Recommended for Adults in Groups Demonstrated to Benefit Strong RCT evidence shows that reduction in ASCVD events from statin therapy exceeds adverse events for 4 patient groups : those with clinical ASCVD ( acute coronary syndromes , myocardial infa rct ion , stable angina , coronary or other arterial revascularization , stroke , transient ischemic attack , or peripheral arterial disease of atherosclerotic origin ) when  statins are used for secondary prevention , and those with LDL-C levels 190 mg/dL ; those aged 40 to 75 years with diabetes and LDL-C levels 70 to 189 mg/dL ; and those aged 40 to 75 years without diabetes and with a 10-year ASCVD risk 7.5 % when statins are used for primary prevention . Moderate evidence supports consideration of statin therapy for primary prevention in individuals with a 10-year ASCVD risk of 5 % to < 7.5 % . Routine initiation of statin therapy is not recommended in adults with New York Heart Association heart failure class II to IV or those receiving maintenance hemodialysis . R and omized , controlled trials in these groups showed no reduction in ASCVD . 3 . Statins have an Acceptable Margin of Safety When Used in Properly Selected Individuals and Appropriately Monitored Strong RCT evidence supports safety of statins when they are used as directed in conjunction with regular follow-up assessment s in properly selected patients . Adjustment of statin intensity is recommended in individuals older than 75 years with a history of statin intolerance or other characteristics ( 2 ) or those receiving drug therapy that may increase statin adverse events . Routine monitoring of hepatic aminotransferase level or creatine kinase level is not recommended unless clinical ly indicated by symptoms suggesting hepatotoxicity or myopathy . Given the potential for decreasing ASCVD events and death , the relationship of muscle and other symptoms to statin treatment must be confirmed . Therefore , eliciting a history of muscle symptoms before statin initiation and carefully monitoring symptoms during statin discontinuation and rechallenge is recommended . Severe myopathy , rhabdomyolysis , and possibly hemorrhagic stroke are rare complications of statin therapy . Although statin therapy modestly increases the risk for type 2 diabetes , ASCVD risk reduction outweighs the excess risk for diabetes for high-intensity statins in secondary prevention or for 10-year ASCVD risk 7.5 % . Similarly , ASCVD risk reduction outweighs the excess risk for diabetes for moderate-intensity statin therapy in adults with a 10-year ASCVD risk 5 % . 4 . Engage in a ClinicianPatient Discussion Before Initiating Statin Therapy , Especially for Primary Prevention in Patients With Lower ASCVD Risk Decisions to initiate statin therapy in primary prevention should be based on clinical judgment and preferences of informed patients . In adults without clinical ASCVD or diabetes whose LDL-C level is < 190 mg/dL , calculating the estimated 10-year ASCVD risk should be the start of the clinicianpatient discussion and should not automatically lead to statin initiation . As the absolute risk for ASCVD events decreases , so does the net benefit of the intervention . Therefore , discussion of the potential for ASCVD event reduction , adverse effects , drugdrug interactions , and patient preferences is especially important for lower-risk primary prevention . The discussion provides the opportunity to encourage healthy lifestyle habits and control other risk factors . Additional factors may be considered when a risk-based decision is uncertain , including LDL-C levels 160 mg/dL , family history of premature ASCVD , elevated  lifetime ASCVD risk  , high-sensitivity C-reactive protein level 2.0 mg/L ,  coronary artery calcification score  > 300 Agatston units , and anklebrachial index < 0.9 . After age 75 years , comorbid conditions , anticipated longevity , safety considerations , and patient preferences should play a large role in decision making . 5 . Use the Newly Developed Pooled Cohort Equations for Estimating 10-Year ASCVD Risk The Pooled Cohort Equations are currently the best available method for estimating 10-year ASCVD risk to guide statin initiation ( 4 , 6 ) . Application of the inclusion and exclusion criteria from RCTs is cumbersome and results in underidentifying high-risk and overidentifying low-risk individuals for statin treatment . The Pooled Cohort Equations were developed using recent data from 5 NHLBI-sponsored , longitudinal , population -based cohorts of African American and white men and women ( ARIC [ 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 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 Visceral fat ( VF ) increases with the menopause and is an independent predictor of the metabolic syndrome , diabetes , and cardiovascular disease ( CVD ) in women . Little is known about how hormonal changes during the menopausal transition are related to the increase in VF . We aim ed to determine the relationship between bioavailable testosterone and VF in middle-aged women at various stages of the menopausal transition and whether this relationship is independent of age and other CVD risk factors . The Study of Women 's Health Across the Nation ( SWAN ) is a longitudinal , community-based study . This report uses baseline data from a population -based longitudinal ancillary study at the Chicago site to examine the cross-sectional relationship between testosterone and computed tomography (CT)-assessed VF  in women at different stages of the menopausal transition . Included are 359 women ( 47.2 % black ) , aged 42 - 60 years , who were r and omly selected from a complete community census in which a 72 % participation rate was achieved . In multivariate models , bioavailable testosterone was associated with VF independent of age , race , percent total body fat , and other cardiovascular risk factors . Bioavailable testosterone was a stronger predictor than estradiol and was interchangeable in its strength of association with sex hormone-binding globulin ( SHBG ) . As bioavailable testosterone was associated with VF even after adjusting for insulin resistance , this suggests that it plays an important role in regional fat distribution . Our findings may have direct implication s in explaining the effect of menopause-related testosterone predominance on VF accumulation and subsequent cardiovascular risk AIM To produce dietetic guidelines summarizing the systematic review evidence on dietary advice for secondary prevention of cardiovascular disease . METHODS The Cochrane Library , MEDLINE and EMBASE were comprehensively search ed for systematic review s on aspects of diet and heart health . Review s were included if they search ed systematic ally for r and omised controlled trials relating to diet and secondary prevention of cardiovascular disease . Two members of the UK Heart Health and Thoracic Dietitians Group critically appraised each review . The quality and results of each review were discussed and summarized in a whole group meeting . The guidelines were trialled in seven dietetic departments and modified where necessary . RESULTS Providing evidence -based dietary information ( including increasing omega-3 fat plus fruit and vegetable intake ) to all people after myocardial infa rct ion will save more lives than concentrating dietary advice on those in need of weight loss or lipid lowering . The practice of prioritizing dietetic time to those with raised lipids is out of date since the advent of statin therapy . CONCLUSION There is good systematic review evidence that dietary advice to those with cardiovascular disease can reduce mortality and morbidity as well as modify risk factors .  Dietary advice that does this most effectively should be prioritized BACKGROUND Whether menopausal hormone therapy ( MHT ) protects against cardiovascular disease ( CVD )  remains unclear . OBJECTIVE To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause . DESIGN R and omized , controlled trial . ( Clinical Trials.gov : NCT00154180 ) . SETTING Nine U.S. academic centers . PARTICIPANTS Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium ( CAC ) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days . INTERVENTION Oral conjugated equine estrogens ( o-CEE ) , 0.45 mg/d , or transdermal 17β-estradiol ( t-E2 ) , 50 mcg/d , each with 200 mg of oral progesterone for 12 days per month , or placebo for 48 months . MEASUREMENTS Primary end point was annual change in carotid artery intima-media thickness ( CIMT ) . Secondary end points included changes in markers of CVD risk . RESULTS Of 727 r and omly assigned women , 89.3 % had at least 1 follow-up CIMT and 79.8 % had CIMT at 48 months . Mean CIMT increases of 0.007 mm/y were similar across groups . The percentages of participants in whom CAC score increased did not differ significantly across groups . No changes in blood pressure were observed with o-CEE or t-E2 . Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone-binding globulin but not interleukin-6 increased with o-CEE . Insulin resistance decreased with t-E2 . Serious adverse events did not differ by treatment . LIMITATION Power to compare clinical events was insufficient . CONCLUSION Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk . PRIMARY FUNDING SOURCE Aurora Foundation BACKGROUND There is increasing use of hormone replacement therapy ( HRT ) by post-menopausal women . Observational epidemiological studies have shown reductions in cardiovascular risk factors in  HRT users in the USA , but no r and omized controlled trials of HRT have been carried out in the primary practice setting . Previous studies of cardiovascular risk factors have shown a variety of responses according to type of progestagen and oral or topical administration . None has examined the effect of route using an identical progestagen . OBJECTIVES Our aim was to establish differences , if any , in alteration in cardiovascular risk factors with HRT in post-menopausal women according to route of administration of HRT , oral , transdermal and implant , using first oestrogen alone then oestrogen plus norethisterone , or testosterone for implant . METHODS Subjects were recruited by letter of invitation to women aged 50 - 65 years from lists in general practice s local to the Charing Cross Hospital Lipid Clinic in West London . Their menopausal status was confirmed and they were r and omized to one of three treatment groups or acted as controls . They attended for three visits ; at baseline , HRT was initiated as oestrogen alone , oral or transdermal . At the 3-month visit , HRT with the progestagen , norethisterone , was given cyclically , continuously or transdermally until the final visit at 6 months . A separate group of women from the menopause clinic at Chelsea and Westminster Hospital were studied on oestrogen implant then on implanted oestrogen and testosterone . The outcome measures studied were the separate effects of the four regimes as compared with controls on lipoproteins , glucose , insulin , fibrinogen , factor VII and E-selectin , together with weight , waist : hip ratio and blood pressure . RESULTS The continuous combined oestrogen-progestagen therapy had similar effects on cardiovascular risk factors as oestrogen with cyclical progestagen . All regimes lowered low-density lipoprotein cholesterol , the oral route being more potent than the parenteral ; the effect of transdermal HRT was similar to the implant . Lp(a ) was reduced only with the oral route . Reductions in factor VII and E-selectin were observed in both the oral and transdermal routes . There was no increase in body mass index , waist : hip ratio , blood pressure or glucose and insulin levels with any of the HRT regimes used . Systolic blood pressure was reduced with the transdermal route . CONCLUSIONS This study supports the evidence that oestrogen-progestagen HRT , both oral and transdermal , although attenuating some of the benefit of oestrogen alone on fibrinogen and high-density lipoprotein , significantly reduces cardiovascular risk factors , which should diminish post-menopausal risk of coronary disease 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 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 OBJECTIVE To evaluate the effects of menopause hormonal therapy on disease activity in women with systemic lupus erythematosus ( SLE ) . METHODS We conducted a double-blind , r and omized clinical trial involving 106 women with SLE who were in the menopausal transition or in early or late postmenopause . Patients received a continuous-sequential estrogen-progestogen regimen ( n = 52 ) or placebo ( n = 54 ) . Disease activity was assessed at baseline and at 1 , 2 , 3 , 6 , 9 , 12 , 15 , 18 , 21 , and 24 months , according to the SLE Disease Activity Index ( SLEDAI ) . The primary outcome measure was global disease activity , estimated by measuring the area under the SLEDAI curve . Secondary outcome measures included maximum SLEDAI score , change in SLEDAI score , incidence of lupus flares , median time to flare , medication use , and adverse events . Results were studied using intent-to-treat analysis . RESULTS At baseline , demographic and disease characteristics were similar in both groups . Mean + /- SD SLEDAI scores were 3.5 + /- 3.3 and 3.1 + /- 3.4 in the menopause hormonal therapy and placebo groups , respectively ( P = 0.57 ) . Disease activity remained mild and stable in both groups throughout the trial . There were no significant differences between the groups in global or maximum disease activity , incidence or probability of flares , or medication use . Median time to flare was 3 months in both groups . Thromboses occurred in 3 patients who received menopause hormonal therapy and in 1 patient who received placebo . One patient in each group died during the trial due to sepsis . CONCLUSION Menopause hormonal therapy did not alter disease activity during 2 years of treatment . However , an apparently increased risk of thrombosis seems to be a real threat in women with SLE who receive menopausal hormone therapy 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 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 UNLABELLED  Interleukin-10 ( IL-10 ) is a cytokine with pleiotropic properties . Limited biochemical and clinical evidence suggest a link between IL-10 and coronary heart disease ( CHD ) . However , more data are needed to clarify the relationship between IL-10 and risk for CHD events . METHODS The present study was a secondary analysis of the  estrogen replacement and atherosclerosis ( ERA ) trial , a r and omized clinical trial that examined the effects of hormone replacement therapy on post-menopausal women with known coronary atherosclerosis .  IL-10 concentration , measured at baseline , was treated as both a continuous and categorical variable . Cox proportional hazards models were used to compute hazard ratios as estimates of relative risk for CHD events . RESULTS There were 71 events over an average 3.2 year follow-up .  Incident rates were higher for individuals with IL-10 concentrations equal to or greater than the median level ( 1.04 pg/mL ) compared to those individuals below the median level ( 30 % versus 18.5 % , p=0.02 ) . The cumulative incidence of CHD events was significantly greater in individuals with IL-10 concentrations > or=1.04 pg/mL ( p=0.01 ) . A one st and ard deviation increase in baseline IL-10 concentration was associated with a 34 % greater risk of a CHD event ( HR 1.34 [ 1.06 - 1.68 ] , p=0.01 ) . This elevated risk was not altered by interleukin-6 , C-reactive protein , or additional cardiovascular risk factors . IL-10 concentration and risk for CHD events was most pronounced in diabetics ( HR 2.4 [ 1.46 - 3.83 ] , p=0.0005 ) . CONCLUSION In the ERA trial , elevated IL-10 concentration was associated with an increased risk for future cardiovascular events in post-menopausal women with established coronary atherosclerosis . Further study of the relationship between IL-10 and the pathogenesis and progression of atherosclerosis and cardiovascular events is warranted Observational epidemiological studies have shown that mortality from coronary heart disease is reduced in post-menopausal women by hormone replacement therapy ( HRT ) . The aim of this study was to measure sE-selectin levels in post-menopausal females before and after HRT  and to compare these with pre-menopausal females and aged matched males . Post-menopausal females ( n = 70 ) were given HRT or no treatment to act as a control group . sE-selectin levels were significantly lower in the pre-menopausal ( n = 36 ) when compared with the post-menopausal females ( n = 70 ) ( p = 0.027 ) , whereas no difference between two age matched male groups was found ( n = 40 ) . Oral and transdermal HRT significantly decreased sE-selectin levels ( p<0.0001 and p = 0.0005 respectively ) with no change in the control group . The reduction in the levels of this marker of endothelial activation after HRT , may reflect a decrease in leucocyte/endothelial interaction which may reduce atherosclerotic risk in post-menopausal females 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 OBJECTIVE To assess beneficial effects of a soy rich diet on the main biomarkers of cardiovascular health in menopause , compared with the effects of the hormone replacement therapy ( HRT ) . METHODS 187 healthy asymptomatic postmenopausal women , aged 39 - 60 , were recruited and r and omized into three groups : a soy rich diet group , a HRT group , and a control group .  Lipid profile , body mass index , blood pressure , endometrial thickness , uterine artery resistance index ( RI ) , were evaluated in all the participants at the baseline , after 6 months , and at the end of the study . RESULTS After a 6-month intervention period , the lipid profile in the soy rich diet group showed a favourable outcome , similar to that observed in the HRT group , but compliance to the diet was low . CONCLUSION Soy products may be used in the prevention of cardiovascular risk in postmenopausal women because of their efficacy in contrasting the negative effects of menopause on the cardiovascular system , but our findings should be confirmed ; moreover , suitable strategies to improve the compliance have to be considered Summary We evaluated whether age moderated the effect of impact + resistance exercise on hip BMD in older post-menopausal breast cancer survivors ( BCS ) .  Exercise was more beneficial among younger than older women within our sample , suggesting that much older BCS may require different training programs to improve hip health . Purpose Previously , we reported that a program of resistance + impact training stopped bone loss at the spine in older , post-menopausal BCS but had no effect on bone mineral density ( BMD ) at the hip . Aging may blunt the responsiveness of the hip to mechanical loading , so we conducted a secondary data analysis to evaluate whether age moderated the effect of exercise on hip BMD . Methods We analyzed data from our r and omized , controlled trial in older ( ≥ 50 years of age at diagnosis ) , post-menopausal , post-adjuvant treatment BCS ( n = 106 ) comparing women assigned to impact + resistance exercise ( POWIR ) or  to a control program of low-intensity stretching ( FLEX ) . We examined effect modification by age on BMD at three hip sites ( greater trochanter , femoral neck , and total hip ) using hierarchical linear modeling adjusting for time since diagnosis and use of adjuvant hormone therapy . Results Age moderated the effect of exercise on total hip BMD such that younger women in POWIR were more likely to see a positive net benefit than FLEX compared to older women where there was little difference between groups ( p = 0.02 ) . Conclusions The skeletal response to loading at the hip within post-menopausal BCS diminishes with age . Whether more vigorous exercise programs and /or longer training periods are required to favorably change hip health in older BCS will require future study and careful thought about the risks and benefits of tougher training programs OBJECTIVES This prospect i ve study examined whether changes in traditional and novel coronary heart disease ( CHD ) risk factors are greater within a year of the final menstrual period ( FMP ) , relative to changes that occur before or after that interval , in a multiethnic cohort . BACKGROUND Underst and ing the influence of menopause on CHD risk remains elusive and has been evaluated primarily in Caucasian sample s. METHODS SWAN ( Study of Women 's Health Across the Nation ) is a prospect i ve study of the menopausal transition in 3,302 minority ( African American , Hispanic , Japanese , or Chinese ) and Caucasian women . After 10 annual examinations , 1,054 women had achieved an FMP not due to surgery and without hormone therapy use before FMP .  Measured CHD risk factors included lipids and lipoproteins , glucose , insulin , blood pressure , fibrinogen , and C-reactive protein . We assessed which of 2 models provided a better fit with the observed risk factor changes over time in relation to the FMP : a linear model , consistent with chronological aging , or a piecewise linear model , consistent with ovarian aging . RESULTS Only total cholesterol , low-density lipoprotein cholesterol , and apolipoprotein B demonstrated substantial increases within the 1-year interval before and after the FMP , consistent with menopause-induced changes . This pattern was similar across ethnic groups . The other risk factors were consistent with a linear model , indicative of chronological aging . CONCLUSIONS Women experience a unique increase in lipids at the time of the FMP . Monitoring lipids in perimenopausal women should enhance primary prevention of CHD OBJECTIVES The aim of our study was to determine the effect of the menopause on various coronary heart disease ( CHD ) risk factors and on the global risk of CHD in a population based sample of women , making the difference between menopause and age related effects . STUDY DESIGN The Third French MONICA cross-sectional survey on cardiovascular risk included 1730 r and omly selected women , aged 35 - 64 years , representative from the general population . MAIN OUTCOME MEASURES Women were defined as post-menopausal ( postM ; n=696 ) , peri-menopausal ( periM ; n=183 ) or pre-menopausal ( preM ; n=659 ) based on the date of last menses . Socio-demographic , clinical and biological data were collected . Analyses of variance were used to compare means . RESULTS PostM women had significantly higher age-adjusted levels of total cholesterol ( 6.0mmol/L in postM vs. 5.7mmol/L in preM , p<0.05 ) and LDL cholesterol ( 3.9mmol/L vs. 3.6mmol/L , p<0.05 ) . There was no difference in HDL cholesterol or triglyceride levels , glycemia or blood pressure . Further adjustment on body mass index and hormonal treatments did not modify the results . No risk factor was significantly different between periM and postM. However , the Framingham 10-year risk of CHD was higher in postM , as compared with periM ( 5.1 % vs. 5.0 % , p<0.05 ) . In postM women , lipids and the Framingham risk were not associated with elapsed time since menopause . CONCLUSIONS The CHD risk increases during the sixth decade could be explained not only by estrogen deprivation but also by an effect on lipid profile , which is likely to occur in the peri-menopause period 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 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 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 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 ) Objective : To examine the efficacy and tolerability of escitalopram ( ESCIT ) compared to estrogen and progestogen therapy ( EPT ) for the treatment of symptomatic peri- and postmenopausal women . Design : Forty women ( aged 40 - 60 years ) with depressive disorders and menopause-related symptoms were r and omly assigned to an 8-week open trial with ESCIT ( flexible dose , 10 - 20 mg/day ; fixed dose , 10 mg/day for the first 4 weeks ) or estrogen plus progestogen therapy ( ethinyl estradiol 5 & mgr;g/day plus norethindrone acetate 1 mg/day ) . Primary outcome measures included Montgomery-Asberg Depression Rating Scale and the Greene Climacteric Scale at week 8 . Secondary outcome measures included the Clinical Global Impressions as well as sleep and quality of life assessment s. Results : Thirty-two women ( 16 on EPT , 16 on ESCIT ) were included in the analyses . Full remission of depression ( score of < 10 on the Montgomery-Asberg Depression Rating Scale ) was observed in 75 % ( 12/16 ) of subjects treated with ESCIT , compared to 25 % ( 4/16 ) treated with EPT ( P = 0.01 , Fisher 's exact tests ) . Remission of menopause-related symptoms ( > 50 % decrease in Greene Climacteric Scale scores ) was noted in 56 % ( 9/16 ) of women treated with ESCIT compared to 31.2 % ( 5/16 ) on EPT ( P = 0.03 , Pearson 's & khgr;2 tests ) . Improvement in sleep , hot flashes , and quality of life was observed with both treatments . Conclusions : ESCIT is more efficacious than EPT for the treatment of depression and has a positive impact on other menopause-related symptoms . ESCIT may constitute a treatment option for symptomatic menopausal women who are unable or unwilling to use hormone therapy Hormone-replacement therapy ( HRT ) is widely used by post-menopausal women . Although this treatment may slightly increase the incidence of breast cancer , more and more cases are diagnosed while women are taking HRT . The purpose of this study was to ascertain the influence of HRT on prognostic factors and outcome of breast cancer . Data on all breast-cancer patients , including precise information on HRT  , was prospect ively and systematic ally recorded in a data base . From 1985 to 1995 , 1379 post-menopausal women fulfilled the eligibility criteria for this study . All were treated by us ( P.B. and L.P. ) in our ward of a large public hospital of Marseilles , France . The clinical features , laboratory findings and survival rates in 142 HRT users who developed breast cancer while being treated were compared with those of 284 matched never user breast-cancer patients . Patients who developed breast cancer during HRT had fewer locally advanced cancers and smaller and better-differentiated cancers . Lymph-node involvement was significantly less frequent in the user group than in the non-user group ( non-significant ) . Estradiol receptivity was both qualitatively and quantitatively lower in users . There was no significant difference with regard to recurrence and metastasis-free survival and overall survival . We conclude that HRT does not affect the prognosis of breast cancer . Regular surveillance during HRT allows early detection of smaller lesions . The higher number of well-differentiated cancers and the distribution of hormone receptivity may reflect interaction between neoplastic tissue and exogenous hormones OBJECTIVES The aim of this study was to examine the association between brachial artery flow-mediated dilation ( FMD ) and cardiovascular events in a cohort of initially asymptomatic post-menopausal women , with adjustment for the presence of the major cardiovascular risk factors . BACKGROUND Conventional major cardiovascular risk factors ( cigarette smoking , hypercholesterolemia , hypertension , and diabetes ) fail to explain nearly 50 % of cardiovascular events . Defining the magnitude of future risk for the development of clinical events is a major focus of effective primary prevention . Evaluation of endothelial function , utilizing the noninvasive measurement of the brachial artery FMD , may serve as a screening tool to individualize high-risk patients . METHODS We conducted a prospect i ve study on 2,264 post-menopausal women , age 54 + /- 6 years . The length of the follow-up was 45 + /- 13 months ( range 6 to 65 months ) . RESULTS During observation , 90 major events were recorded . Risk-adjusted relative risk values result ed 1.0 , 1.33 ( 95 % confidence interval [ CI ] 1.09 to 4.09 ) , and 4.42 ( 95 % CI 2.97 to 8.01 ) for women in the higher , intermediate , and lower tertile of FMD , respectively ( p < 0.0001 for trend ) . The event rate for women in the lower tertile ( FMD < or=4.5 % ) was greater than the combined event rate noted in the other 2 tertiles ( women in the lower tertile accounted for 51 events [ 56.6 % of total events ] ) . When added to age and other conventional cardiovascular risk factors ( smoking habits , presence of hypercholesterolemia , history of diabetes , hypertension ) , FMD contributed significantly to the model predicting cardiovascular events ( likelihood ratio chi-square change : 10.22 ; p < 0.0001 ) . CONCLUSIONS In post-menopausal women , the knowledge of FMD provided incremental prognostic information regarding the risk of developing cardiovascular events Context : Recent interventional studies indicate that post-menopausal hormone replacement therapy is associated with an increased risk of cardiovascular mortality and breast cancer .  Isoflavones , a class of plant estrogens , have structural similarities to estradiol . Hence , isoflavones may exert beneficial estrogenic health effects in postmenopausal women with fewer adverse effects . Objective : To evaluate the effect of high-dose isoflavones on self-reported quality of life ( QOL ) , cognition , lipoproteins and and rogen status in post-menopausal women . Design and subjects : Double-blind , r and omized , placebo-controlled , 12-week trial of 93 healthy , ambulatory , post-menopausal women ( mean age 56 yr ) . The study was conducted at a tertiary care center in the United States . Intervention : Participants were r and omly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo ( 20 g whole milk protein ) . Both soy and the placebo were provided in the form of a powder to be mixed with beverages . Main outcome measures : QOL was judged by the Menopause-specific Quality of Life ( MENQOL ) question naire while cognitive function was assessed with st and ard instruments . Total , free , and bioavailable testosterone , gonadotropins , SHBG , and fasting lipids were measured . Results : Eighty-four women ( 90 % ) completed the study ( active=38 , placebo=46 ) . There was a significant improvement in all 4 QOL subscales ( vasomotor , psychosexual , physical , and sexual ) among the women taking isoflavones , while no changes were seen in the placebo group . No significant changes in cognition , serum and rogens or plasma lipids were seen within any of the groups . However , at the end of the study , a group-by-time interaction was observed such that total testosterone and HDL levels were significantly lower in the isoflavones compared to placebo groups . Conclusion : High-dose isoflavones is associated with improved QOL among women who have become menopausal recently . Hence , the timing of isoflavone supplementation with regards to the onset of menopause appears to be important . The use of isoflavones , as an alternative to estrogen therapy , may be potentially useful and seemingly safe in this group of women who are looking for relief from menopausal symptoms CONTEXT The Heart and Estrogen/progestin Replacement Study ( HERS ) found no overall reduction in risk of coronary heart disease ( CHD ) events among postmenopausal women with CHD . However , in the hormone group , findings did suggest a higher risk of CHD events during the first year , and a decreased risk during years 3 to 5 . OBJECTIVE To determine if the risk reduction observed in the later years of HERS persisted and result ed in an overall reduced risk of CHD events with additional years of follow-up . DESIGN AND SETTING R and omized , blinded , placebo-controlled trial of 4.1 years ' duration ( HERS ) and subsequent unblinded follow-up for 2.7 years ( HERS II ) conducted at outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS ; 2321 women ( 93 % of those surviving ) consented to follow-up in HERS II . INTERVENTION Participants were r and omly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate ( n = 1380 ) , or placebo ( n = 1383 ) during HERS ; open-label hormone therapy was prescribed at personal physicians ' discretion during HERS II . The proportions with at least 80 % adherence to hormones declined from 81 % ( year 1 ) to 45 % ( year 6 ) in the hormone group , and increased from 0 % ( year 1 ) to 8 % ( year 6 ) in the placebo group . MAIN OUTCOME MEASURES The primary outcome was nonfatal myocardial infa rct ion and CHD death . Secondary cardiovascular events were coronary revascularization , hospitalization for unstable angina or congestive heart failure , nonfatal ventricular arrhythmia , sudden death , stroke or transient ischemic attack , and peripheral arterial disease . RESULTS There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS , HERS II , or overall . The unadjusted relative hazard ( RH ) for CHD events in HERS was 0.99 ( 95 % confidence interval [ CI ] , 0.81 - 1.22 ) ; HERS II , 1.00 ( 95 % CI , 0.77 - 1.29 ) ; and overall , 0.99 ( 0.84 - 1.17 ) . The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups ( RH , 0.97 ; 95 % CI , 0.82 - 1.14 ) , and in analyses restricted to women who were adherent to r and omized treatment assignment ( RH , 0.96 ; 95 % CI , 0.77 - 1.19 ) . CONCLUSIONS Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up . After 6.8 years , hormone therapy did not reduce risk of cardiovascular events in women with CHD . Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD 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 BACKGROUND Abnormal uterine bleeding is the direct cause of a significant health care burden for women , their families , and society as a whole . Up to 30 % of women will seek medical assistance for this problem during their reproductive years . This guideline replaces previous clinical guidelines on the topic and is aim ed to enable health care providers with the tools to provide the latest evidence -based care in the diagnosis and the medical and surgical management of this common problem . OBJECTIVE To provide current evidence -based guidelines for the diagnosis and management of  abnormal uterine bleeding ( AUB ) among women of reproductive age . OUTCOMES Outcomes evaluated include the impact of AUB on quality of life and the results of interventions including medical and surgical management of AUB . METHODS Members of the guideline committee were selected on the basis of individual expertise to represent a range of practical and academic experience in terms of location in Canada , type of practice , subspecialty expertise , and general gynaecology background . The committee review ed relevant evidence in the English medical literature including published guidelines . Recommendations were established as consensus statements . The final document was review ed and approved by the Executive and Council of the SOGC . RESULTS This document provides a summary of up-to- date evidence regarding diagnosis , investigations , and medical and surgical management of AUB . The result ing recommendations may be adapted by individual health care workers when serving women with this condition . CONCLUSIONS Abnormal uterine bleeding is a common and sometimes debilitating condition in women of reproductive age . St and ardization of related terminology , a systematic approach to diagnosis and investigation , and a step-wise approach to intervention is necessary . Treatment commencing with medical therapeutic modalities followed by the least invasive surgical modalities achieving results satisfactory to the patient is the ultimate goal of all therapeutic interventions . EVIDENCE Published literature was retrieved through search es of MEDLINE and the Cochrane Library in March 2011 using appropriate controlled vocabulary ( e.g. uterine hemorrhage , menorrhagia ) and key words ( e.g. menorrhagia , heavy menstrual bleeding , abnormal uterine bleeding ) . Results were restricted to systematic review s , r and omized control trials/controlled clinical trials , and observational studies written in English and published from January 1999 to March 2011 . Search es were up date d on a regular basis and incorporated in the guideline to February 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology-related agencies , clinical practice guideline collection s , clinical trial registries , and national and international medical specialty societies . VALUES The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care ( Table ) . BENEFITS , HARMS , AND COSTS Implementation of the guideline recommendations will improve the health and well-being of women with abnormal uterine bleeding , their families , and society . The economic cost of implementing these guidelines in the Canadian health care system was not considered Breast cancer is the most common cancer type in women and the fourth leading cause of cancer death in the United States ( 1 ) . The goal of screening is to reduce morbidity and mortality , both specific to breast cancer and overall , with acceptable tradeoffs ( 2 , 3 ) . The most commonly used screening test is mammography . Recommended strategies vary for breast cancer screening in average-risk women . Ages to start and discontinue mammography , screening intervals , the role of imaging methods other than mammography , and the role of clinical breast examination ( CBE ) have been points of disagreement among guideline developers . Purpose and Target Population The goal of this American College of Physicians ( ACP ) guidance statement is to critically review selected guidelines from around the world and their included evidence to assist clinicians in making decisions about breast cancer screening in asymptomatic women with average risk for breast cancer . Included screening methods are CBE and breast imaging ( that is , mammography , ultrasonography , magnetic resonance imaging [ MRI ] , and digital breast tomo synthesis [ DBT ] ) . This guidance statement does not address breast self-examination because no evaluated guideline recommends it for screening . The target population for this guidance statement is women with average risk for breast cancer . The target audience is all clinicians . Age is the single most important risk factor for breast cancer . Included guidelines generally define average-risk women as those who do not have a personal history of breast cancer or a previous diagnosis of a high-risk breast lesion , are not at high risk for breast cancer due to genetic mutations known to increase that risk ( such as BRCA1/2 gene mutation or another familial breast cancer syndrome ) , and were not exposed to radiation therapy to the chest in childhood ( 4 , 5 ) . However , definitions of average risk vary among guidelines . In addition , although risk factors ( including early menarche , late menopausal onset , oral contraceptive or menopausal hormone therapy , increased breast density on mammography , and a family member with a history of postmenopausal breast cancer ) may put a woman at greater risk for breast cancer than women without these factors , the evaluated guidelines generally include women with these factors under the umbrella of average risk . Therefore , our guidance statement applies to these women . Guidelines vary somewhat in target population s and screening methods addressed ( Table [ 411 ] and Appendix ) . Both the U.S. Preventive Services Task Force ( USPSTF ) and the World Health Organization ( WHO ) include women with dense breasts and those with a single family member with breast cancer in their guideline 's target population ( 5 , 6 ) . The Canadian Task Force on Preventive Health Care ( CTFPHC ) guideline also includes women with dense breasts ; however , it explicitly mentions that women with a first-degree relative with breast cancer are considered to be at increased risk and are thus excluded from the guideline ( 7 ) . Table . Summary of Included Recommendations in Assessed Guidelines for Breast Cancer Screening of Average-Risk Women Methods The ACP Clinical Guidelines Committee develops guidance statements on topics where several conflicting guidelines are available . Guidance statements rely on evidence presented or referenced in selected guidelines and accompanying evidence reports ; they do not include de novo review s or search es of the literature outside the body of evidence referenced by the guidelines . The goal of ACP guidance statements is to provide clinicians with a rigorous review of the available guidelines and their included evidence and to develop subsequent guidance based on an assessment of the benefits and harms reported by each guideline and its evidence . Unlike ACP guidelines , guidance statements are not derived from a systematic evidence review and hence do not use GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) ( 12 ) to assess the quality of evidence or strength of recommendations . Data Sources and Guideline Selection We search ed the National Guideline Clearinghouse and the Guidelines International Network library for breast cancer screening guidelines from national organizations that addressed breast imaging ( that is , mammography , ultrasonography , MRI , or DBT ) and CBE in women and were published in English between 1 January 2013 and 15 November 2017 . We search ed Web sites housing the selected guidelines for up date s on 10 December 2018 . We excluded guidelines that addressed specific population s ( such as pregnant women and women at increased risk for breast cancer ) or were more than 5 years old ( thus considered inactive ) . We also excluded guidelines that directly endorsed another guideline , such as that of the American Academy of Family Physicians , which endorsed the USPSTF guideline . Our search yielded 3 guidelines , from the American College of Radiology ( published in 2017 ; literature search end date , February 2016 ) ( 9 ) , American Cancer Society ( ACS ) ( published in 2015 ; literature search end date , March 2014 ) ( 4 ) , and USPSTF ( published in 2016 ; literature search end date , June 2015 ) ( 5 ) . We also selected 3 guidelines not identified in either data base but commonly used in clinical practice , from the National Comprehensive Cancer Network ( NCCN ) ( published in 2018 ; literature search end date not reported ) ( 10 ) , WHO ( published in 2014 ; literature search end date , December 2012 ) ( 6 ) , and American College of Obstetricians and Gynecologists ( published in 2017 ; literature search end date not applicable ) ( 8) . In addition , we selected the CTFPHC guideline , which was up date d after our initial search ( published in 2018 ; literature search end date , January 2017 ) ( 7 ) . The American College of Obstetricians and Gynecologists guideline was based on guidelines from the ACS , NCCN , and USPSTF and supporting evidence review s. Critical Appraisal Five co authors independently review ed , assessed , and scored each guideline using the AGREE II ( Appraisal of Guidelines for Research and Evaluation II ) instrument ( 13 , 14 ) ( Appendix Table 1 ) . Appendix Table 1 . Scaled AGREE II Domain Scores for Each Guideline and Overall Assessment Clinician Peer Review The guidance statement was peer- review ed through Annals of Internal Medicine and by ACP Regents and Governors , who represent ACP members at the regional and international level . Public Member Review The development process for the guidance statement included participation by public members ( 2 of the Clinical Guidelines Committee and 7 of ACP 's Public Panel ) to share their perspectives , values , and preferences . Critical Appraisal of Evaluated Guidelines The major difference between high- and low-scoring guidelines ( Appendix Table 1 ) was methodology . Guidelines from ACS ( 4 ) , CTFPHC ( 7 ) , USPSTF ( 5 ) , and WHO ( 6 ) scored highest on the AGREE II instrument , whereas those from the American College of Obstetricians and Gynecologists ( 8) , American College of Radiology ( 9 ) , and NCCN ( 10 ) scored lowest . In addition to our review of each guideline , we examined the evidence supporting the 4 that scored highest ( ACS , CTFPHC , USPSTF , and WHO ) . We also considered recommendations for adoption or adaptation from these 4 guidelines when developing our own guidance . Several factors were important in considering guideline quality . The ACS , CTFPHC , USPSTF , and WHO guidelines best articulated benefits , harms , and strength of the evidence and how these link to recommendations . The lower-scoring guidelines often inadequately described how they considered these factors in developing the recommendations , or they relied on lower- quality evidence . The guidelines varied in the studies they reported , weighting of observational or modeling studies relative to r and omized controlled trials ( RCTs ) , and emphasis on relative versus absolute effects . The guidelines rarely addressed the small absolute effect on breast cancer mortality ; the long lead time to any reduction in this mortality , especially in women with estimated life expectancy less than 15 to 20 years ; and the low incidence of breast cancer for women younger than 60 years . Mammography Depending on the guideline , the recommended age to discuss initiating screening is 40 years ( 4 , 5 , 8) and the recommended age to start screening ranges from 40 ( 9 , 10 ) to 45 ( 4 ) to 50 ( 58 ) years . Most guidelines agree to screen average-risk women with  mammography  between ages 50 and 74 years . However , WHO and CTFPHC recommend that screening in women aged 50 to 69 years should include shared decision making because screening is conditional on a woman 's values and preferences . For women aged 70 to 75 years , WHO recommends screening only in the context of both rigorous research and shared decision making . Other areas of disagreement include screening in women aged 40 to 49 years , screening in women aged 75 years or older , and recommended screening intervals ( Table ) . Intervals range from annual ( particularly in women aged 40 to 49 years ) to biennial or triennial . Guidelines from ACS , USPSTF , and WHO conclude that a close balance exists between screening benefits and harms for women in their 40s ( for ACS , 40 to 44 years ) and that decisions are influenced by patient preferences . The WHO guideline suggests population -based screening programs in women aged 40 to 49 years only in the context of rigorous research , monitoring , and evaluation and if shared decision-making strategies are implemented . The CTFPHC conditionally recommends against screening in women aged 40 to 49 years ( without a first-degree family history of breast cancer ) ; however , it states that some women in this age group may wish to be screened and that clinicians should engage in shared decision making with women who express interest ( Appendix ) . Appendix Table 2 summarizes the available data from the 4 guidelines with the highest AGREE II scores ( ACS , CTFPHC , USPSTF , and WHO ) . Appendix Table 2 . Summary of Evidence on Screening Serum lipoproteins were measured in 72 post-menopausal women , 40 of whom had been taking the synthetic oestrogen , mestranol , for a period of 10 yr and 32 of whom had been taking identical placebo tablets . Mestranol therapy was found to increase serum triglycerides , decrease low density lipoprotein ( LDL ) cholesterol and increase high density lipoprotein ( HDL ) cholesterol . The increase in HDL cholesterol was due principally to a marked increase in the cardioprotective HDL2 fraction . It is concluded that long-term mestranol therapy has a beneficial effect on serum lipoproteins which may help to protect post-menopausal women against fatal ischaemic heart disease AIM AND OBJECTIVE To evaluate the influence of an exercise programme on postmenopausal women with symptoms of anxiety and depression .  BACKGROUND The menopause is a period of hormonal changes when mood variations are probably more severe than at any other period of women 's lives . DESIGN Prospect i ve study with control group and pre- and post-treatment measures , after six months treatment . Conducted at two healthcare clinics , in the province of Granada ( Spain ) . METHODS A convenience sample of 60 postmenopausal women aged 60 - 70 years , with symptoms of depression and anxiety , was recruited . The women were r and omly divided into two groups : ( 1 ) control group , no treatment ( n = 30 ) ; ( 2 ) exercise group , which carried out a programme of mixed physical exercises with musical support ( n = 30 ) . All subjects answered question naires for the Hamilton Anxiety Scale and the Brink and Yesavage Geriatric Depression Scale before and after treatment . RESULTS In the exercise group , statistically significant improvements were observed in subjects with moderate and severe depression ( 18 and 22 % , respectively ) and in those with symptoms of anxiety . No such changes were observed in the control group . CONCLUSIONS A controlled programme of physical exercise for postmenopausal women alleviates symptoms of anxiety and depression , and its inclusion in primary healthcare programmes should be considered . RELEVANCE TO CLINICAL PRACTICE Menopausal women may benefit from physical exercise , which attenuates the effects of the physiological and psychological changes associated with the menopause and prevents pathologic changes The purpose of this study was to test the efficacy of a multimodal intervention ( Women 's Wellness Program ) to improve  women 's cardiovascular risk factors .  This 12-week r and omized experiment with a control group targeted women 50–65 years living in the general population . Women in the intervention group were provided with a consultation with a registered nurse at which time biophysical cardiovascular risk measures were taken and health education was provided in both verbal and written form . Women were encouraged to review their smoking , nutrition , and water intakes and to commence an exercise program that included aerobic fitness exercises . Women in the control group continued their normal activities . The sample consisted of 90 women aged 50–65 years . Pre- and postintervention assessment utilized seven measures of cardiovascular risk factors : waist-to-hip ratio ( WHR ) , body mass index ( BMI ) , blood pressure , heart rate , weight , exercise levels , and smoking . Analysis of covariance indicated that the intervention was effective in improving women 's aerobic exercise activity and decreasing smoking . The data from all five biophysical outcome measures supported the efficacy of the intervention , with significant decreases seen in the women 's WHR , BMI , blood pressure , and measured weight . Study implication s suggest that this type of intervention may provide an effective , clinical ly manageable therapy for women who prefer a self-directed approach to preventing and decreasing cardiovascular risk factors 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 The evidence that higher levels of physical activity and /or lower levels of physical inactivity are associated with beneficial health-related outcomes stems mainly from observational studies . Findings from these studies often differ from r and omised controlled trials and systematic review s currently demonstrate mixed results , due partly to heterogeneity in physical activity interventions , method ologies used and population s studied . As a result , translation into clinical practice has been difficult . It is therefore essential that an overview is carried out to compare and contrast systematic review s , and to identify those physical activity interventions that are the most effective in preventing and /or treating major chronic disease . This protocol has been registered on PROSPERO 2013 : CRD42013003523 . Methods We will carry out an overview of Cochrane systematic review s. We will search the Cochrane Data base of Systematic Review s for systematic review s of r and omised controlled trials that have a primary focus on disease-related outcomes . We will restrict review s to those in selected major chronic diseases . Two authors will independently screen search outputs , select studies , extract data and assess the quality of included review s using the assessment of multiple systematic review s tool ; all discrepancies will be resolved by discussing and reaching a consensus , or by arbitration with a third author . The data extraction form will summarise key information from each review , including details of the population ( s ) ( for example , disease condition ) , the context ( for example , prevention , treatment or management ) , the participants , the intervention(s ) , the comparison(s ) and the outcomes . The primary outcomes of interest are the prevention of chronic disease and /or improved outcomes , in the treatment or management of chronic disease . These outcomes will be summarised and presented for individual chronic diseases ( for example , any change in blood pressure in hypertension or glucose control in diabetes ) . Secondary outcomes of interest are to describe the structure and delivery of physical activity interventions  across chronic disease conditions and adverse events associated with physical activity . Discussion We anticipate that our results could inform research ers , guideline groups and policymakers of the most efficacious physical activity interventions in preventing and /or managing major chronic disease 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 Supplement . Supplementary Material . Each year an estimated 425000 U.S. women have a hysterectomy for benign gynecologic conditions ( 1 , 2 ) , and one third ( 3 ) to one half ( 4 ) of them undergo concurrent oophorectomy to minimize ovarian cancer risk . Several observational studies have found that , although it does reduce subsequent risk for ovarian ( 57 ) and breast ( 5 , 8) cancer , bilateral salpingo-oophorectomy ( BSO ) also confers long-term health risks beyond those result ing from hysterectomy itself , especially when ovary removal occurs early ( before age 45 to 50 years ) . Observational studies also suggest that BSO-associated elevations in all-cause mortality ( 5 , 912 ) , coronary heart disease ( CHD ) ( 10 , 1315 ) , and other adverse outcomes are attenuated among women treated with menopausal estrogen therapy ( 4 ) . Given the acute declines ( 16 , 17 ) and sustained reductions ( 18 , 19 ) in endogenous sex hormones that occur after BSO , it is biologically plausible that estrogen therapy might confer long-term benefits , including reduction in all-cause mortality , in women who have undergone this procedure , and such benefits may be greater than in women with conserved ovaries . The Women 's Health Initiative ( WHI ) Estrogen-Alone Trial , a large-scale , r and omized trial of estrogen therapy in 10739 women aged 50 to 79 years with prior hysterectomy with or without BSO , provides a unique opportunity to investigate these issues , which have not been examined in a r and omized trial setting . Because prior analyses of the benefits and risks of estrogen therapy for the WHI study population indicate variation by age at r and om assignment ( 20 , 21 ) , assessing the effects of such therapy not only according to BSO status but also jointly by BSO status and age is of interest . Results of such analyses may inform clinical decision making about estrogen therapy . Methods Study Design The WHI Estrogen-Alone Trial , including the design , compliance , and outcome adjudication procedures , is described elsewhere ( 2023 ) . A total of 10739 postmenopausal women aged 50 to 79 years with prior hysterectomy were recruited from 1993 to 1998 at 40 U.S. clinical centers and r and omly assigned to oral conjugated equine estrogens ( CEE [ Premarin ; Pfizer ] ) ( 0.625 mg/d ) or placebo . Primary outcomes were incident CHD and invasive breast cancer . Each center obtained institutional review board approval , and all participants provided written informed consent . The intervention was stopped on 29 February 2004 ( after a median of 7.2 years [ interquartile range , 6.4 to 8.1 years ] ) , earlier than planned , because of an increased risk for stroke not offset by a lower risk for CHD in the CEE group ( 23 ) . Postintervention follow-up was available through 31 December 2014 ( median , 18 years of cumulative follow-up ) for mortality end points and 30 September 2014 for other incident events . Mortality end points were ascertained by regular surveillance of the cohort through the National Death Index and by next-of-kin or postal service reports ( 20 , 22 ) . Summary statistics may differ slightly from those in previous publications because of more thorough end point ascertainment in this report . After the trial ended , participants were told their r and om assignment ; fewer than 4 % reported personal posttrial use of systemic estrogen . Statistical Analysis Intervention-phase analyses included all r and omly assigned participants with known oophorectomy status ( n = 9939 ) , stratified by whether they reported having undergone surgical removal of both ovaries ( BSO ) before r and om assignment . Women reporting no BSO  , and those reporting single or partial oophorectomy , were classified as not having undergone BSO . Of these , nearly three quarters had both ovaries intact , one quarter had 1 ovary removed , and 3 % had part of an ovary removed . Participants were analyzed according to their r and om assignment until the last intervention contact , using time-to-event methods based on the intention-to-treat principle . A composite global index of monitored clinical events was calculated as the time to first event for CHD , invasive breast cancer , stroke , pulmonary embolism , colorectal cancer , hip fracture , and death . Results are presented for the trial 's primary outcomes ( CHD and invasive breast cancer ) , all-cause mortality , and the global index . Analyses of other end points in the global index and other major end points ( total myocardial infa rct ion , coronary revascularization , total cancer , total cardiovascular mortality , and total cancer mortality ) , as in previous reports ( 20 , 21 , 24 , 25 ) , are presented in Appendix Figures 1 and 2 and should be interpreted cautiously because of multiple comparisons . Appendix Figure 1 . Results for various health outcomes in women with BSO in the WHI Estrogen-Alone Trial , by 10-year age group , during cumulative follow-up ( intervention phase plus postintervention phase ) . History of disease was missing for CABG or PCI ( n = 53 ) and total cancer ( n = 37 ) . For the corresponding analyses , baseline hazard functions were stratified according to their missing disease history coded as no. BSO = bilateral salpingo-oophorectomy ; CABG = coronary artery bypass grafting ; CEE = conjugated equine estrogens ; CVD = cardiovascular disease ; HR = hazard ratio ; MI = myocardial infa rct ion ; PCI = percutaneous coronary intervention ; WHI = Women 's Health Initiative . * Percentages are annualized . Difference in estimated absolute risks ( CEE alone minus placebo ) per 10000 PY . P value is 1degree-of-freedom test of trend for the interaction ( product term ) between the indicator variable for r and omization group and age group ( assigned integer values of 0 , 1 , or 2 ) based on a stratified score ( log-rank ) test . Appendix Figure 2 . Results for various health outcomes in women without BSO in the WHI Estrogen-Alone Trial , by 10-year age group , during cumulative follow-up ( intervention phase plus postintervention phase ) . History of disease was missing for  CABG or PCI ( n = 77 ) and total cancer ( n = 55 ) . For the corresponding analyses , baseline hazard functions were stratified according to their missing disease history coded as no. BSO = bilateral salpingo-oophorectomy ; CABG = coronary artery bypass grafting ; CEE = conjugated equine estrogens ; CVD = cardiovascular disease ; HR = hazard ratio ; MI = myocardial infa rct ion ; PCI = percutaneous coronary intervention ; WHI = Women 's Health Initiative . * Percentages are annualized . Difference in estimated absolute risks ( CEE alone minus placebo ) per 10000 PY . P value is 1degree-of-freedom test of trend for the interaction ( product term ) between the indicator variable for r and omization group and age group ( assigned integer values of 0 , 1 , or 2 ) based on a stratified score ( log-rank ) test . Hazard ratios ( HRs ) were estimated using Cox proportional hazards models stratified by BSO status ( yes or no ) at enrollment , age , r and omization status in the WHI-DM ( Women 's Health Initiative Dietary Modification Trial ) , prior cardiovascular or other disease ( if appropriate ) , and study phase ( time-dependent strata ) . Preplanned analyses included presentation of intervention-phase and cumulative follow-up HRs and forest plots for women with and without BSO separately , then additionally stratified by 10-year age group . Hazard ratios may exhibit within- or between-phase time dependencies ( 20 , 21 ) . Hazard ratios for varying cumulative follow-ups have been previously reported ( 20 , 21 , 24 , 25 ) , with additional follow-up and extended cumulative incidence curves ( 26 ) included in the current analyses . Cumulative incidence curves were st and ardized using inverse probability weighting ( 26 ) and computed for the full cohort so that BSO and r and omization groups were balanced with respect to age and other variables described earlier ( as used to stratify the baseline hazard functions for the primary analysis ) . Incidence curves by 10-year age group were then computed using these weights . Within each BSO stratum , interactions between r and omization group and age group were assessed with a 1degree-of-freedom test for linear trend , with each age group assigned an integer value of 0 , 1 , or 2 . Exploratory analyses were also stratified by age at BSO . In addition , we examined whether the overall influence of CEE depended on time elapsed ( < 10 , 10 to < 20 , or 20 years ) from age at BSO to age when r and omly assigned to CEE ( defined as gap time ) by including gap-time interaction variables . Statistical tests were based on a 2-sided stratified score ( log-rank ) test , with nominal ( unadjusted ) P values of 0.05 or less considered statistically significant . P values should be interpreted cautiously because of multiple comparisons . Sensitivity analyses censored participants who took fewer than 80 % of study pills during the preceding follow-up period , excluded women who reported unilateral or partial oophorectomy , stratified by prer and omization use of hormone therapy , and adjusted for characteristics that differed by BSO status or age group . The latter analysis included the baseline variables of age , clinic-measured baseline body mass index ( BMI ) , systolic and diastolic blood pressure as linear covariates , and indicator variables for medications recorded at baseline ( aspirin and medications for diabetes , hypertension , and hyperlipidemia ) to account for differences in cardiovascular and mortality risk factors associated with BSO status ( 27 ) , with additional stratification of the baseline hazard functions by race or ethnicity . This select list of covariates maintained the integrity of the r and omization by excluding fewer than 0.5 % of r and omly assigned participants because of missing covariates . Statistical analyses were conducted using SAS , version 9.4 ( SAS Institute ) , and R , version 3.4 , packages survival ( 28 ) and rmeta ( 29 ) ( R Foundation for Statistical Computing ) . Role of the Funding Source The WHI is funded by the National Heart , Lung , and Blood Institute ( NHLBI ) ; National Institutes of Health ; and U.S. Department of Health and Human Services . Wyeth Ayerst BACKGROUND Case-control studies have reported that exogenous estrogen use is associated with increased  risk of skin cancer .  The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma  were evaluated in post hoc analyses of the Women 's Health Initiative r and omized placebo-controlled hormone therapy trials of combined estrogen plus progestin ( E + P ) and estrogen only ( E-alone ) . METHODS Postmenopausal women aged 50 - 79 years were r and omly assigned to conjugated equine estrogen ( 0.625 mg/d ) plus medroxyprogesterone acetate ( 2.5 mg/d ) or placebo in the E + P trial if they had an intact uterus ( N = 16,608 ) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy ( N = 10,739 ) ; the mean follow-up was 5.6 and 7.1 years , respectively . Incident nonmelanoma skin cancers ( n = 980 [ E + P trial ] ; n = 820 [ E-alone trial ] ) and melanomas ( n = 57 [ E + P trial ] ; n = 38 [ E-alone trial ] ) were ascertained by self-report . Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records . Incidences of nonmelanoma skin cancer and melanoma were compared between the two r and omization groups within each trial using hazard ratios ( HRs ) , with corresponding 95 % confidence intervals ( CIs ) and Wald statistic P values from Cox proportional hazards models . All statistical tests were two-sided . RESULTS Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone ( combined analysis of E + P and E-alone ) and placebo groups ( nonmelanoma skin cancer : HR = 0.98 , 95 % CI = 0.89 to 1.07 ; melanoma : HR = 0.92 , 95 % CI = 0.61 to 1.37 ) . Results were similar for the E + P and E-alone trials when analyzed individually . CONCLUSIONS Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma . These findings do not support a role of menopausal estrogen , with or without progestin , in the development of skin cancer in postmenopausal women Cyclical etidronate has been shown to be effective in the treatment of established postmenopausal osteoporosis but less is known about its effects on early menopausal bone loss .  The aim of the study was to establish the effects of cyclic etidronate therapy on spinal and proximal femoral bone mineral loss in early post-menopausal women . One hundred and seven women who were within 6 months to 3 years of the menopause were recruited into a 2-year , r and omised , placebo-controlled , double-blind trial . Spinal bone mineral density was within 2 SD of the age-matched mean reference value at baseline . Bone mineral density in the lumbar spine and proximal femur was assessed by dual energy X-ray absorptiometry at baseline and thereafter at 6 monthly intervals for 2 years . Urinary collagen cross-links ( deoxypyridinoline and pyridinoline ) were measured at the same time points . Seventy-seven women completed the study . At the end of the treatment period , the mean bone mineral density change from baseline in the treated group was + 0.14 % and −0.06 % in the lumbar spine and femoral neck , respectively , compared to −1.49 and −2.22 in the control group . Overall , there was a significant difference between the two groups at both these sites ( p=0.01 and 0.001 , respectively ) . No significant differences between the groups were demonstrated at the greater trochanter or Ward ’s triangle . The conclusion was that cyclical etidronate therapy  prevents bone loss in the spine and femoral neck in early postmenopausal women . It provides a safe and effective therapeutic option for the prevention of postmenopausal osteoporosis in women who are unwilling or unable to tolerate hormone replacement therapy 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 : The aim of this study was to determine the effect of DRIs on hot flash symptoms in menopausal women . Design : This was a r and omized , double-blind , placebo-controlled trial of menopausal women , aged 38 to 60 years , who experienced 4 to 14 hot flashes per day . After a 1-week run-in period , a total of 190 menopausal women were r and omized to receive a placebo or 40 or 60 mg/day of a DRI for 12 weeks . The primary outcome was the mean changes from baseline to week 12 in the frequency of hot flashes recorded in the participant diary . The secondary outcomes included changes in quality of life and hormonal profiles . Results : A total of 147 women ( 77 % ) completed the study . It was found that 40 and 60 mg of DRI improved hot flash frequency and severity equally . At 8 weeks hot flash frequency was reduced by 43 % in the 40-mg DRI group and by 41 % in the 60-mg DRI group , compared with 32 % in the placebo group ( P = not significant vs placebo ) . The corresponding numbers for 12 weeks were 52 % , 51 % , and 39 % , respectively ( P = 0.07 and 0.09 vs placebo ) . When comparing the two treatment groups with the placebo group , there were significant reductions in mean daily hot flash frequency . The supplement ( either 40 or 60 mg ) reduced hot flash frequency by 43 % at 8 weeks ( P = 0.1 ) and 52 % at 12 weeks ( P = 0.048 ) but did not cause any significant changes in endogenous sex hormones or thyroid hormones . Menopausal quality of life improved in all three groups , although there were no statistically significant differences between groups . Conclusions : DRI supplementation may be an effective and acceptable alternative to hormone treatment for menopausal hot flashes 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 Rationale : Menopause is associated with changes in sex hormones , which affect immunity , inflammation , and osteoporosis and may impair lung function . Lung function decline has not previously been investigated in relation to menopause . Objectives : To study whether lung function decline , assessed by FVC and FEV1 , is accelerated in women who undergo menopause . Methods : The population ‐based longitudinal European Community Respiratory Health Survey provided serum sample s , spirometry , and question naire data about respiratory and reproductive health from three study waves ( n = 1,438 ) . We measured follicle‐stimulating hormone and luteinizing hormone and added information on menstrual patterns to determine menopausal status using latent class analysis . Associations with lung function decline were investigated using linear mixed effects models , adjusting for age , height , weight , pack‐years , current smoking , age at completed full‐time education , spirometer , and including study center as r and om effect . Measurements and Main Results : Menopausal status was associated with accelerated lung function decline . The adjusted mean FVC decline was increased by −10.2 ml/yr ( 95 % confidence interval [ CI ] , −13.1 to −7.2 ) in transitional women and −12.5 ml/yr ( 95 % CI , −16.2 to −8.9 ) in post‐menopausal women , compared with women menstruating regularly . The adjusted mean FEV1 decline increased by −3.8 ml/yr ( 95 % CI , −6.3 to −2.9 ) in transitional women and −5.2 ml/yr ( 95 % CI , −8.3 to −2.0 ) in post‐menopausal women . Conclusions : Lung function declined more rapidly among transitional and post‐menopausal women , in particular for FVC , beyond the expected age change . Clinicians should be aware that respiratory health often deteriorates during reproductive aging BACKGROUND Concerns regarding the risk of estrogen replacement have result ed in a significant increase in the use of soy products by menopausal women who , despite the lack of evidence of the efficacy of such products , seek alternatives to menopausal hormone therapy . Our goal was to determine the efficacy of soy isoflavone tablets in preventing bone loss and menopausal symptoms . METHODS The study design was a single-center , r and omized , placebo-controlled , double-blind clinical trial conducted from July 1 , 2004 , through March 31 , 2009 . Women aged 45 to 60 years within 5 years of menopause and with a bone mineral density T score of -2.0 or higher in the lumbar spine or total hip were r and omly assigned , in equal proportions , to receive daily soy isoflavone tablets , 200 mg , or placebo . The primary outcome was changes in bone mineral density in the lumbar spine , total hip , and femoral neck at the 2-year follow-up . Secondary outcomes included changes in menopausal symptoms , vaginal cytologic characteristics , N -telopeptide of type I bone collagen , lipids , and thyroid function . RESULTS After 2 years , no significant differences were found between the participants receiving soy tablets ( n = 122 ) and those receiving placebo ( n = 126 ) regarding changes in bone mineral density in the spine ( -2.0 % and -2.3 % , respectively ) , the total hip ( -1.2 % and -1.4 % , respectively ) , or the femoral neck ( -2.2 % and -2.1 % , respectively ) . A significantly larger proportion of participants in the soy group experienced hot flashes and constipation compared with the control group . No significant differences were found between groups in other outcomes . CONCLUSIONS In this population , the daily administration of tablets containing 200 mg of soy isoflavones for 2 years did not prevent bone loss or menopausal symptoms . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00076050 Objective : To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to , and further from , menopause . Methods : In this r and omized , double-blind , placebo-controlled trial , healthy women within 6 years of menopause or 10 + years after menopause were r and omly assigned to oral 17β-estradiol 1 mg/d or placebo .  Women with a uterus received cyclic micronized progesterone vaginal gel or placebo . The primary outcome assessed at 2.5 and 5 years , compared between treatment groups , was change in a st and ardized composite of neuropsychological test scores assessing verbal episodic memory . Secondary outcomes assessed executive functions and global cognition . Results : A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months . For verbal memory , the mean estradiol minus placebo st and ardized difference in composite scores ( −0.06 , 95 % confidence interval −0.22 to 0.09 ) was not significant ( 2-tailed p = 0.33 ) . Differences were similar in early and late postmenopause groups ( 2-tailed interaction p = 0.88 ) . Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition . Conclusions : Estradiol initiated within 6 years of menopause does not affect verbal memory , executive functions , or global cognition differently than therapy begun 10 + years after menopause . Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause . Classification of evidence : This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10 + years after menopause Aim . To evaluate with vali date d instruments changes in quality of life and sexuality in women receiving hormonal replacement therapy ( AHT ) .  Design . R and omised , double-blind , double-dummy study with two parallel treatment arms . Patients and methods . Forty-seven healthy post-menopausal women , aged 45–64 years , were evaluated using the Female Sexual Function Index ( FSFI ) and the menopause-specific quality of life question naire ( MENQOL ) . Of them , 40 diagnosed with sexual dysfunction were r and omised ( 1:1 ) to receive daily 0.625 mg of conjugated estrogens plus 1.25 mg of methyl-testosterone and 100 mg of micronised progesterone or placebo . After 3 months follow-up , FSFI and MENQOL question naires were administered for a second time . Results . Quality of life was unchanged in the placebo group whereas AHT significantly improved scores of vasomotor , psychological , physical and sexual symptoms . As expected , FSFI was not modified in the placebo group while in AHT group the FSFI score improved significantly . In addition , at the end of the study , 68.7 % of subjects of the AHT group did not fit did not fit the criteria for sexual dysfunction as per the FSFI ( p < 0.0001 ) . Conclusions . Adding methyl-testosterone to hormone therapy  improves quality of life and sexuality in post-menopausal women with sexual dysfunction BACKGROUND St and ard methods to prevent chemotherapy-induced early menopause in young , breast cancer patients are unavailable to date . Pre clinical data has suggested that luteinising hormone-releasing hormone ( LH-RH ) analogs given during treatment can decrease the gonado-toxicity induced by chemotherapy . This phase II study aim ed to assess the activity of such a method in young , breast cancer patients undergoing adjuvant chemotherapy . PATIENTS AND METHODS Premenopausal patients received the LH-RH analog goserelin 3.6 mg every 4 weeks before and during chemotherapy . According to two-stage optimal phase II Simon design , treatment was considered clinical ly interesting if it was able to prevent menopause in 19 out of 29 patients of the study population . The resumption of ovarian function was defined by a resumption of menstrual activity or by a follicle-stimulating hormone ( FSH ) value < or = 40 IU/l within 12 months after the last cycle of chemotherapy . RESULTS Thirty patients were enrolled and 29 were evaluable . Median age was 38 years ( range 29 - 47 ) . All but one patient received CEF regimen ( cyclophosphamide , epirubicin , 5-fluorouracil ) .  Resumption of menstrual activity was observed in 21 patients ( 72 % ; 95 % CI 52 % to 87 % ) and a FSH value < or = 40 IU/l in 24 patients ( 83 % ; 95 % CI 63 % to 93 % ) . Menses resumption was observed in 16 out of 17 patients ( 94 % ) with age < 40 years and in five out of 12 patients ( 42 % ) with age > or = 40 years . CONCLUSION Goserelin given before and during chemotherapy may prevent premature menopause in the majority of patients . The different success rate by age , however , indicates the need of a prospect i ve evidence of the efficacy of such a strategy Postmenopausal women are believed to have a higher risk of coronary artery disease than premenopausal women . In this study , we prospect ively determined changes in coronary risk factors that were attributable to natural menopause in 541 healthy , initially premenopausal women 42 to 50 years of age . After approximately 2 1/2 years , 69 women had spontaneously stopped menstruating for at least 12 months , and 32 women had stopped natural menstruation and received hormone-replacement therapy for a period of at least 12 months . An equal number of age-matched premenopausal women in the study group served as controls . In women who had a natural menopause and did not receive hormone-replacement therapy , serum levels of high-density lipoprotein ( HDL ) cholesterol declined as compared with those of premenopausal controls ( -0.09 vs. 0.00 mmol per liter ; P = 0.01 ) , and levels of low-density lipoprotein ( LDL ) cholesterol increased ( + 0.31 vs. + 0.14 mmol per liter ; P = 0.04 ) . In menopausal women who received hormone-replacement therapy , HDL and LDL cholesterol levels did not change , but the levels of triglycerides ( + 0.42 vs. -0.04 mmol per liter ; P less than 0.001 ) , apolipoprotein A-I ( + 0.18 vs. + 0.03 g per liter ; P less than 0.01 ) , and apolipoprotein A-II ( + 0.05 vs. -0.03 g per liter ; P less than 0.05 ) increased as compared with premenopausal controls . Natural menopause did not affect blood pressure , plasma glucose or insulin levels , body weight , the total number of kilojoules consumed in the diet , or the total number of kilojoules expended in physical activity . These results suggest that a natural menopause has an unfavorable effect on lipid metabolism , which may contribute to an increase in the risk of coronary disease .  Hormone-replacement therapy may prevent some of these changes BACKGROUND : Eczema is the most common inflammatory skin disease of childhood , characterized by an itchy red rash that usually involves the face and skin folds . There is currently no curative treatment for eczema , so the reduction of eczema incidence through disease prevention is a desirable goal . Potential interventions for preventing eczema include exclusive breastfeeding , hydrolysed protein formulas and soy formulas when bottle feeding , maternal antigen avoidance , omega oil supplementation , prebiotics and probiotics . OBJECTIVES : This overview of review s aims to present the current body of data from Cochrane and non-Cochrane review s to provide the most up-to- date evidence on the efficacy and safety of interventions to prevent eczema in infants and children at different risk levels for developing allergic disease . METHODS : Our pool of Cochrane and non-Cochrane review s came from the 2010 United Kingdom National Health Service ( NHS ) Evidence Skin Disorders Annual Evidence Up date s Mapping Exercise on Atopic Eczema . This group used a comprehensive search strategy last conducted in August 2010 to identify all systematic review s on eczema prevention . We identified all review s that met our pre-specified inclusion criteria , and data were extracted , analysed , compiled into tables and synthesized using quantitative and qualitative methods . MAIN RESULTS : Seven systematic review s containing 39 relevant trials with 11 897 participants were included in this overview . Overall , there was no clear evidence that any of the main interventions review ed reduced eczema incidence . In subgroup analyses of infants at high risk of allergic disease , an observational study found that exclusive breastfeeding for at least six months compared with introduction of solids at three to six months decreased the incidence of eczema by 60 % ( risk ratio ( RR ) : 0.40 ; 95 % confidence interval ( CI ) : 0.21 , 0.78 ) , and a r and omized controlled trial found that prebiotics compared with no prebiotics  decreased incidence by 58 % ( RR : 0.42 ; 95 % CI : 0.21 , 0.84 ) . However , each of these findings was based on the results of a single small trial , and no intervention reduced eczema incidence beyond the first two years of life . Although we pre-specified incidence of atopic eczema ( i.e. eczema associated with immunoglobulin E ( IgE ) sensitization ) as a primary outcome , data on whether participants diagnosed with eczema were truly atopic were largely lacking from systematic review s. Similarly , data on atopy , measured using skin prick tests or specific IgE tests to allergens , were not reported in many review s. No interventions were found to decrease atopy when reported . Adverse events data were generally lacking , but data from a trial of probiotics versus no probiotics showed significantly more spitting up in the first one ( RR : 1.88 ; 95 % CI : 1.03 , 3.45 ) and two ( RR : 1.69 ; 95 % CI : 1.02 , 2.80 ) months of life , but no overall increase in risk of gastrointestinal symptoms in the first year . AUTHORS # ENTITYSTARTX02019 ; CONCLUSIONS : Although there is currently no clear evidence showing that any of the interventions examined in this overview prevent eczema in participants not selected for risk of allergic disease , there is some evidence that exclusive breastfeeding for at least six months and prebiotics might reduce eczema incidence in high-risk participants . However , these conclusions are based on limited evidence with method ological shortcomings . Future research on prevention of eczema is needed and should examine different types of hydrolysed formulas , prebiotics and probiotics , as well as enhancement of the skin barrier and other novel approaches in infants at different risk levels for developing allergic disease Purpose of review Provide evidence -based recent data on oral micronized progesterone ( OMP ) and progestins in menopausal hormonal therapy ( MHT ) . Recent findings Medroxyprogesterone acetate ( MPA ) increases breast cancer acting through the glucocorticoid receptor ; progestins in MHT increase thrombosis more than oral estrogens ; MPA , but not OMP or other progestins , increase monocyte cell endothelium adhesion ; MPA and estradiol (E2)/MPA have negative brain effects , whereas E2/progesterone ( P4 ) has neuroregenerative brain effects . The ‘ window of opportunity ’ cardiovascular disease hypothesis is not supported by a r and omized controlled trial showing that transdermal estradiol with sequential OMP in early menopause does not prevent increased carotid intimal media thickness ; P4 in the cardiac electrical system opposes E2 effects and prevents sudden death/long QT syndrome ;  transdermal estradiol/OMP does not increase venous thromboembolism in observational data . P4 decreases breast cell proliferation and improves prognosis through P4 receptor alteration of estrogen receptor & agr ; genetic effects ;  OMP with conjugated equine estrogen (CEE)/estrogen (E)/E2 does not increase breast cancer in two prospect i ve cohorts , one population -based . Endometrial cancer is increased in MHT of CEE/E/E2+cyclic OMP at 200 mg/day . Summary New data show CEE/E/E2+MPA/P mechanisms for negative breast cancer , venous thromboembolism , cardiovascular system , and brain effects .  OMP/P4 counterbalances CEE/E/E2-related negative effects on breast cancer and long QT syndrome .  OMP effectively treats vasomotor symptoms and sleep disturbances , and could safely be used alone for symptomatic menopause For the current issue of the Journal , we asked Drs Anna Taddio and C Meghan McMurtry to comment on and put into context the Cochrane Review on psychological interventions for needle-related procedural pain and distress in children and adolescents ( 1 ) . Background This review is an up date d version of the original Cochrane review published in Issue 4 , 2006 . Needle-related procedures are a common source of pain and distress for children . Our previous review on this topic indicated that several psychological interventions were efficacious in managing paediatric needle pain including distraction , hypnosis and combined cognitive behavioural interventions . Considerable additional research in the area has been published since that time . Methods Search strategy Search es of the following data bases were conducted for relevant r and omized controlled trials ( RCTs ): Cochrane Central Register of Controlled Trials ( CENTRAL ) ; MEDLINE ; EMBASE ; PsycINFO ; the Cumulative Index to Nursing and Allied Health Literature ( CINAHL ) ; and Web of Science . Requests for relevant studies were also posted on various electronic list servers . An up date d search was conducted in March 2012 and again in March 2013 . Selection criteria Participants included children and adolescents two to 19 years of age undergoing needle-related procedures . Only RCTs with ≥5 participants in each study arm comparing a psychological intervention group with a control or comparison group were eligible for inclusion . Data analysis Two review authors extracted data and assessed trial quality , and a third author helped with data extraction and coding for one non-English study . Included studies were coded for quality using the Cochrane Risk of bias tool . St and ardized mean differences with 95 % CIs were calculated for all analyses using Review Manager version 5.2 . Results Thirty-nine trials with a total of 3394 participants were included . The most commonly studied needle-related procedures were veni-puncture , intravenous line insertion and immunization .  Studies included children two to 19 years of age , with the most evidence available for children < 12 years of age . Consistent with the original review , the most commonly studied psychological interventions for needle procedures were distraction , hypnosis and cognitive behavioural therapy ( CBT ) . The majority of included studies ( 19 of 39 ) examined distraction only . The additional studies from this review up date continued to provide strong evidence for the efficacy  of distraction and hypnosis . No evidence was available to support the efficacy of preparation and information , combined CBT ( ≥2 cognitive or behavioural strategies combined ) , parent coaching plus distraction , suggestion or virtual reality for reducing children ’s pain and distress . No conclusions could be drawn about interventions of memory alteration , parent positioning plus distraction , blowing out air or distraction plus suggestion because evidence was available from single studies only . In addition , the risk of bias scores indicated several domains with high or unclear bias scores ( eg , selection , detection and performance bias ) , suggesting that the method ological rigour and reporting of RCTs of psychological interventions continue to exhibit considerable room for improvement . Conclusions Overall , there is strong evidence supporting the efficacy of distraction and hypnosis for needle-related pain and distress in children and adolescents , with no evidence currently available for preparation and information or both , combined CBT , parent coaching plus distraction , suggestion or virtual reality . Additional research is needed to further assess interventions that have only been investigated in one RCT to date ( ie , memory alteration , parent positioning plus distraction , blowing out air and distraction plus suggestion ) . There are continuing issues with the quality of trials examining psychological interventions for needle-related pain and distress . The full text of the Cochrane Review is available in The Cochrane Library ( 1 ) 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 BACKGROUND Axillary lymph node clearance ( ALNC ) improves locoregional control and provides prognostic information for early breast cancer treatment , but effects on survival are controversial . This multicentre , r and omized pragmatic equivalence trial compares outcomes for post-menopausal early invasive breast cancer patients after locoregional treatment with ALNC and adjuvant therapies to outcomes after locoregional treatment  without ALNC and adjuvant therapies . METHODS From 1995 - 2005 , women aged ≥ 50 years with early breast cancer ( tumor ≤ 10 mm ) and clinical ly-negative axillary nodes were r and omized to receive treatment with ALNC ( Ax ) or without ( no-Ax ) . Adjuvant therapies were prescribed according to hormonal receptor status and individual histological results . The primary endpoint was overall survival ( OS ) ; secondary endpoints were event-free survival ( EFS ) and functional outcomes . The trial was terminated due to lack of equivalence and low accrual after first interim analyses . TRIAL REGISTRATION NCT00210236 . RESULTS Of 625 patients , 297 no-Ax and 310 Ax patients were maintained for final per- protocol analyses . OS and EFS at five years were not equivalent ( Ax vs. no-Ax : 98 % vs. 94 % and 96 % vs. 90 % respectively ) . Recurrence was higher for no-Ax , particularly in the first five years after surgery . Axillary nodes were positive for 14 % Ax patients but only 2 % no-Ax patients experienced axillary node recurrence . Functional impairments were greater after ALNC . CONCLUSION Our results fail to demonstrate equivalence of outcomes when ALNC is omitted from post-menopausal early breast cancer patient treatment . However the low locoregional recurrence rates warrant further examination over a longer duration , in particular to consider whether these would impact on survival OBJECTIVE : To determine the safety and efficacy of a transdermal nanostructured formulation of progesterone ( 10 % ) combined with estriol ( 0.1 % ) + estradiol ( 0.25 % ) for relieving postmenopausal symptoms . METHODS : A total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern . Confocal Raman spectroscopy of hormones in skin layers was performed . Clinical parameters , serum concentrations of estradiol and follicle-stimulating hormone , blood pressure , BI-RADS classification from bilateral mammography , and symptomatic relief were compared between baseline and 60 months post-treatment . Clinical trials.gov : NCT02033512 . RESULTS : An improvement in climacteric symptoms was reported in 92.5 % of women evaluated before and after 60 months of treatment . The serum concentrations of estradiol and follicle-stimulating hormone changed significantly ( p<0.05 ) after treatment ; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04±4.9 to 57.12±4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women . No adverse health-related events were attributed to this hormone replacement therapy protocol . CONCLUSION : The nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause . This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women CONTEXT Menopausal hormone therapy has long been credited with many benefits beyond the indications of relieving hot flashes , night sweats , and vaginal dryness , and it is often prescribed to treat urinary incontinence ( UI ) . OBJECTIVE To assess the effects of menopausal hormone therapy on the incidence and severity of symptoms of stress , urge , and mixed UI in healthy postmenopausal women . DESIGN , SETTING , AND PARTICIPANTS Women 's Health Initiative multicenter double-blind , placebo-controlled , r and omized clinical trials of menopausal hormone therapy in 27,347 postmenopausal women aged 50 to 79 years enrolled between 1993 and 1998 , for whom UI symptoms were known in 23,296 participants at baseline and 1 year . INTERVENTIONS Women were r and omized based on hysterectomy status to active treatment or placebo in either the estrogen plus progestin ( E + P ) or estrogen alone trials . The E + P hormones were 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate ( CEE + MPA ) ; estrogen alone consisted of 0.625 mg/d of conjugated equine estrogen ( CEE ) . There were 8506 participants who received CEE + MPA ( 8102 who received placebo ) and 5310 who received  CEE alone ( 5429 who received placebo ) . MAIN OUTCOME MEASURES Incident UI at 1 year among women without UI at baseline and severity of UI at 1 year among women who had UI at baseline . RESULTS Menopausal hormone therapy increased the incidence of all types of UI at 1 year among women who were continent at baseline . The risk was highest for stress UI ( CEE + MPA : relative risk [ RR ] , 1.87 [ 95 % confidence interval { CI } , 1.61 - 2.18 ] ; CEE alone : RR , 2.15 [ 95 % CI , 1.77 - 2.62 ] ) , followed by mixed UI ( CEE + MPA : RR , 1.49 [ 95 % CI , 1.10 - 2.01 ] ; CEE alone : RR , 1.79 [ 95 % CI , 1.26 - 2.53 ] ) . The combination of CEE + MPA had no significant effect on developing urge UI ( RR , 1.15 ; 95 % CI , 0.99 - 1.34 ) , but CEE alone increased the risk ( RR , 1.32 ; 95 % CI , 1.10 - 1.58 ) . Among women experiencing UI at baseline , frequency worsened in both trials ( CEE + MPA : RR , 1.38 [ 95 % CI , 1.28 - 1.49 ] ; CEE alone : RR , 1.47 [ 95 % CI , 1.35 - 1.61 ] ) . Amount of UI worsened at 1 year in both trials ( CEE + MPA : RR , 1.20 [ 95 % CI , 1.06 - 1.36 ] ; CEE alone : RR , 1.59 [ 95 % CI , 1.39 - 1.82 ] ) . Women receiving menopausal hormone therapy  were more likely to report that UI limited their daily activities ( CEE + MPA : RR , 1.18 [ 95 % CI , 1.06 - 1.32 ] ; CEE alone : RR , 1.29 [ 95 % CI , 1.15 - 1.45 ] ) and bothered or disturbed them ( CEE + MPA : RR , 1.22 [ 95 % CI , 1.13 - 1.32 ] ; CEE alone : RR , 1.50 [ 95 % CI , 1.37 - 1.65 ] ) at 1 year . CONCLUSIONS Conjugated equine estrogen alone and CEE + MPA increased the risk of UI  among continent women and worsened the characteristics of UI among symptomatic women after 1 year . Conjugated equine estrogen with or without progestin should not be prescribed for the prevention or relief of UI 1 . A r and omized controlled trial of the effect of oral hormone replacement therapy plus calcium compared with calcium alone on balance , muscle performance and falls was conducted over 48 weeks in 116 post-menopausal women ( aged 45 - 70 years ) , all of whom had suffered a distal radial fracture during the previous 3 months . Treatment was with Prempak C or Premarin 0.625 mg in the test group with 1 g calcium daily ( S and ocal ) in both groups . Measurements were made of balance , assessed as sway , leg extensor power and self-paced walking speed , at 12-week intervals over 24 weeks . H and grip strength was measured every 12 weeks for 48 weeks , and falls in the preceding 12 weeks were recorded at each visit . 2 . There was no relation between initial levels of oestradiol and any other variable assessed , except body mass . Levels of follicle-stimulating hormone in the test group were in the premenopausal range . There was no significant change attributable to hormone replacement therapy at any time point in any of the outcome variables . The only significant difference was an increase of 4.2 % ( 95 % confidence interval 0.7 - 7.6 % ) in leg extensor power in the control group ( calcium alone ) compared with the group treated with hormone replacement therapy . 3 . Of the total group , 37 % fell again during the year , with three patients suffering a further fracture . Frequent fallers swayed significantly more often than the others , but there was no evidence that their muscle strength was poorer or that the group treated with hormone replacement therapy fell less frequently . 4 . Hormone replacement therapy did not increase muscle performance , improve balance or reduce falls over a year in middle-aged women Changes in  FSH and estradiol ( E2 ) across the menopausal transition are clearly not linear . The present study utilizes data from 204 women who completed the 13-year prospect i ve Melbourne Women 's Midlife Health Project .  E2 , FSH , symptoms , self-rated health , mood , sexual function and coronary heart disease ( CHD ) risk were measured longitudinally . We presumed an s-shaped curve for each hormone and estimated five parameters for each hormone curve for each woman : baseline , final value , range , slope at inflexion point and age at inflexion point . These parameters were found to adequately estimate the curve for each hormone . The median age of transition observed for E2 occurs > 1 year later than the median age of transition observed for FSH . FSH parameters did not affect any of the health outcomes analysed . Hot flushes , night sweats , sleeping problems , vaginal dryness and to a lesser extent self-rated health were highly significantly associated with E2 range and slope . Sexual response and CHD risk were highly significantly associated with final E2 level ( post-menopausally ) . These findings have clinical relevance in identifying which symptoms will be triggered by steep transitions of E2 such as sudden withdrawal and which health parameters may require a maintenance level of E2 Background — It is well known that statins reduce the risk of cardiovascular disease . However , the effect of statins in women for the primary prevention of cardiovascular disease has not been determined . We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of  cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin . Methods and Results — Patients with hypercholesterolemia ( 5.7 to 7.0 mmol/L ) and no history of coronary heart disease or stroke were r and omized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for ≥5 years . We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up . The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men . The occurrence of cardiovascular events was 26 % to 37 % lower in the diet plus pravastatin treatment group than in the diet alone group . Although these differences did not reach statistical significance , the overall risk reductions were similar to those in men . Notably , women ≥60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease ( 45 % ) , coronary heart disease plus cerebral infa rct ion ( 50 % ) , and stroke ( 64 % ) than did women treated with diet alone . Conclusions — Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men , and this benefit is more marked in older women . This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels 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 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 Background Premature menopause is a major concern of younger women undergoing adjuvant therapy for breast cancer . Hormone replacement therapy is contraindicated in women with a history of breast cancer . Non-hormonal medications show a range of bothersome side-effects . There is growing evidence that cognitive behavioral therapy ( CBT ) and physical exercise can have a positive impact on symptoms in naturally occurring menopause . The objective of this study is to investigate the efficacy of these interventions among women with breast cancer experiencing treatment-induced menopause . Methods / design In a r and omized , controlled , multicenter trial , we are evaluating the effectiveness of CBT/relaxation , of physical exercise and of these two program elements combined , in reducing menopausal symptoms , improving sexual functioning , reducing emotional distress , and in improving the health-related quality of life of younger breast cancer patients who experience treatment-induced menopause . 325 breast cancer patients ( aged < 50 ) are being recruited from hospitals in the Amsterdam region , and r and omly allocated to one of the three treatment groups or a ' waiting list ' control group . Self-administered question naires are completed by the patients at baseline , and at 12 weeks ( T1 ) and 6 months ( T2 ) post- study entry . Upon completion of the study , women assigned to the control group will be given the choice of undergoing either the CBT or physical exercise program . Discussion Cognitive behavioral therapy and physical exercise are potentially useful treatments among women with breast cancer undergoing treatment-induced , premature menopause . For these patients , hormonal and non-hormonal therapies are contraindicated or have a range of bothersome side-effects . Hence , research into these interventions is needed , before dissemination and implementation in the current health care system can take place . Trial registration The study is registered at the Netherl and s Trial Register ( NTR1165 ) and Clinical Trials.gov ( NCT00582244 ) 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 Background Many national and international guidelines recommend that the initiation of blood pressure (BP)-lowering drug treatment for the primary prevention of cardiovascular disease ( CVD ) should no longer be based on BP level alone , but on absolute cardiovascular risk . While BP-lowering drug treatment is beneficial in high-risk individuals at any level of elevated BP , clinicians are concerned about legacy effects on patients with low-to-moderate risk and mildly elevated BP who remain “ untreated ” . Objective We aim to investigate the legacy effect of delayed BP-lowering pharmacotherapy in middle-aged individuals ( 45 - 65 years ) with mildly elevated BP ( systolic BP 140 - 159 mmHg and /or diastolic BP 90 - 99 mmHg ) stratified by absolute risk for primary prevention of CVD , but particularly in the low-risk ( < 10 % five-year absolute risk ) group . Methods R and omized trials of BP-lowering therapy versus placebo or pretreated subjects in active comparator studies with posttrial follow-up will be identified using a 2-step process . First , r and omized trials of BP-lowering therapy will be identified by ( 1 ) retrieving the references of trials included in published systematic review s of BP-lowering therapy , ( 2 ) retrieving studies published by the Blood Pressure Lowering Treatment Trialists ’ Collaboration ( BPLTTC ) , and ( 3 ) checking studies referenced in the 1993 World Health Organization/International Society of Hypertension meeting memor and um on BP management . Posttrial follow-up studies will then be identified by forward citation search ing the r and omized trials identified in step 1 through Web of Science . The search will include r and omized controlled trials with at least 1-year in-trial period and a posttrial follow-up phase . Age is the major determinant of absolute cardiovascular risk , so the participants in our review will be restricted to middle-aged adults who are more likely to have a lower cardiovascular risk profile . The primary outcome will be all-cause mortality . Secondary outcomes will include cardiovascular mortality , fatal stroke , fatal myocardial infa rct ion , and death due to heart failure . Results The search es for existing systematic review s and BPLTTC studies were piloted and modified . The study is expected to be completed before June 2018 . Conclusions The findings of this study will contribute to the body of knowledge concerning the beneficial , neutral , or harmful effects of delayed BP-lowering drug treatment on the primary prevention of CVD in patients with mildly elevated BP and low-to-moderate CVD risk . Trial Registration PROSPERO International Prospect i ve Register of Systematic Review s : CRD42017058414 ; https://www.crd.york.ac.uk/ PROSPERO /display_record.asp?ID = CRD42017058414 ( Archived by WebCite ® at http://www.webcitation.org/6t6sa8O2Q BACKGROUND Systematic review s may be compromised by selective inclusion and reporting of outcomes and analyses . Selective inclusion occurs when there are multiple effect estimates in a trial report that could be included in a particular meta- analysis ( e.g. from multiple measurement scales and time points ) and the choice of effect estimate to include in the meta- analysis is based on the results ( e.g. statistical significance , magnitude or direction of effect ) . Selective reporting occurs when the reporting of a subset of outcomes and analyses in the systematic review is based on the results ( e.g. a protocol -defined outcome is omitted from the published systematic review ) . OBJECTIVES To summarise the characteristics and synthesis e the results of empirical studies that have investigated the prevalence of selective inclusion or reporting in systematic review s of r and omised controlled trials ( RCTs ) , investigated the factors ( e.g. statistical significance or direction of effect ) associated with the prevalence and quantified the bias . SEARCH METHODS We search ed the Cochrane Methodology Register ( to July 2012 ) , Ovid MEDLINE , Ovid EMBASE , Ovid PsycINFO and ISI Web of Science ( each up to May 2013 ) , and the US Agency for Healthcare Research and Quality ( AHRQ ) Effective Healthcare Program 's Scientific Re source Center ( SRC ) Methods Library ( to June 2013 ) . We also search ed the abstract books of the 2011 and 2012 Cochrane Colloquia and the article alerts for method ological work in research synthesis published from 2009 to 2011 and compiled in Research Synthesis Methods . SELECTION CRITERIA We included both published and unpublished empirical studies that investigated the prevalence and factors associated with selective inclusion or reporting , or both , in systematic review s of RCTs of healthcare interventions . We included empirical studies assessing any type of selective inclusion or reporting , such as investigations of how frequently RCT outcome data is selectively included in systematic review s based on the results , outcomes and analyses are discrepant between protocol and published review or non-significant outcomes are partially reported in the full text or summary within systematic review s. DATA COLLECTION AND ANALYSIS Two review authors independently selected empirical studies for inclusion , extracted the data and performed a risk of bias assessment . A third review author resolved any disagreements about inclusion or exclusion of empirical studies , data extraction and risk of bias . We contacted authors of included studies for additional unpublished data . Primary outcomes included overall prevalence of selective inclusion or reporting , association between selective inclusion or reporting and the statistical significance of the effect estimate , and association between selective inclusion or reporting and the direction of the effect estimate . We combined prevalence estimates and risk ratios ( RRs ) using a r and om-effects meta- analysis model . MAIN RESULTS Seven studies met the inclusion criteria . No studies had investigated selective inclusion of results in systematic review s , or discrepancies in outcomes and analyses between systematic review registry entries and published systematic review s. Based on a meta- analysis of four studies ( including 485 Cochrane Review s ) , 38 % ( 95 % confidence interval ( CI ) 23 % to 54 % ) of systematic review s added , omitted , up grade d or down grade d at least one outcome between the protocol and published systematic review . The association between statistical significance and discrepant outcome reporting between protocol and published systematic review was uncertain . The meta-analytic estimate suggested an increased risk of adding or upgrading ( i.e. changing a secondary outcome to primary ) when the outcome was statistically significant , although the 95 % CI included no association and a decreased risk as plausible estimates ( RR 1.43 , 95 % CI 0.71 to 2.85 ; two studies , n = 552 meta-analyses ) . Also , the meta-analytic estimate suggested an increased risk of downgrading ( i.e. changing a primary outcome to secondary ) when the outcome was statistically significant , although the 95 % CI included no association and a decreased risk as plausible estimates ( RR 1.26 , 95 % CI 0.60 to 2.62 ; two studies , n = 484 meta-analyses ) . None of the included studies had investigated whether the association between statistical significance and adding , upgrading or downgrading of outcomes was modified by the type of comparison , direction of effect or type of outcome ; or whether there is an association between direction of the effect estimate and discrepant outcome reporting . Several secondary outcomes were reported in the included studies . Two studies found that reasons for discrepant outcome reporting were infrequently reported in published systematic review s ( 6 % in one study and 22 % in the other ) . One study ( including 62 Cochrane Review s ) found that 32 % ( 95 % CI 21 % to 45 % ) of systematic review s did not report all primary outcomes in the abstract . Another study ( including 64 Cochrane and 118 non-Cochrane review s ) found that statistically significant primary outcomes were more likely to be completely reported in the systematic review abstract than non-significant primary outcomes ( RR 2.66 , 95 % CI 1.81 to 3.90 ) . None of the studies included systematic review s published after 2009 when reporting st and ards for systematic review s ( Preferred Reporting Items for Systematic review s and Meta-Analyses ( PRISMA ) Statement , and Method ological Expectations of Cochrane Intervention Review s ( MECIR ) ) were disseminated , so the results might not be generalisable to more recent systematic review s. AUTHORS ' CONCLUSIONS Discrepant outcome reporting between the protocol and published systematic review is fairly common , although the association between statistical significance and discrepant outcome reporting is uncertain . Complete reporting of outcomes in systematic review abstract s is associated with statistical significance of the results for those outcomes . Systematic review outcomes and analysis plans should be specified prior to seeing the results of included studies to minimise post-hoc decisions that may be based on the observed results . Modifications that occur once the review has commenced , along with their justification , should be clearly reported . Effect estimates and CIs should be reported for all systematic review outcomes regardless of the results . The lack of research on selective inclusion of results in systematic review s needs to be addressed and studies that avoid the method ological weaknesses of existing research are also needed AIM Previous clinical studies suggest hormone replacement therapy ( HRT ) alleviates menopausal symptoms and may improve health-related quality of life ( HRQL ) . Most studies on HRT and HRQL were limited in duration ( 12 months or less ) and scope ( few and non-st and ard HRQL measures ) . The aim of this paper is to assess HRQL in the Estrogen Replacement and Atherosclerosis ( ERA ) trial . METHODS A subset of women within a r and omized , blinded , placebo-controlled secondary prevention trial has been studied in outpatient and community setting s at 5 US sites . A total of 246 postmenopausal women with angiographically documented heart disease ( mean age 66 years , 83 % Caucasian ) were enrolled in the ERA trial . Participants received either 0.625 mg/day conjugated equine estrogen only , estrogen plus 2.5 mg/day medroxyprogesterone acetate , or placebo .  HRQL was assessed using vali date d question naire instruments at baseline and follow-up ( mean 3.2 years of trial ) . Physical and mental functioning , life satisfaction , depressive symptoms , urinary incontinence , sleep disturbance , and frequency and intensity of physical symptoms were evaluated . RESULTS In this group of women with established coronary disease , active therapy was not significantly associated with more favorable outcomes for any HRQL . The estrogen-only group reported more urinary incontinence than the placebo group ( p<0.05 ) . Analyses restricted to adherent women ( those who took > or = 80 % of pills ) showed a similar pattern of results , showing that the estrogen only group reported significantly higher urinary incontinence compared to placebo ( p<0.01 ) . CONCLUSION The hormone replacement regimens in the ERA trial did not improve HRQL of postmenopausal women with heart disease Women diagnosed with breast cancer often experience early menopause secondary to treatment effects , yet physicians may be reluctant to prescribe hormone replacement therapy ( HRT ) because of the potential increased risk of recurrence . To assess the burden of menopausal symptoms , HRT use , and alternative treatments in recent breast cancer survivors , a population -based , case-control study was conducted among breast cancer survivors and age-matched controls . Wisconsin women 18 - 69 years old with a new diagnosis of breast cancer 8 - 11 months prior to interview ( n = 110 ) and control subjects r and omly selected from population lists ( n = 73 ) responded to a st and ardized telephone question naire that elicited information on menopausal symptoms , estrogen and alternative therapies ( prescription medications , vitamins , herbal preparations , soy products , acupuncture , chiropractic ) used to alleviate symptoms . We used multivariate logistic regression to obtain odds ratios and 95 % confidence intervals ( CI ) for symptoms of menopause , use of estrogen , and use of alternative therapies .  Breast cancer survivors were 5.3 ( 95 % CI 2.7 - 10.2 ) times more likely to experience symptoms , 25 ( 95 % CI 8.3 - 100 ) times less likely to use estrogen , and 7.4 ( 95 % CI 2.5 - 21.9 ) times more likely to use alternatives than controls .  Soy , vitamin E , and herbal remedies were the most common alternative therapies reported by participants ; use was greater in cases compared to controls . Most soy users reported increasing soy products specifically to reduce the chances of a diagnosis of recurrent breast cancer . Among cases ,  tamoxifen  users ( n = 62 ) reported a higher prevalence of symptoms and a higher prevalence of  alternative treatments .  This is the first population -based survey of menopausal symptoms and treatments that compares breast cancer cases with disease-free controls . Cases are both more likely to experience menopausal symptoms and less likely to use HRT  than controls . Instead , cases treat menopausal symptoms with vitamin E and soy products , even though the safety and efficacy of these therapies are unproven . The increased use of soy products in this population has not been previously documented BACKGROUND A number of factors contribute to increased risk of coronary heart disease ( CHD ) among postmenopausal women , including atherogenic changes in serum cholesterol profiles , weight gain , and decreases in physical activity during the menopause . To date , no study has attempted to prevent elevations in primary CHD risk factors as women experience menopause . METHODS A sample of 535 healthy premenopausal women , ages 44 - 50 , were recruited for an ongoing 5-year r and omized prevention trial testing whether increases in low-density lipoprotein cholesterol ( LDL-C ) and body weight can be prevented during the menopause with a dietary and behavioral intervention . The aim was to reduce total dietary and saturated fat and cholesterol , prevent weight gain , and increase physical activity levels . Changes in CHD risk factors after the first 6 months of treatment were analyzed comparing 253 intervention and 267 assessment -only control participants . RESULTS The intervention group showed significant reductions in total cholesterol ( -0.34 mmol/liter ) , LDL-C ( -0.28 mmol/liter ) , triglycerides ( -0.04 mmol/liter ) , weight ( -4.8 kg ) , waist-hip ratio ( -0.008 ) , systolic blood pressure ( -3.5 mm Hg ) , diastolic blood pressure ( -2.2 mm Hg ) , serum glucose levels ( -0.06 mmol/liter ) , and HDL-C ( -0.06 mmol/liter ) and significant increases in physical activity ( + 383 kcal ) . No significant changes were observed in the control group . CONCLUSION Six-month results suggested that participants were receptive to the preventive approach to CHD risk reduction and were successful in making initial positive lifestyle changes . Follow-up data will evaluate long-term adherence to the intervention and the interaction between adherence and physiological changes during menopause Background : Early menopause , defined as the cessation of ovarian function before the age of 45 y , affects ∼10 % of women and is associated with higher risk of cardiovascular disease , osteoporosis , and other conditions . Few modifiable risk factors for early menopause have been identified , but emerging data suggest that high vitamin D intake may reduce risk . Objective : We evaluated how intakes of vitamin D and calcium are associated with the incidence of early menopause  in the prospect i ve Nurses ' Health Study II ( NHS2 ) . Design : Intakes of vitamin D and calcium from foods and supplements were measured every 4 y with the use of a food-frequency question naire . Cases of incident early menopause were identified from all participants who were premenopausal at baseline in 1991 ; over 1.13 million person-years , 2041 women reported having natural menopause before the age of 45 y. We used Cox proportional hazards regression to evaluate relations between intakes of vitamin D and calcium  and incident early menopause while accounting for potential confounding factors . Results : After adjustment for age , smoking , and other factors , women with the highest intake of dietary vitamin D ( quintile median : 528 IU/d ) had a significant 17 % lower risk of early menopause than women with the lowest intake [ quintile median : 148 IU/d ; HR : 0.83 ( 95 % CI : 0.72 , 0.95 ) ; P-trend = 0.03 ] . Dietary calcium intake in the highest quintile ( median : 1246 mg/d ) compared with the lowest ( median : 556 mg/d ) was associated with a borderline significantly lower risk of early menopause ( HR : 0.87 ; 95 % CI : 0.76 , 1.00 ; P-trend = 0.03 ) . Associations were stronger for vitamin D and calcium from dairy sources than from nondairy dietary sources , whereas high supplement use was not associated with lower risk . Conclusions : Findings suggest that high intakes of dietary vitamin D and calcium may be modestly associated with a lower risk of early menopause . Further studies evaluating 25-hydroxyvitamin D concentrations , other dairy constituents , and early menopause are warranted OBJECTIVE To examine the change in menopausal symptoms and cardiovascular risk factors in response to 4 months of daily 100‐mg soy isoflavone in postmenopausal women . METHODS In this double‐blind , placebo‐controlled study , 80 women were r and omly assigned to isoflavone ( n = 40 ) and placebo ( n = 40 ) treatment . The menopausal Kupperman index was used to assess change in menopausal symptoms at baseline and after 4 months of treatment . Cardiovascular risk factors were assessed by evaluating plasma lipid levels , body mass index , blood pressure , and glucose levels in the participants . To examine the effects of this regime on endogenous hormone levels , follicle‐stimulating hormone ( FSH ) , luteinizing hormone ( LH ) , and 17β‐estradiol  were measured . Transvaginal sonography was performed to quantify endometrial thickness . RESULTS The data showed a decrease in menopausal symptoms ( P < .01 , paired t test , two‐tailed , between baseline and isoflavone groups , and P < .01 , unpaired t test , between placebo and isoflavone groups ) . Total cholesterol and low‐density lipoprotein decreased significantly in the isoflavone group compared with the baseline or placebo group ( P < .001 , paired t test , two‐tailed , between baseline and isoflavone groups , and P < .01 , unpaired t test , between placebo and isoflavone groups ) . The isoflavone treatment appeared to have no effect on blood pressure , plasma glucose , and high‐density lipoprotein and triglyceride levels . CONCLUSION This study suggests that isoflavone 100‐mg regime treatment may be a safe and effective alternative therapy for menopausal symptoms and may offer a benefit to the cardiovascular system Objective : To investigate the variability and determinants of menopause age in two European cohort studies , the European Respiratory Health Survey and the Swiss Air Pollution and Lung Disease in Adults Cohort . Methods : Age at menopause was estimated in 5,288 women , aged 30 to 60 years , r and omly selected in nine European countries between 1998 and 2002 . Determinants of natural and surgically induced menopause were investigated by Cox regression and heterogeneity by meta- analysis .  Follicle-stimulating hormone and luteinizing hormone levels were assessed in a sub sample . Results : A quarter of the women were postmenopausal by age 50.8 years . Median age of natural menopause was 54 years . Hormone levels were within expected ranges for premenopausal and postmenopausal women . Surgically induced menopause was highly prevalent ( 22%-47 % ) , associated with earlier timing of menopause . Determinants of earlier menopause were current smoking ( hazard ratio [ HR ] , 1.59 ; 95 % CI , 1.27 - 1.98 ) , body mass index greater than 30 kg/m2 ( HR , 1.32 ; 95 % , CI , 1.02 - 1.70 ) , and low physical activity ( HR , 1.37 ; 95 % , CI , 1.12 - 1.67 ) . The determinant for later menopause was multiparity ( HR , 0.74 ; 95 % CI , 0.62 - 0.89 ) . Predictors were similar for naturally and surgically induced menopause . Oral contraceptive use yielded heterogeneous effects on timing of menopause . Later birth was associated with later menopause ( HR , 0.934 ; 95 % CI , 0.91 - 0.96 ) . This evidence of a secular trend is heterogeneous across countries . Conclusions : Age at menopause varies across Europe , shifting toward higher ages . This secular trend seems paradoxical because several adult determinants , that is , overweight , smoking , sedentarity , and nulliparity , associated with early menopause are on the rise in Europe . The heterogeneity of the secular trend suggests additional country-specific factors not included in the study , such as improved childhood nutrition and health , that have an influence on reproductive aging Background . Gabapentin ( GPT ) , a widely used drug in neurology , has been proposed as a non-hormonal option for the management of hot flushes in menopausal women with contraindications for estrogen therapy . Objective . To compare GPT versus low-dose transdermal estradiol ( E2 ) for treating post-menopausal women with moderate to very severe hot flushes . Methods . A total of 45 post-menopausal women with moderate to very severe hot flushes were prospect ively and single-blinded r and omised to receive oral GPT 600 mg/night or transdermal 25 μg/day E2 per week  . Hot flush intensity and frequency were assessed with the Menopause Rating Scale and a numeric scale respectively at baseline and at 1 , 4 and 8 weeks . Side effects were also assessed . Results . Hot flush intensity and frequency significantly decreased for both groups at 1 , 4 and 8 weeks of treatment as compared to baseline ; however , this decrease was statistically more evident for the E2 group . Although the percentage of hot flush intensity and frequency reduction at the end of the treatment was higher for E2 , this was not statistically significant ( 68.2 % vs. 60.6 % for intensity and 70.1 % vs. 58.9 % for frequency , respectively , p > 0.05 , NS ) . Encountered side effects included : drowsiness , dizziness , fatigue ( GPT group ) and mastodynia , vaginal spotting and a local allergic reaction ( E2 group ) . Compliance to treatment was 95.6 % ( GPT group ) as compared to 90.9 % for the E2 group . Conclusion . Despite statistical significant differences , from a clinical point of view oral GPT 600 mg was as effective as low-dose transdermal E2 in controlling moderate to severe hot flushes in post-menopausal women , and should be recommended as an alternative option in those with contraindications to estrogen therapy . More research is warranted in this regard 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 CONTEXT Endogenous hormones are a primary cause of breast cancer . Adiposity affects circulating hormones , particularly in postmenopausal women , and may be a modifiable risk factor for breast cancer . OBJECTIVE To assess the associations of  adult weight change since age 18 years and since menopause with the risk of breast cancer among postmenopausal women . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study within the Nurses ' Health Study . A total of 87,143 postmenopausal women , aged 30 to 55 years and free of cancer , were followed up for up to 26 years ( 1976 - 2002 ) to assess  weight change since age 18 years . Weight change since menopause  was assessed among 49,514 women who were followed up for up to 24 years . MAIN OUTCOME MEASURE Incidence of invasive breast cancer . RESULTS Overall , 4393 cases of invasive breast cancer were documented . Compared with those who maintained weight , women who gained 25.0 kg or more since age 18 years were at an increased risk of breast cancer ( relative risk [ RR ] , 1.45 ; 95 % confidence interval [ CI ] , 1.27 - 1.66 ; P<.001 for trend ) , with a stronger association among women who have never taken postmenopausal hormones ( RR,1.98 ; 95 % CI , 1.55 - 2.53 ) . Compared with weight maintenance , women who gained 10.0 kg or more since menopause were at an increased risk of breast cancer ( RR , 1.18 ; 95 % CI , 1.03 - 1.35 ; P = .002 for trend ) . Women who had never used postmenopausal hormones , lost 10.0 kg or more since menopause , and kept the weight off were at a lower risk than those who maintained weight ( RR , 0.43 ; 95 % CI , 0.21 - 0.86 ; P = .01 for weight loss trend ) . Overall , 15.0 % ( 95 % CI , 12.8%-17.4 % ) of breast cancer cases in this population may be attributable to weight gain of 2.0 kg or more since age 18 years and 4.4 % ( 95 % CI , 3.6%-5.5 % ) attributable to weight gain of 2.0 kg or more since menopause . Among those who did not use postmenopausal hormones , the population attributable risks are 24.2 % ( 95 % CI , 19.8%-29.1 % ) for a weight gain since age 18 years and 7.6 % ( 95 % CI , 5.9%-9.7 % ) for  weight gain  since menopause . CONCLUSIONS These data suggest that weight gain during adult life , specifically since menopause , increases the risk of breast cancer among postmenopausal women , whereas weight loss after menopause is associated with a decreased risk of breast cancer . Thus , in addition to other known benefits of healthy weight , our results provide another reason for women approaching menopause to maintain or lose weight , as appropriate 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 Cardiovascular disease mortality rates have decreased in men during the past 20 years , but have steadily increased in women . In the United States , > 500,000 women die of coronary artery disease ( CAD ) every year . Although many factors can influence an individual 's risk for CAD , some factors are unique to women , including reproductive status . Menopause is associated with significant elevations in serum cholesterol levels and a 3-fold increase in the risk of CAD . It has been suggested that these changes result from a reduction in the level of estrogen . However , recent data from prospect i ve clinical trials have not found any evidence that hormone replacement therapy protects against cardiovascular disease . On the other h and , several studies have shown that , in women , lipid lowering with statin therapy can reduce coronary events . On the strength of these findings , the Beyond Endorsed Lipid Lowering with Electron-Beam Computed Tomography Scanning ( BELLES ) trial-a 1-year , multicenter , r and omized , double-blind , parallel-group study -has been specifically design ed to determine the benefits of aggressive statin therapy on the progression of atherosclerosis in postmenopausal women BACKGROUND Postmenopausal bleeding is a clinical ly important complaint in general gynecologic practice . The incidence of spontaneous postmenopausal bleeding in the general population is approximately 10 % immediately after menopause , and 5 % in all menopausal women . OBJECTIVES The study was aim ed to reveal the histopathologic diagnosis of postmenopausal uterine bleeding , and to investigate the correlation between various clinical factors and endometrial carcinoma . We also evaluated the role of endometrial volume calculation in the clinical use for the endometrial histopathologic findings . MATERIAL S AND METHODS In this prospect i ve observational study , we recruited 163 postmenopausal women with abnormal uterine bleeding from January 2008 through December 2010 . Women who had hematologic disease , or had nonuterine pelvic diseases were excluded . Clinical characteristics such as age , body mass index ( BMI ) , associated diseases , and previous postmenopausal hormone therapy were checked . They were evaluated by transvaginal ultrasonography and underwent endometrial biopsy for the endometrial histopathologic examination . RESULTS Among the endometrial histopathologic findings , atrophic endometrium was the most common finding ( 32.7 % ) , followed by hyperplastic endometrium ( 10.4 % ) , endometrial carcinoma ( 10.4 % ) , and endometrial polyp ( 9.2 % ) . The prevalence of endometrial hyperplasia and cancer was not significantly different at the 5 mm cut-off thickness of the endometrium , but significantly higher in women with ≥ 3 mL of endometrial volume . However , the incidence of endometrial cancer and hyperplasia in women with endometrial bleeding was not significantly different with or without previous or current hormone therapy . CONCLUSIONS Endometrial biopsy should be performed to exclude endometrial hyperplasia and carcinoma in postmenopausal women with endometrial bleeding to perform proper and prompt treatment , especially in old aged women ( > 60 years ) and in patients with endometrial volume ≥ 3 Out of a sample of 162 early post-menopausal women , aged 45 - 54 yr , 131 completed a placebo-controlled study to investigate the effect of  sex hormones on mild climacteric symptoms  with special reference to the dose-response relationship and withdrawal effects . The women were followed up for 42 mth under four different study programmes . All the women were examined every 3 mth and a blind assessment made of the menopausal index estimated according to Kupperman et al. The data revealed a highly significant reduction in climacteric symptoms in the hormone-treated women as compared with the placebo group ( P less than 0.001 ) , a highly significant dose relationship between climacteric symptoms and treatment with 4 , 2 and 1 mg oestradiol , respectively ( P less than 0.001 ) , a highly significant and dose-dependent rebound phenomenon after withdrawal of hormone treatment ( P less than 0.001)--which levelled off after 6 mth following withdrawal-- and complete relief of hot flushes with the two highest doses of oestradiol ( 4 and 2 mg oestradiol ) . It is concluded that sex hormones have a beneficial effect in post-menopausal women with even mild symptoms Studies of the beneficial role of fish consumption in the prevention of CVD are not consistent in their findings , particularly those studies that focus on the risk of stroke . The aim of the present study is to investigate the relationship between the consumption of different types of fish and the subsequent incidence of cerebrovascular disease ( CVA ) . We prospect ively evaluated the association between consumption of different types of fish and CVA in 3958 men and women aged 40 - 79 years who were free of heart disease and had participated in a health examination survey from 1967 to 1972 . A total of 659 incident cases of CVA occurred during a follow-up until the end of 1994 . A dietary history interview method provided data on habitual consumption of fish and other foods over the preceding year at baseline . Total fish intake did not predict CVA , but consumption of salted fish suggested an increased risk of intracerebral haemorrhage . The relative risk of intracerebral haemorrhage between the highest tertile of salted fish consumption and non-consumers was 1.98 ( 95 % CI 1.02 , 3.84 ; P for trend = 0.06 ) after adjustment for age , sex , energy intake , smoking , BMI , physical activity , geographic area , occupation , diabetes , use of post-menopausal hormones , serum cholesterol , hypertension , and consumptions of butter , vegetables , fruits and berries . The relationship between fish consumption and stroke risk is not straightforward . How the fish is prepared for consumption may play an important role , affecting the association In post-menopausal period vulvo-vaginal atrophy (VVA)-related symptoms may seriously affect women 's quality of life . Hormonal replacement therapy effectively relieves these symptoms but it is not always safe or accepted , and a non-hormonal treatment is often needed instead . Over a period of 12 weeks , we tested the effect of a twice-a-week vulvo-vaginal application of a hyaluronic acid , AC collagen , isoflavones and vitamins-based cream ( Perilei Pausa ® ) on 35 women in post-menopausal period , reporting VVA-related symptoms . After 12 weeks of treatment with Perilei Pausa ® a significant improvement in vaginal dryness , vulvo-vaginal itching , dyspareunia ( P < 0.001 ) , dysuria ( P = 0.02 ) , nocturia ( P = 0.009 ) and pollakiuria ( P = 0.005 ) was reported by the women . Colposcopical score assessing the intensity of atrophic colpitis , cervico-vaginal paleness and petechiae was also reduced ( P = 0.037 , P = 0.016 and P = 0.032 , respectively ) . No significant difference in terms of maturation value of cervico-vaginal epithelium was observed . In conclusion , Perilei Pausa ® may represent an effective and safe alternative treatment of symptomatic VVA in post-menopausal women Early menarche and late menopause are risk factors for the development of breast cancer . An adequate hormonal mechanism for those observations has not been described . Because obesity has also been associated with increased breast cancer risk , we examined the relationship among height , weight , adiposity , and menstrual cycle characteristics in women who prospect ively recorded menstrual cycle intervals and reproductive events as part of the Menstrual and Reproductive History Research Program . Within this study cohort , adult height , weight , and a derived index of adiposity were related to both earlier age at menarche and later age at menopause . The association of early age at menarche with adiposity persisted from age 18 yr through middle age and into the menopausal years . There was no relationship between body mass and age at first pregnancy , another breast cancer risk factor . Women who were heavier at 18 yr of age and thereafter gained 5 lb or more had significantly greater mean menstrual cycle length and variability during the 7-yr period after menarche than the other members of the cohort . There was no obvious relationship between weight indices and menstrual cycle pattern during mature reproductive life or during the 7 yr before menopause . Our data suggest that menarcheal and menopausal age may have a common relationship to nutritional status and to constitutional features that pre date the onset of menarche and persist into later life Obesity protects against osteoporosis , but the magnitude of this association has been difficult to assess from cross-sectional or short term studies . We examined the time course of bone loss as a function of body mass index ( BMI ) in early and late postmenopausal women . Our study population ( n = 300 ) was a r and om sample of the population -based Kuopio Osteoporosis Risk Factor and Prevention ( OSTPRE ) Study , Finl and . We excluded women without complete BMD results , premenopausal women during the second bone densitometry and women who had used hormone replacement therapy , bisphosphonates or calcitonin .  BMI along with femoral neck and spinal bone mineral density ( BMD ) were assessed three times by dual-energy X-ray absorptiometry during a mean follow-up of 10.5 years ( SD 0.5 ) . The mean baseline age was 53.6 years ( SD 2.8 ) , time since menopause 2.9 years ( SD 4.3 ) and BMI 27.3 kg/m2 ( SD 4.4 ) . The data was analyzed by linear mixed models . Thus , we were able to approximate the bone loss up to 20 postmenopausal years . To illustrate , a woman with a baseline BMI of 20 kg/m2 became osteopenic 2 ( spine ) and 4 ( femoral neck ) years after menopause , while obesity ( BMI of 30 kg/m2 ) delayed the incidence of osteopenia by 5 ( spine ) and 9 ( femoral neck ) years , respectively . The delay was due to high baseline BMD of the obese , while bone loss rate was similar for both lean and obese subjects . This lean versus obese difference may also be partly due to altered X-ray attenuation due to fat mass BACKGROUND Estrogen plus progestin therapy increases the risk for coronary heart disease ( CHD ) in postmenopausal women . However , this increased risk might be limited to the first years of use and to women who start therapy late in menopause . OBJECTIVE To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause . DESIGN Women 's Health Initiative r and omized , double-blinded , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00000611 ) SETTING 40 U.S. clinical centers . PATIENTS 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998 . INTERVENTION Conjugated equine estrogens , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , or placebo . MEASUREMENTS Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting . RESULTS Compared with no use of hormone therapy , the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 ( 95 % CI , 1.55 to 3.62 ) for the first 2 years and 1.69 ( CI , 0.98 to 2.89 ) for the first 8 years . For women within 10 years after menopause , the hazard ratios were 1.29 ( CI , 0.52 to 3.18 ) for the first 2 years and 0.64 ( CI , 0.21 to 1.99 ) for the first 8 years , and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years ( CI , 2 years to 10 years ) . LIMITATION The analysis may not have fully adjusted for joint determinants of adherence and CHD risk . Sample sizes for some subgroup analyses were small . CONCLUSION No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use , including in women who initiated therapy within 10 years after menopause . A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use . PRIMARY FUNDING SOURCE National Heart , Lung , and Blood Institute Background : The Women 's Health Initiative r and omized trial found greater coronary heart disease ( CHD ) risk in women assigned to estrogen/progestin therapy  than in those assigned to placebo . Observational studies had previously suggested reduced CHD risk in hormone users . Methods : Using data from the observational Nurses ’ Health Study , we emulated the design and intention-to-treat ( ITT ) analysis of the r and omized trial . The observational study was conceptualized as a sequence of “ trials , ” in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy . Results : The ITT hazard ratios ( HRs ) ( 95 % confidence intervals ) of CHD for initiators versus noninitiators were 1.42 ( 0.92–2.20 ) for the first 2 years , and 0.96 ( 0.78–1.18 ) for the entire follow-up . The ITT HRs were 0.84 ( 0.61–1.14 ) in women within 10 years of menopause , and 1.12 ( 0.84–1.48 ) in the others ( P value for interaction = 0.08 ) . These ITT estimates are similar to those from the Women 's Health Initiative . Because the ITT approach causes severe treatment misclassification , we also estimated adherence-adjusted effects by inverse probability weighting . The HRs were 1.61 ( 0.97–2.66 ) for the first 2 years , and 0.98 ( 0.66–1.49 ) for the entire follow-up . The HRs were 0.54 ( 0.19–1.51 ) in women within 10 years after menopause , and 1.20 ( 0.78–1.84 ) in others ( P value for interaction = 0.01 ) . We also present comparisons between these estimates and previously reported Nurses ’ Health Study estimates . Conclusions : Our findings suggest that the discrepancies between the Women 's Health Initiative and Nurses ’ Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up BACKGROUND Results of observational studies suggest that hormone replacement therapy ( HRT ) could reduce the risk of coronary heart disease ( CHD ) , but those of r and omised trials do not indicate a lower risk in women who use oestrogen plus progestagen .  The aim of this study was to ascertain whether or not unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infa rct ion . METHODS The study was a r and omised , blinded , placebo controlled , secondary prevention trial of postmenopausal women , age 50 - 69 years ( n=1017 ) who had survived a first myocardial infa rct ion . Individuals were recruited from 35 hospitals in Engl and and Wales . Women received either one tablet of oestradiol valerate ( 2 mg ; n=513 ) or placebo ( n=504 ) , daily for 2 years . Primary outcomes were reinfa rct ion or cardiac death , and all-cause mortality . Analyses were by intention-to-treat . Secondary outcomes were uterine bleeding , endometrial cancer , stroke or other embolic events , and fractures . FINDINGS Frequency of reinfa rct ion or cardiac death did not differ between treatment groups at 24 months ( rate ratio 0.99 , 95 % CI 0.70 - 1.41 , p=0.97 ) . Similarly , the reduction in all-cause mortality between those who took oestrogen and those on placebo was not significant ( 0.79 , 0.50 - 1.27 , p=0.34 ) . The relative risk of any death ( 0.56 , 0.23 - 1.33 ) and cardiac death ( 0.33 , 0.11 - 1.01 ) was lowest at 3 months post-recruitment . INTERPRETATION Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infa rct ion This issue of JAMA contains the latest US Preventive Services Task Force ( USPSTF ) recommendation statement on statins for prevention of cardiovascular disease in adults,1 along with the accompanying evidence report and systematic review 2 on which the recommendations are based . The evidence report summarized data from 19 trials including a total of 71 344 patients and concluded that statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and cardiovascular disease ( CVD ) events . Thus , the task force recommended “ initiating use of lowto moderate-dose statins in adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 10 % or greater ( B recommendation ) ” or “ 7.5 % to 10 % ( C recommendation ) .”1 Although the task force did their usual careful job of review ing the evidence , the evidence for treating asymptomatic persons with statins does not appear to merit a grade B or even a grade C recommendation . The task force evidence report estimated an absolute benefit for use of statins of 0.40 % for all-cause mortality and 0.43 % for cardiovascular mortality and indicated that the absolute benefit was greater for patients at greater baseline risk.2 Notably , the evidence report did not exclude studies that included patients taking statins for secondary prevention , who have a higher baseline risk of cardiac events and death and thus are more likely to benefit from therapy that inflates the benefit attributed to a primary prevention population . The task force did perform a sensitivity analysis that excluded 3 trials with persons for whom there were prior “ hard ” cardiovascular events and obtained similar results of benefits ( eTable 5 in the article by Chou et al2 ) . This sensitivity analysis did not exclude WOSCOPS , which included patients receiving statins for secondary prevention—5 % had angina and 3 % had intermittent claudication,3 accounting for 15 % of the total weight in the meta- analysis . In contrast , a meta- analysis of 11 studies and 65 229 patients receiving statins for primary prevention , in which patients receiving statins for secondary prevention were excluded , found no benefit of statins for reducing all-cause mortality.4 The confidence intervals of these 2 analyses overlap , and the difference between these findings likely reflects differences in studies included . The USPSTF and authors of the evidence report did not have access to the primary data ( clinical study reports and anonymized patient-level data ) from the statin clinical trials . Rather , they had to rely on peer- review ed published reports as the basis for these recommendations . Exacerbating the potential bias , all of the trials included in the task force evidence report2 were industry-sponsored except 1 trial,5 and that trial contributed 0.2 % of the weight to the mortality calculation . Industry-sponsored studies have been shown to report greater benefit and lesser adverse effects than noncommercially sponsored trials of the same drugs.6 Whether this is true for statins and primary prevention of CVD is unknown . Among the 19 r and omized clinical trials of statins vs placebo or no statin included in the evidence report for the task force recommendations , only 15 reported all-cause mortality , 10 reported cardiovascular mortality , 12 reported fatal and nonfatal myocardial infa rct ion  , and 13 reported fatal and nonfatal stroke.2,7  Reliance on selective reporting of the most important outcomes , which are likely included in the clinical trial data , makes reporting bias possible . Furthermore , after allcause mortality , the comparative incidence of serious adverse events between treatment and control groups is arguably the second most important measure of the effect of active therapy in r and omized clinical trials . Underst and ing the evidence base in evaluating harms of statin therapy is also critically important . Although the benefits of any preventive therapy accrue according to risk of disease ( greater benefit in higher-risk patients ) , the harms of therapy usually distribute equally over all risk levels . Thus , persons at low risk have little chance of benefit but equal chance of harms and thus are more likely to have a net harm . The evidence base for harms of statins , despite the introduction of these drugs more than 20 years ago , is incomplete . Many of the trials did not ask about commonly reported statin effects , such as muscle pains and weakness , and only recorded myopathy , for which an increase in creatine kinase levels was required . Because most muscle problems do not involve an increase in creatine kinase levels , this leads to a significant underestimate of muscle problems . Other studies have estimated that closer to 20 % of statin users have muscle problems.8 Additionally , the actual trial data are largely held by the Cholesterol Treatment Trialists ’ Collaboration on behalf of the industry sponsor and have not been made available to other research ers , despite multiple requests over many years.9 Although reported rates of adverse events in clinical trials are low , this does not reflect the experience of clinicians who see patients who are taking statins . For instance , the experience of an NPR reporter with a calculated 2.9 % risk of heart disease over 10 years using the recommended American College of Cardiology/American Heart Association ( ACC/AHA ) risk calculator,10 but still prescribed a statin , and experiencing adverse effects from the medication , is typical of what many Related articles at jama.com 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 OBJECTIVE To assess the efficacy and safety of a 300 mug/d testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women on concomitant estrogen therapy . METHODS Five hundred thirty-three women with hypoactive sexual desire disorder who had undergone previous hysterectomy and bilateral oophorectomy were enrolled in a 24-week , multicenter , double-blind , placebo-controlled trial . Patients were r and omly assigned to receive placebo or the testosterone patch twice weekly . The primary efficacy endpoint was change from baseline at week 24 in the frequency of total satisfying sexual activity , measured by the Sexual Activity Log . Secondary measures included sexual desire using the Profile of Female Sexual Function and personal distress as measured by the Personal Distress Scale . Hormone levels , adverse events , and clinical laboratory measures were review ed . RESULTS Total satisfying sexual activity significantly improved in the testosterone patch group compared with placebo after 24 weeks ( mean change from baseline , 1.56 compared with 0.73 episodes per 4 weeks , P = .001 ) . Treatment with the testosterone patch also significantly improved sexual desire ( mean change , 10.57 compared with 4.29 , P < .001 ) and decreased personal distress ( P = .009 ) . Serum free , total , and bioavailable testosterone concentrations increased from baseline . Overall , adverse events were similar in both groups ( P > .05 ) . The incidence of and rogenic adverse events was higher in the testosterone group ; most and rogenic adverse events were mild . CONCLUSION In surgically menopausal women with hypoactive sexual desire disorder , a 300 mug/d testosterone patch significantly increased satisfying sexual activity and sexual desire , while decreasing personal distress , and was well tolerated through up to 24 weeks of use We investigated the association between blood flow in the extremities and hot flashes , and compared change in blood flow following hormone replacement therapy ( HRT ) and Gui-zhi-fu-ling-wan ( Keishi-bukuryo-gan ) , a herbal therapy in post-menopausal women with hot flashes . Three hundred and fifty-two post-menopausal women aged 46 - 58 years ( mean : 53.4 + /- 3.6 years ) with climacteric complaints participated in the study . One hundred and thirty-one patients with hot flashes  were treated with HRT ( 64 cases ) or herbal therapy ( 67 cases ) . Blood flow was measured with laser doppler fluxmetry under the jaw , in the middle finger and in the third toe . Post-menopausal women with hot flashes ( 129 cases ) showed significantly higher blood flow under the jaw ( 13.6 + /- 4.13 ) than women without hot flashes ( 166 cases ) ( 5.48 + /- 0.84 ) ( p < 0.0001 ) . Blood flow at this site decreased significantly with either therapy ( p < 0.0001 ) . On the other h and , the administration of Gui-zhi-fu-lingwan significantly increased ( p = 0.002 ) the blood flow in the lower extremities , whereas HRT decreased the blood flow . Thus , we have demonstrated that Gui-zhi-fu-ling-wan did not affect the activity of vasodilator neuropeptides on sensory neurons of systemic peripheral vessels uniformly . Therefore , Gui-zhi-fu-ling-wan , rather than HRT , is suggested as an appropriate therapy for treatment of hot flashes in the face and upper body with concomitant coldness in the lower body , which is one of the symptoms of menopause To determine the relation of menopause to the risk of coronary heart disease , we analyzed data on a prospect i ve cohort of 121,700 U.S. women 30 to 55 years old who were followed from 1976 to 1982 . Information on menopausal status , the type of menopause , and other risk factors was obtained in 1976 and up date d every two years by mailing question naires . Through 1982 , the follow-up rate was 98.3 percent for mortality and 95.4 percent for nonfatal events . After we controlled for age and cigarette smoking , women who had had a natural menopause and who had never taken replacement estrogen had no appreciable increase in the risk of coronary heart disease , as compared with premenopausal women ( adjusted rate ratio , 1.2 ; 95 percent confidence limits , 0.8 and 1.8 ) . Again compared with premenopausal women , the occurrence of a natural menopause together with the use of estrogens did not affect the risk ( rate ratio , 0.8 , 95 percent confidence limits , 0.4 and 1.3 ) . Women who had undergone bilateral oophorectomy and who had never taken estrogens after menopause had an increased risk ( rate ratio , 2.2 ; 95 percent confidence limits , 1.2 and 4.2 ) . However , the use of estrogens in the postmenopausal period appeared to eliminate this increased risk among these women as compared with premenopausal women ( rate ratio , 0.9 ; 95 percent confidence limits , 0.6 and 1.6 ) . These data suggest that , in contrast to a natural menopause , bilateral oophorectomy increases the risk of coronary heart disease . This increase appears to be prevented by estrogen-replacement therapy Background and Purpose — Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective , use of isoflavone soy protein ( ISP ) supplementation as a primary preventive therapy remains unexplored . We determined whether ISP reduces sub clinical atherosclerosis assessed as carotid artery intima-media thickness progression . Methods — In a double-blind , placebo-controlled trial , 350 postmenopausal women 45 to 92 years of age without diabetes and cardiovascular disease were r and omized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7 years . Results — Overall , mean ( 95 % CI ) carotid artery intima-media thickness progression rate was 4.77 ( 3.39–6.16 ) & mgr;m/year in the ISP group and 5.68 ( 4.30–7.06 ) & mgr;m/year in the placebo group . Although carotid artery intima-media thickness progression was reduced on average by 16 % in the ISP group relative to the placebo group , this treatment effect was not statistically significant ( P=0.36 ) . Among the subgroup of women who were r and omized within 5 years of menopause , ISP participants had on average a 68 % lower carotid artery intima-media thickness progression rate than placebo participants 2.16 ( −1.10 to 5.43 ) versus 6.79 ( 3.56–10.01 ) & mgr;m/year ( P=0.05 ) . ISP supplementation had a null effect on women who were > 5 years beyond menopause when r and omized . There were no major adverse events from ISP supplementation . Conclusions — ISP supplementation did not significantly reduce sub clinical atherosclerosis progression  in postmenopausal women . Subgroup analysis suggests that ISP supplementation may reduce sub clinical atherosclerosis in healthy young ( median age , 53 years ) women at low-risk for cardiovascular disease who were < 5 years postmenopausal . These first trial results of their kind warrant further investigation . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00118846 Context Studies of the role of endogenous sex hormones in  cardiovascular disease ( CVD ) in men have been inconclusive . Contribution A total of 2084 men from 2 Framingham Heart Study cohorts had levels of  total serum estrogen , testosterone , and dehydroepi and rosterone sulfate ( DHEA-S )  measured in 1981 to 1985 for the original cohort and in 1987 to 1991 for the offspring cohort . Testosterone and DHEA-S levels were not associated with CVD risk . Estrogen levels were inversely related : Risk for CVD in the highest quartile was 0.68 ( 95 % CI , 0.50 to 0.92 ) times that in the lowest level . Caution s Investigators studied only white men and did not study free unbound hormone levels . Implication s Endogenous estrogen may be vasculoprotective in men , which is in contrast to the effects of exogenous estrogen . The Editors Male sex is an independent risk factor for cardiovascular disease ( CVD ) ( 1 ) . Scientists have postulated that the 5- to 10-year lag period in CVD incidence in women ( compared with men ) may be related to differences in endogenous sex hormones ( 27 ) . Indeed , substantial evidence suggests that sex hormones ( testosterone , estrogen , and dehydroepi and rosterone sulfate [ DHEA-S ] ) influence traditional and newer CVD risk factors ( 27 ) . Interest in the role of sex hormones in the pathogenesis of CVD has been rekindled by the observation that men with genetic defects of estrogen synthesis ( 8) or action ( 9 ) develop premature atherosclerosis . In addition , genetic variation in estrogen receptor- has been associated with prevalent CVD ( 10 , 11 ) , and and rogen and estrogen receptor expression in coronary arteries has been reported to influence coronary atherosclerosis in men ( 12 ) . In contrast to the aforementioned data , prospect i ve studies relating circulating sex hormone levels to incident CVD in men have been inconclusive . For example , low serum testosterone levels have been associated with greater progression of sub clinical atherosclerosis in 2 previous investigations ( 13 , 14 ) , but other studies have reported no association of testosterone levels with CVD events ( 1521 ) . On a parallel note , low DHEA-S levels have been linked to greater CVD risk in some studies ( 18 , 2224 ) but not in other studies ( 13 , 20 , 2529 ) . Investigations relating serum estradiol levels to CVD risk in men have generally found no statistically significant association ( 1520 ) . Some previous investigations were limited by modest sample sizes ( 14 , 17 , 18 , 22 , 25 , 26 ) ; an insufficient number of CVD events ( 1518 , 22 , 23 , 26 ) ; and , in some instances , a retrospective study design ( 1721 , 25 , 26 ) . In addition , some reports ( 15 , 22 , 24 ) focused on CVD death ( they did not evaluate nonfatal CVD events ) . Thus , a large prospect i ve community-based study relating sex hormones to CVD risk with adequate power to detect modest potential associations is needed . Accordingly , we evaluated the associations of serum levels of sex hormones that were measured at a routine baseline examination with CVD incidence in a prospect ively assembled cohort of participants . Methods Study Sample The Framingham Heart Study , a prospect i ve study of the risk factors for the development of heart disease and stroke , began in 1948 with the recruitment of 5209 men and women between 30 and 60 years of age who resided in Framingham , Massachusetts ( 30 ) . The Framingham Offspring Study began in 1971 with the recruitment of 5124 participants who were the children of the original cohort and the spouses of the children ( 31 ) . Participants in the original cohort are examined every 2 years , while offspring cohort members are assessed every 4 years . At each Framingham Heart Study examination , attendees undergo a physical examination and laboratory assessment of risk factors ( 31 ) . We evaluated 2789 men who attended the 17th biennial examination ( 19811983 ) of the original cohort or the fourth quadrennial examination ( 19871991 ) of the offspring cohort . We measured serum total testosterone and estradiol levels at these examinations , and we measured DHEA-S levels at the 18th examination ( 19831985 ) for the original cohort and at the fourth examination for the offspring cohort . We excluded 705 men because of prevalent CVD ( n= 541 ) and nonavailable testosterone data ( n= 164 ) . After exclusions , 2084 men ( 74.7 % ; 525 original cohort participants ) without previous CVD were eligible . Data on serum estradiol levels and serum DHEA-S levels were available in 2047 men and 1928 participants , respectively . All participants gave written informed consent , and the institutional review board at the Boston Medical Center approved the study protocol . Biochemical Assessment of Sex Hormones As described previously ( 32 ) , we measured total testosterone , total estradiol , and DHEA-S levels from serum sample s by using radioimmunoassays ( Diagnostic Products Corp. , Los Angeles , California ) for total testosterone ( interassay coefficient of variation , 11 % ) , total estradiol ( interassay coefficient of variation , 4 % ) , and DHEA-S ( interassay coefficient of variation , 11 % ) . We also measured serum luteinizing hormone levels at the baseline examinations ( interassay coefficient of variation , 6 % ) . Cardiovascular Outcomes All participants were under continuous surveillance for the occurrence of  CVD events and death . Participants are evaluated periodically at the Framingham Heart Study and through health history up date s between examinations ( obtained via telephone interviews ) . Three experienced investigators obtained and review ed hospitalization and physician office visit records . We defined incident CVD as coronary heart disease ( recognized or unrecognized myocardial infa rct ion , angina pectoris , coronary insufficiency , or coronary heart disease death ) , cerebrovascular disease ( stroke or transient ischemic attack ) , congestive heart failure ( by Framingham criteria ) , or peripheral vascular disease ( intermittent claudication ) . Criteria for the diagnoses of cardiovascular events have been described elsewhere ( 33 ) . We considered that an unrecognized myocardial infa rct ion occurred if we found electrocardiographic evidence of clinical ly significant loss of R waves or appearance of pathologic Q waves on serial tracings in the absence of a clinical ly recognized event ( 33 ) . We defined the follow-up period a priori as 10 years from the baseline examination ( up to 1995 for the original cohort and 2002 for the offspring cohort ) to permit equal duration s of follow-up of original and offspring cohort participants and because sex hormone levels change considerably with age ( 34 ) . The analyses that combined the original and offspring cohorts had greater statistical power and allowed us to evaluate participants over a wider age range . Statistical Analyses Serum testosterone levels were normally distributed . Serum estradiol and DHEA-S levels were skewed and were log-transformed . We examined the associations between baseline sex hormone levels and CVD incidence during follow-up ( separate analyses for each hormone ) . We chose incident CVD as the outcome because the effects of sex hormones are not limited to a given vascular territory and this maximized our statistical power and limited multiple statistical testing ( as opposed to analysis for each CVD component ) . We stratified all analyses by the cohort ( offspring cohort vs. original cohort ) . We verified that the assumption of proportionality of hazards was satisfied for each hormone . We calculated age- and multivariable-adjusted 10-year incidence rates for CVD for each hormone quartile ( 35 ) . We prespecified 2 types of models : Primary analyses evaluated the sex hormones as continuous variables to maximize statistical power ( model A ) , and additional analyses compared CVD risk in hormone quartiles 2 to 4 with that in quartile 1 ( referent ) ( model B ) . These models facilitated assessment of potential nonlinear relations . For each hormone , we used proportional hazards regression ( 36 ) that adjusted for 1 ) age alone and 2 ) age , smoking , systolic and diastolic blood pressure , antihypertensive medication use , ratio of total and high-density lipoprotein ( HDL ) cholesterol , diabetes mellitus , and body mass index ( BMI ) . We evaluated models adjusted for age alone because some risk factors may fall along the causal pathway from estradiol to CVD . Adjustment for BMI was performed because adiposity is a strong correlate of sex hormone levels ( 37 ) and of sex hormonebinding globulin ( 38 ) . Sex hormonebinding globulin strongly influences measurements of total circulating sex hormone levels and the amount of bound hormone versus free hormone . We also evaluated models without BMI as a covariate to assess whether adjustment for BMI attenuated relations of sex hormones with CVD and models that were adjusted additionally for the use of aspirin or lipid-lowering medications , alcohol consumption , and education level . We incorporated statistical interaction terms to evaluate effect modification by age , BMI , smoking status , systolic blood pressure , and total cholesterolHDL cholesterol ratio . To gain additional insights into potential nonlinearity of associations between hormone levels and CVD risk , we examined generalized additive Cox models using penalized splines ( 39 , 40 ) for hormones that were statistically significantly related to CVD risk . Because potential relationships of sex hormones to CVD risk may be mediated by the development of risk factors during follow-up , we prespecified examination of time-dependent Cox models ( updating established CVD risk factors [ covariates in the multivariable-adjusted proportional hazards regression ] every 4 years at follow-up examinations ) for analyses of any sex hormone that was statistically significantly related to CVD events in the initial analyses . Additional Analyses We performed secondary analyses relating CVD risk to the estradioltestosterone ratio ( 37 , 41 ) . In addition , we investigated whether hypogonadism was related to CVD risk . We defined hypogonadism empirically as a serum testosterone level less than 10.4 nmol/L ( Findings of systematic review s incorporating meta analysis are by nature hypothesis generating and should be carefully and judiciously interpreted . This need is epitomized by two of the largest review s of interventions to support risk factor reduction after a diagnosis of coronary heart disease ( Table 1 ) . These review s both included r and omized trials published in a similar timeframe ( up to 2003 or 2004 ) that compared the effects of various risk factor reduction programmes for patients with confirmed coronary heart disease to usual care . In 2004 , a Cochrane review found that supervised and unsupervised exercise-based cardiac rehabilitation provided to patients with different forms of coronary heart disease lowered all cause total mortality by 20 % and cardiac mortality by 26 % in 48 trials of 8940 patients . The review ers concluded that there was ‘ no difference in mortality effect between exercise-only cardiac rehabilitation and comprehensive cardiac rehabilitation , or by exercise dose or duration of followup ’ . Also , the exercise-based programmes did not reduce recurrent myocardial infa rct ion and the need for repeat coronary revascularization to statistically significant levels . Around the same time , a second review of 63 trials involving 21,295 patients who had undergone secondary cardiac prevention programmes found reductions of total mortality of 15 % and of acute myocardial infa rct ion of 17 % . However , in contrast to the previous review , the secondary prevention programmes significantly reduced the rate of recurrent heart attacks . Also , benefits did not differ between programmes ‘ that incorporated education and counselling about coronary risk factors with a supervised exercise programme , those that included risk factor education or counselling but no exercise component , and those that consisted of only a structured exercise programme ’ . On first reading , these review s appear to offer different conclusions on effects on cardiovascular morbidity and regarding the benefits of supervised exercise . Either could be cited selectively to support or refute the benefits of exercise programmes for morbidity or to support or refute the incorporation of supervised exercise into services . Why might these different conclusions have come about and how should they be interpreted ? Firstly , it is unlikely that the different conclusions arise from differences in quality as both review s were of high quality as defined by PRISMA criteria and included many of the same trials : 37 of the 48 ( 77 % ) exercise-based trials were included in the 63 ( 59 % ) secondary prevention trials . Rather , issues of statistical power can explain the differences noted in morbidity . The forest plot analyses showed that , although exercise-based programmes in the Cochrane review did not reach statistically significant headline ‘ effect sizes ’ , there was a tendency towards reduced recurrent myocardial infa rct ion and the need for repeat coronary revascularization . The larger review of secondary prevention programmes considered over twice the number of events in the analysis of recurrent myocardial infa rct ion and found that secondary prevention programmes significantly reduced the rate of recurrent heart attacks . Hence , focusing only on the presence or absence of 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 Caution about taking estrogen for treating  postmenopausal vasomotor symptoms has led to increasing substitution of herbal regimens despite few tests of their effectiveness . Contribution The authors r and omly assigned 351 perimenopausal or postmenopausal women to herbal treatments ( black cohosh , multibotanicals , or multibotanicals plus counseling about dietary soy ) , estrogen with or without progesterone , or placebo . At 3 , 6 , and 12 months , patients receiving the herbal interventions had the same change in vasomotor symptoms as those receiving placebo ( except for more severe symptoms at 12 months for patients taking multibotanicals plus dietary soy ) . Estrogen substantially decreased vasomotor symptoms . Caution s Most participants were white and were well-educated . Implication s Herbal regimens did not reduce postmenopausal vasomotor symptoms in this sample of women . The Editors Hormone therapy remains the recommended treatment for vasomotor symptoms , but trials have shown serious risks with even short-term use ( 1 , 2 ) . The use of herbs , particularly black cohosh , multibotanical supplements , and dietary soy for menopausal symptoms has grown dramatically ( 36 ) . Few of these approaches have been scientifically evaluated . Women and providers are seeking safe , effective alternatives to hormone therapy . We design ed the Herbal Alternatives for Menopause Trial ( HALT ) to provide rigorous evidence on the efficacy and short-term safety of commonly used naturopathic approaches for management of vasomotor symptoms . Methods Design Overview and Setting HALT was a 1-year double-blind , r and omized , controlled trial design ed to investigate the effects of 3 naturopathic approaches for  vasomotor symptom relief and hormone therapy compared with placebo . Study methods have been described elsewhere ( 7 ) . The Group Health Institutional Review Board approved this study , and a data and safety monitoring committee monitored it . The study was conducted at Group Health , an integrated health plan in Washington State . Participants Eligibility criteria were as follows : age 45 to 55 years ; late menopausal transition ( 1 skipped menses within the preceding 12 months ) or postmenopausal ( no bleeding within 12 months , or follicle-stimulating hormone level > 20 IU/mL if patient had undergone hysterectomy without bilateral oophorectomy ) ; and 2 or more vasomotor symptoms per day over 2 weeks ( 6 moderate to severe symptoms ) . Women in menopausal transition were included because many are highly symptomatic and trial data are lacking for this group . Exclusion criteria were the following : contraindications to hormone therapy ; use of hormone therapy or oral contraceptives within 3 months before the trial ; use of herbal medicines for menopausal symptoms within 1 month before the trial ; soy allergy ; bilateral oophorectomy ; history of breast cancer ; and nonadherence during the run-in period ( < 80 % of capsules taken ) . From May 2001 through August 2003 , women were recruited by using direct mail . Screening calls determined initial eligibility . Women attended an orientation visit at which eligibility was confirmed , physical measurements were collected , and placebo medication and question naires for the 2-week run-in period were provided . R and omization and Interventions Participants were r and omly assigned by using SAS software ( SAS Institute , Inc. , Cary , North Carolina ) , stratified by previous hormone therapy and hysterectomy ; block sizes within strata ranged from 5 to 25 . Treatment assignments were sent to the University of Washington Research Pharmacy , where medications were bottled and labeled with a sequential identification number without treatment group indication . At the r and omization visit , vasomotor symptom diaries and medication counts were examined to confirm eligibility and adherence . The study nurse determined the appropriate stratum , assigned the participant the next study number in that stratum without knowledge of group assignment , and distributed study medications . The publication of results from the Women 's Health Initiative ( WHI ) estrogenprogestin trial ( 2 ) raised new concerns about the safety of estrogen therapy . New study participants were given the choice of 5-arm ( including hormone therapy ) versus 4-arm ( no hormone therapy ) r and omization . Current participants gave consent again , incorporating risk estimates from the WHI , and were given the option of finding out whether they had been assigned to hormone therapy ; 16 were unblinded , 1 discontinued use of the study drug , and all remained enrolled . Following publication of the WHI Memory Study ( 8 , 9 ) , we informed participants of those findings and restricted r and omization to herbs and placebo . No further women were unblinded or discontinued use of the study drug . Naturopathic medicine provided the model for study interventions . The herbal products , doses , and soy diet were based on approaches used by naturopaths when the study was design ed ( 7 ) . The study groups were as follows : 1 ) black cohosh  ( Actaea racemosa or Cimicifuga racemosa , 160 mg daily ; 2.5 % triterpene glycosides ; 70 % ethanol extract ) ; 2 )  multibotanical ;  3 )  multibotanical plus soy diet counseling ; 4 ) conjugated equine estrogen , 0.625 mg daily , with ( for women with a uterus ) or without ( for women without a uterus ) medroxyprogesterone acetate , 2.5 mg ; and 5 ) placebo . The multibotanical delivered daily doses of the following : black cohosh , 200 mg ; alfalfa ( Medicago sativa ) , 400 mg ; boron , 4 mg ; chaste tree ( Vitex agnus-castus ) , 200 mg ; dong quai ( Angelica sinensis ) , 400 mg ; false unicorn ( Chamaelirium luteum ) , 200 mg ; licorice ( Glycyrrhiza glabra ) , 200 mg ; oats ( Avena sativa ) , 400 mg ; pomegranate ( Punica granatum ) , 400 mg ; Siberian ginseng ( Eleutherococcus senticosus , st and ardized constituents 0.8 % eleutherosides E and B ) , 400 mg . Black cohosh was provided by Pure World , Inc. , ( Hackensack , New Jersey ) . The multibotanical , ProGyne , was purchased from Progena Professional Formulations ( Albuquerque , New Mexico ) and encapsulated to study specifications . Both companies follow current good manufacturing practice s , and single batches were used . ConsumerLab.com ( White Plains , New York ) tested the products after the study commenced . Dong quai , false unicorn , and pomegranate were not detected , suggesting that they were of poor quality or did not contain the tested marker compounds . Other marker compounds were detected in the approximate doses as labeled ( 7 ) . The Appendix Table describes the herbal products in detail . Appendix Table . Consoli date d St and ards of Reporting Trials ( CONSORT ) Requirements for Controlled Trials of Herbal Interventions To facilitate blinding , medications and lactose placebo were encapsulated to provide 2 white and 2 blue capsules to each woman , and medication boxes were labeled with a unique identification number that did not indicate study group . The soy food intervention was modeled after a successful 5-a-day intervention ( 10 ) . We chose soy foods because of uncertainty about the efficacy of isoflavone supplements and because naturopaths commonly recommend whole soy foods . Participants received 5 telephone calls from a clinical dietitian and a 34-page booklet recommending 2 soy food servings per day ( 12 to 20 g of soy protein ) ( 7 ) . Other participants received 1 telephone call and a similar booklet reinforcing fruit and vegetable intake . Participants were instructed not to discuss dietitian calls with study nurses and were unaware that soy counseling was linked to the multibotanical . Outcomes and Measurements The primary outcomes were change from baseline ( measured over 2-week run-in period ) to 3 , 6 , and 12 months ( each measured for 4 weeks ) and change from baseline to the average for all follow-ups with regard to the mean frequency and intensity of vasomotor symptoms ( daytime hot flashes plus night sweats ) and the mean Wiklund Vasomotor Symptom Subscale score ( 11 , 12 ) . We also evaluated change from baseline to follow-up ( months 3 , 6 , and 12 and average change ) for daytime hot flash rate , night sweat rate , and the total Wiklund Menopause Symptom Scale score . Symptom diaries and global ratings of menopause symptoms are almost universally used in studies of vasomotor symptoms . Participants used a  vasomotor symptom diary  to record daytime hot flashes and night sweats , rating intensity as mild , moderate , or severe ( scale , 1 to 3 ) , as recommended by the U.S. Food and Drug Administration ( 13 ) . Women completed the Wiklund Menopause Symptom Scale , rating the severity of 13 menopausal symptoms ( sweats , hot flashes , sleep disturbance , fatigue , vaginal dryness , depression , headache , irritability , muscle/joint pain , breast tenderness , nervousness , palpitations , and dizziness/fainting on a scale of 0 ( none ) to 10 ( severe ) ( 11 ) . Soy food intake was monitored by using a self-reported , vali date d soy food question naire ( 14 ) . Follow-up Procedures Participants returned to the research clinic at 3 , 6 , and 12 months . Question naires were collected , and study medication was dispensed . Medication adherence counts were conducted by staff without participant contact and without knowledge of treatment assignment . Study nurses encouraged adherence and monitored adverse events during monthly telephone calls and at visits . Adverse events were identified through participants ' responses to the question , Have you had any medical problems or been hospitalized ? Responses were recorded and adverse events were followed until they were resolved . The study nurse determined intensity ( mild , moderate , or severe ) and whether the event was serious ( yes or no ) . Events were review ed by the study physician , who determined whether the event was study related , without knowledge of group assignment . Adverse events were coded by using the Coding Symbols for Thesaurus of Adverse Reaction Terms ( 15 ) . The Data and Safety Monitoring Committee review ed study progress and unblinded outcome and safety data 5 times . Statistical Analysis The study was powered to detect an effect of Background Multiple treatments are frequently available for a given condition , and clinicians and patients need a comprehensive , up-to- date synthesis of evidence for all competing treatments . We aim ed to quantify the waste of research related to the failure of systematic review s to provide a complete and up-to- date evidence synthesis over time . Methods We performed a series of systematic overviews and networks of r and omized trials assessing the gap between evidence covered by systematic review s and available trials of second-line treatments for advanced non-small cell lung cancer . We search ed the Cochrane Data base of Systematic Review s , Data base of Abstract s of Review s of Effects , MEDLINE , EMBASE , and other re sources sequentially by year from 2009 to March 2 , 2015 . We sequentially compared the amount of evidence missing from systematic review s to the r and omized evidence available for inclusion each year . We constructed cumulative networks of r and omized evidence over time and evaluated the proportion of trials , patients , treatments , and treatment comparisons not covered by systematic review s on December 31 each year from 2009 to 2015 . Results We identified 77 trials ( 28,636 patients ) assessing 47 treatments with 54 comparisons and 29 systematic review s ( 13 published after 2013 ) . From 2009 to 2015 , the evidence covered by existing systematic review s was consistently incomplete : 45 % to 70 % of trials ; 30 % to 58 % of patients ; 40 % to 66 % of treatments ; and 38 % to 71 % of comparisons were missing . In the cumulative networks of r and omized evidence , 10 % to 17 % of treatment comparisons were partially covered by systematic review s and 55 % to 85 % were partially or not covered . Conclusions We illustrate how systematic review s of a given condition provide a fragmented , out-of- date panorama of the evidence for all treatments . This waste of research might be reduced by the development of live cumulative network meta-analyses Long-term endocrine therapy for breast cancer may have clinical implication s as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease . In this study , a companion sub protocol to the ATENA ( Adjuvant post-Tamoxifen Exemestane versus Nothing Applied ) trial , we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of post-menopausal women with operable breast cancer in the adjuvant setting to that of observation alone following deprivation of 5–7 years primary treatment with tamoxifen . In this open-label , r and omized , parallel group study , 340 post-menopausal patients with operable breast cancer who had been treated with tamoxifen for 5–7 years were r and omized to either 5 additional years of exemestane ( 25 mg/day ; n=172 ) or observation alone ( n=168 ) . Assessment s of total cholesterol , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) and total serum triglycerides ( TRG ) were performed at baseline , and at 6 and 12 months . Total TRG levels were significantly reduced compared with baseline for the exemestane and the observational arm . Both total cholesterol and LDL levels were significantly increased above that of baseline values by 6 months , maintained through to 12 months , with no significant difference between the two treatment arms . There was no significant alteration observed for HDL over time or between the two arms . We conclude that sequential adjuvant treatment with exemestane in post-menopausal operable breast cancer patients following cessation of 5–7 years of tamoxifen does not appear to significantly alter the lipidemic profile for at least 12 months compared with an observational arm OBJECTIVE The purpose of this study was to investigate the hormonal changes during the menopausal transition in a non- clinical population . METHODS Fifty-nine healthy Norwegian women participated in a five year prospect i ve longitudinal study during the transition from pre- to post-menopause , starting one to four years before menopause , and ending one to four years postmenopausal . None of these women were given hormone replacement therapy ( HRT ) . Blood sample s were collected every 12 months and luteinizing hormone ( LH ) , follicle stimulating hormone ( FSH ) , steroid hormone binding globuline ( SHBG ) , prolactin ( PRL ) , estradiol ( E2 ) , estrone ( E1 ) , testosterone , and rostendione , dehydroepi and rostendione-sulphate ( DHEA-S ) , and thyroid stimulating hormone ( TSH ) were analyzed . RESULTS The serum levels of FSH and LH , E2 and E1 profile essentially confirmed previous data obtained in cross-sectional studies . A continuous increase in serum FSH and LH and a concomitant fall in E2 and E1 were observed in all women before menopause and in the two postmenopausal years . Both and rostendione and testosterone showed a decline three years before menopause . After the menopause , however , there were fluctuations in the testosterone levels . And rostendione correlated positively with both E2 and E1 and testosterone postmenopausally . Body mass index ( BMI ) did correlate with testosterone , but not with and rostendione . BMI correlated negatively with SHBG . No correlation was found between BMI and E2 , E1 , FSH and LH . CONCLUSION This longitudinal prospect i ve study of hormonal changes during the transition from pre- to postmenopause indicates that not only estrogen hormonal changes , but and rogen hormonal changes as well , precedes the menopause by several years BACKGROUND AND PURPOSE Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack . The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high-risk population was determined . METHODS This was a prospect i ve , multicentre , cluster-r and omized controlled trial with blinded assessment of outcomes and intention-to-treat analysis . Patients hospitalized for stroke/transient ischaemic attack and aged ≥18 years were recruited from four hospitals . General practice s treating recruited patients were r and omized to provide either usual care or an individualized management programme comprising nurse-led education and review of care plans by stroke specialists in addition to usual care . The primary outcome was a change in cardiovascular Framingham Risk Score between baseline and 12 months . RESULTS From January 2010 to November 2013 , 156 general practice s ( 280 patients ) were r and omly assigned to usual care ( control ) and 159 ( 283 patients ) to the intervention . The median age was 70.1 years ; 65 % were male . Overall , > 80 % of participants were prescribed recommended secondary prevention therapies at baseline . The primary efficacy analysis comprised 533 participants , with 30 either dying or lost to follow-up . In adjusted analyses , no significant between-group difference was found in the cardiovascular risk score at 12 months ( 0.04 , 95 % confidence interval -1.7 , 1.8 ) . CONCLUSIONS The effectiveness of an organized secondary prevention programme for stroke may be limited in patients from high-performing hospitals with regular post-discharge follow-up and communication with general practice
We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality , cardiovascular death , non-fatal myocardial infa rct ion , angina , or revascularisation .
There was no strong evidence of effect on risk of stroke in this group .
Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall , for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events
BACKGROUND Evidence from systematic review s of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women , however the results of r and omised controlled trials ( RCTs ) have had mixed results .
This is an up date d version of a Cochrane review published in 2013 .
OBJECTIVES To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women , and whether there are differential effects between use in primary or secondary prevention .
Secondary aims were to undertake exploratory analyses to ( i ) assess the impact of time since menopause that treatment was commenced ( ≥ 10 years versus < 10 years ) , and where these data were not available , use age of trial participants at baseline as a proxy ( ≥ 60 years of age versus < 60 years of age ) ; and ( ii ) assess the effects of length of time on treatment .