Hormone replacement therapy and the prevention of postmenopausal osteoporosis Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM) Adverse effects of a SERM (Levormeloxifene). Safety parameters and bone mineral density 12 months after treatment withdrawal. Gynecologic effects of arzoxifene in postmenopausal women with osteoporosis or low bone mass Isoflavone treatment for acute menopausal symptoms Comparison of Oral Estrogens and Estrogens Plus Androgen on Bone Mineral Density, Menopausal Symptoms, and Lipid‐Lipoprotein Profiles in Surgical Menopause Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis Randomized prospective trial of estrogen-replacement therapy in women with a history of breast cancer. Comparative controlled trial of a novel oral estrogen therapy, estradiol acetate, for relief of menopause symptoms 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. Menopausal Symptoms in Older Women and the Effects of Treatment With Hormone Therapy Effects of bazedoxifene/conjugated estrogens on quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial Digitized mammography: a clinical trial of postmenopausal women randomly assigned to receive raloxifene, estrogen, or placebo. Body mass index does not influence response to treatment, nor does body weight change with lower doses of conjugated estrogens and medroxyprogesterone acetate in early postmenopausal women A randomized phase II presurgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor-positive breast cancer Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study
Fracture prevention is one of the public health priorities worldwide . Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis , the most common metabolic bone disease . Different effective treatments for osteoporosis are available . Hormone replacement therapy ( HRT ) at different doses rapidly normalizes turnover , preserves bone mineral density ( BMD ) at all skeletal sites , leading to a significant , reduction in vertebral and non-vertebral fractures .  Tibolone , a selective tissue estrogenic activity regulator ( STEAR ) , is effective in the treatment of vasomotor symptoms , vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT . Selective estrogen receptor modulators ( SERMs ) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures . The combination of bazedoxifene and conjugated estrogens , defined as tissue selective estrogen complex ( TSEC ) , is able to reduce climacteric symptoms , reduce bone turnover and preserve BMD . In conclusion , osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms . The use of a st and ard dose of HRT for osteoporosis prevention is based on biology , epidemiology , animal and pre clinical data , observational studies and r and omized , clinical trials . The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover , with compelling scientific evidence OBJECTIVE To evaluate the endometrial safety of a tissue selective estrogen complex ( TSEC ; pairing of a selective estrogen receptor modulator [ SERM ] with estrogens ) composed of bazedoxifene/conjugated estrogens ( BZA/CE ) in postmenopausal women . DESIGN R and omized , double-blind , multicenter , placebo- and active-controlled , phase 3 study ( Selective estrogen Menopause And Response to Therapy [SMART]-1 ) . SETTING Outpatient clinical . PATIENT(S ) Healthy , postmenopausal women ( n = 3,397 ) age 40 - 75 with an intact uterus . INTERVENTION(S ) Single tablets of BZA ( 10 , 20 , or 40 mg ) combined with CE ( 0.625 or 0.45 mg ) ; raloxifene ( 60 mg ) ; or placebo daily for 2 years . MAIN OUTCOME MEASURE(S ) Incidence of endometrial hyperplasia at 12 months in the efficacy evaluable population . RESULT ( S ) Treatment with BZA ( 20 or 40 mg)/CE ( 0.625 or 0.45 mg ) was associated with low rates ( < 1 % ) of endometrial hyperplasia that were not significantly different from those reported with placebo over 24 months . Endometrial thickness with BZA ( 20 or 40 mg)/CE ( 0.625 or 0.45 mg ) was not significantly different from that with placebo . CONCLUSION ( S ) When combined with CE ( 0.625 mg or 0.45 mg ) , BZA ( 20 mg ) was the lowest effective dose that prevented endometrial hyperplasia over 2 years of study , creating the possibility for a new , progestin-free menopausal therapy ABSTRACT Objectives Bazedoxifene/conjugated estrogens ( BZA/CE ) has demonstrated efficacy in improving vasomotor and vulvar/vaginal atrophy symptoms in postmenopausal women . This study evaluated the endometrial safety of BZA/CE and effects on bone mineral density ( BMD ) compared with CE/medroxyprogesterone acetate ( MPA ) and placebo . Methods The Selective estrogens , Menopause , And Response to Therapy (SMART)-4 trial was a 1-year , multicenter , double-blind , r and omized , placebo– and active-controlled , phase-3 study in non-hysterectomized , postmenopausal women ( n = 1061 ; aged 40 − < 65 years ) . Subjects received BZA 20 mg/CE 0.45 or 0.625 mg , CE 0.45 mg/MPA 1.5 mg , or placebo daily . Primary endpoints were the incidence of endometrial hyperplasia and the change in lumbar spine BMD at 1 year . Secondary endpoints included the change in total hip BMD and rates of amenorrhea and breast pain . Results At 1 year , no cases of endometrial hyperplasia were identified in the BZA 20-mg/CE 0.45-mg group , while three cases ( 1.1 % ) were confirmed for the BZA 20-mg/CE 0.625-mg group ( 95 % one-sided confidence interval upper limit < 4 % ) . Both BZA/CE doses significantly increased lumbar spine and total hip BMD versus placebo ( p ≤ 0.001 ) and showed low incidences of bleeding and breast tenderness , similar to placebo and significantly lower than for CE 0.45 mg/MPA 1.5 mg ( p < 0.05 ) . BZA/CE treatment was generally safe and well tolerated . Conclusions BZA 20 mg/CE 0.45 and 0.625 mg significantly improved BMD while maintaining endometrial safety and showed a favorable safety/tolerability profile over 1 year . BZA/CE may be a promising therapy for treating menopausal symptoms and preventing osteoporosis in non-hysterectomized , postmenopausal women OBJECTIVE Selective estrogen receptor modulators ( SERMs ) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific . Ospemifene ( FC-1271a ) is a novel SERM compound , which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system , while having antiestrogen-like effects in uterus and breast . In this study , we investigated the effects of ospemifene on the uterine endometrium , vaginal maturation index and hormonal status in healthy postmenopausal women . METHODS The study was conducted as a double-blind , placebo-controlled phase I study , where 40 healthy postmenopausal women volunteers were r and omized to receive daily oral doses of ospemifene either 25 , 50 , 100 or 200 mg or placebo for 12 weeks . Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks ' visit . Serum concentrations of estradiol , luteinizing hormone , follicle stimulating hormone ( FSH ) , sex-hormone binding globulin ( SHBG ) , parathyroid hormone and prolactin were determined from sample s taken at baseline , at 4 days and at 4 , 12 , and 16 weeks ' visits . Climacteric symptoms were assessed using 12 visual analogue scales ( VAS ) at baseline and at the end of the study . RESULTS No clinical ly significant changes were seen in endometrial thickness at any dose level . Ospemifene exerted a very weak estrogenic effect on endometrial histology . On the other h and , it induced a clear estrogenic effect on vaginal epithelium . Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes ; FSH decreased and SHBG increased during the treatment . In general , ospemifene was well tolerated . The 25 and 50 mg doses tended to reduce climacteric symptoms , but no statistically significant differences were observed between different doses of ospemifene and placebo . The highest dose level ( 200 mg ) induced more subjective adverse reactions , especially hot flushes , than lower doses . CONCLUSION Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg . Further studies are needed to substantiate the results of this Phase I pilot study OBJECTIVE To evaluate the efficacy of the tissue-selective estrogen complex , bazedoxifene/conjugated estrogens ( BZA/CE ) , for postmenopausal osteoporosis prevention . DESIGN Multicenter , r and omized , double-blind , placebo- and active-controlled , phase 3 trial ( Selective estrogen Menopause And Response to Therapy [SMART]-1 ) . SETTING Outpatient clinical study . PATIENT(S ) Women ( n = 3,397 ) more than 5 years and 1 - 5 years postmenopause were enrolled in the Osteoporosis Prevention I and II Sub studies , respectively . INTERVENTION(S ) Single tablets of BZA ( 10 , 20 , or 40 mg ) each with CE ( 0.625 or 0.45 mg ) , raloxifene ( 60 mg ) , or a placebo taken daily for 2 years . MAIN OUTCOME MEASURE(S ) The primary outcome for both sub studies was change in bone mineral density of the lumbar spine ; bone mineral density was also measured at the hip . RESULT ( S ) In both sub studies , bone mineral density increased significantly more with all BZA/CE doses compared with placebo at the lumbar spine and total hip , and for most BZA/CE doses compared with raloxifene at the lumbar spine . Osteocalcin and N-telopeptide significantly decreased with all BZA/CE doses vs. placebo and most BZA/CE doses vs. raloxifene . CONCLUSION ( S ) BZA/CE combinations decreased bone turnover and bone loss in postmenopausal women at increased risk for osteoporosis 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 Objectives : The primary objective of the Selective estrogen Menopause And Response to Therapy 3 ( SMART-3 ) trial was to compare the efficacy and safety of two doses of bazedoxifene (BZA)/conjugated estrogens ( CE ) versus placebo for the treatment of moderate to severe vulvar/vaginal atrophy ( VVA ) associated with menopause . Methods : This was a phase 3 , multicenter , double-blind , r and omized , placebo-controlled , and active comparator-controlled study . Healthy postmenopausal women ( n = 664 ; aged 40 - 65 y ) were r and omized to BZA 20 mg/CE 0.625 mg , BZA 20 mg/CE 0.45 mg , BZA 20 mg , or placebo once daily for 12 weeks . Changes in vaginal maturation , vaginal pH , and severity of the most bothersome symptom of VVA from baseline were assessed at screening and at weeks 4 and 12 . Adverse events were recorded throughout the study . Results : BZA 20 mg/CE 0.625 or CE 0.45 mg significantly ( P < 0.01 ) increased superficial cells and decreased parabasal cells compared with placebo . Vaginal pH and most bothersome symptom significantly improved with BZA 20 mg/CE 0.625 mg compared with placebo ( P < 0.05 ) . Improvements in vaginal dryness were also observed with both BZA/CE doses ( P < 0.05 ) . The incidence of treatment-related adverse events were similar across treatment groups . Conclusions : BZA/CE is effective in treating moderate to severe VVA and vaginal symptoms . These data further support the use of a tissue-selective estrogen complex containing BZA/CE as a new menopausal therapy for postmenopausal women Objective : Several observational studies indicate that estrogen deficiency increases the incidence of osteoarthritis in postmenopausal women . To vali date this observation , we investigated the effects of ovariectomy ( OVX ) on cartilage erosion in rats using histology and an established bio-assay of cartilage-specific collagen type II degradation products ( CTX-II ) . Furthermore , we investigated whether estrogen and levormeloxifene , a selective estrogen-receptor modulator ( SERM ) , can prevent the OVX-induced changes in cartilage degradation . The clinical relevance was assessed in postmenopausal women by measuring the changes in CTX-II during 12-month treatment with levormeloxifene versus placebo . Design : Sixty 6-month-old rats were divided in five groups . One group was subjected to sham and the others to OVX , followed by treatment with vehicle alone , estradiol or 0.2 mg/kg/day or 5 mg/kg/day of levormeloxifene . The rats were treated for 9 weeks with biweekly blood and urine sampling for measurement of bone resorption and cartilage turnover . After study termination , hind knees were removed for histological analysis of erosions . The effect of levormeloxifene in post-menopausal women was assessed by measuring CTX-II in sample s from 301 women who were participating in a phase II study of this SERM . Results : OVX rats showed significant increases in the urinary excretion of CTX-II . After 9 weeks this was manifested as increased surface erosion of knee articular cartilage compared with sham-operated rats . Treatment with estrogen or levormeloxifene prevented the OVX-induced changes . There was a significant correlation between the 4-week changes in CTX-II and cartilage erosion at week 9 ( r = 0.64 , P < 0.001 ) . In postmenopausal women treated with levormeloxifene , the urinary excretion of CTX-II was decreased by approximately 50 % and restored CTX-II levels to the premenopausal range . Conclusions : This study is the first to demonstrate that a SERM suppresses cartilage degradation in both rodents and humans , suggesting potential therapeutical benefits in the prevention of destructive joint diseases such as osteoarthritis OBJECTIVE Levormeloxifene is a selective estrogen receptor modulator ( SERM ) . The development of the drug was discontinued due to intolerable adverse effects . This paper follow-up on the adverse events in a group of 234 women that was followed for 12 months without treatment after 12 months of treatment with levormeloxifene . METHODS Adverse events were recorded at all clinical visits . The double-layer thickness of the uterine endometrium was determined by transvaginal ultrasonography . Endometrial biopsies were obtained by pipelle . The biopsies taken at the entrance to the follow-up phase were taken under hysteroscopy-guidance . Bone mineral density of the total body , lumbar spine ( L1-L4 ) , hip and forearm was measured by dual-energy X-ray absorptiometry . RESULTS The most prominent adverse event was increased endometrial thickness over the pre-defined threshold of 8 mm . No cases of proliferative endometrium were reported . Following withdrawal of treatment the mean endometrial thickness approached baseline levels in a dose dependent manner . Hysteroscopic examinations showed that levormeloxifene was related to increased incidence of edema , vascularization and cysticity . In the levormeloxifene groups , a total of eight women had utero-vaginal prolapse and five women reported urinary incontinence ( including worsening of a previously existing condition ) . Bone density in the spine and hip approached baseline levels during the 12 months of follow-up without treatment . CONCLUSION Endometrial thickening , seen in association with the use of some SERM 's , may lead to harmful adverse effects more than 12 months after treatment is initiated . Levormeloxifene prevents the postmenopausal bone loss , but the lowest effective dose is unknown Objective The aim of this study was to report the gynecologic safety findings from the Generations trial , a phase 3 study of the selective estrogen receptor modulator ( SERM ) , arzoxifene . Methods A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract . Gynecologic examinations were performed yearly , and further gynecologic assessment , including endometrial biopsy , was performed in a predefined subset of women and in those who developed vaginal bleeding . Results Overall , 9,354 women were r and omized ( 4,678 to placebo , 4,676 to arzoxifene 20 mg/d ) . There were 13 adjudicated cases of endometrial cancer  ( placebo , 4 cases ; arzoxifene , 9 cases : P = 0.165 ) and 6 cases of endometrial hyperplasia  ( placebo , 2 cases ; arzoxifene , 4 cases ) . Endometrial thickness , assessed at 24- and 36-month transvaginal ultrasounds in a subset of women , increased slightly in women assigned to arzoxifene compared with baseline and women in placebo . At the last measurement , 3 ( 1.7 % ) women assigned to placebo and 21 ( 10.2 % ) assigned to arzoxifene had an endometrial thickness greater than 5 mm ( P < 0.001 for difference between treatment groups ) . Endometrial polyps were more common in women treated with arzoxifene ( n = 37 ) than in women treated with placebo ( n = 18 ; P < 0.05 ) . Vulvular and vaginal inflammation , including mycotic infections , and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo , as were urinary tract infections . Conclusions Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo . The gynecologic effects of arzoxifene seem to differ from those of raloxifene , although both SERMs have a benzothiophene structure . Although all SERMs influence cells through the estrogen receptor , they need to be evaluated independently in terms of their effects on various tissues , including the genital tract Objective : The onset of climacteric symptoms ( hot flashes and night sweats ) is the primary reason for perimenopausal women to start hormone therapy . The association of a lower incidence of postmenopausal symptoms with high intake of soybeans in Asian women suggests that phytoestrogens are an alternative to estrogen therapy . The main effective compounds in soybean are isoflavones , which have a higher binding affinity to estrogen receptor & bgr ; than to estrogen receptor & agr;. The aim of present study was to evaluate the effects of isoflavone treatment in postmenopausal women . Design : This was a double-blind prospect i ve study . Sixty healthy postmenopausal women were r and omly assigned by computer into two groups to receive 60 mg isoflavones or placebo daily for 3 months . Before and after treatment , climacteric symptoms were recorded ; serum was collected to measure the levels of lipoprotein lipids , estradiol , and follicle-stimulating hormone ; and biopsy specimens from endometrium and breast were analyzed to investigate the expression level of steroid receptors and proliferation . Endometrial thickness was measured by ultrasound . Results : Fifty-one women finished the 12-week study . In women receiving 60 mg isoflavones daily , hot flashes and night sweats were reduced by 57 % and 43 % , respectively . The treatment did not change the levels of circulating estradiol or follicle-stimulating hormone . Immunohistochemical staining of endometrial and breast biopsy specimens revealed that isoflavones did not affect expression levels of steroid receptors ; estrogen receptors & agr ; , & bgr ; , and & bgr;cx ; progesterone receptors A and B ; or the proliferation marker Ki67 . No side effects on body weight or lipoprotein lipids were observed . Conclusions : This short-term prospect i ve study implies that isoflavones could be used to relieve acute menopausal symptoms Objective To compare an oral estrogen- and rogen combination with estrogens alone on bone , menopausal symptoms , and lipoprotein profiles in postmenopausal women . Methods Surgically menopausal women received oral esterified estrogens ( 1.25 mg ) , or esterified estrogens ( 1.25 mg ) and methyltestosterone ( 2.5 mg ) daily , for 2 years . Bone mineral density of the lumbar spine and hip , menopausal symptoms , lipoprotein profiles , and biochemical and hematologic indices were evaluated . Results Sixty-six patients were enrolled in the study . Both treatment regimens prevented bone loss at the spine and hip ; combined estrogen- and rogen therapy was associated with a significant increase in spinal bone mineral density compared with baseline ( n = 24 ; mean score ± st and ard error 3.4 ± 1.2 % , P < .01 ) . In the estrogen group , high-density lipoprotein ( HDL ) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly . Cholesterol , HDL cholesterol , and triglycerides decreased significantly in the estrogen- and rogen  group . Menopausal symptoms of somatic origin ( hot flashes , vaginal dryness , and insomnia ) were improved significantly by both treatments . Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group . Conclusion Oral estrogen- and rogen  increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms . Safety indices , including lipoprotein levels , indicated that the combination was well tolerated over the 2 years of treatment The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered 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 Objective : The aim of this study was to examine the endometrial , ovarian , and breast safety of bazedoxifene , a novel selective estrogen-receptor modulator , in postmenopausal women at risk for osteoporosis . Methods : Healthy postmenopausal women ( N = 1,583 ; mean age , 57.6 y ) with lumbar spine or femoral neck bone mineral density T scores between −1 and −2.5 and /or other clinical risk factors for osteoporosis were enrolled in a 24-month , phase 3 , r and omized , double-blind , placebo- and active-controlled trial . They received daily treatment with bazedoxifene 10 , 20 , or 40 mg ; placebo ; or raloxifene 60 mg . Reproductive safety assessment s included periodic transvaginal ultrasound measurements of endometrial thickness , ovarian volume , and presence of ovarian cysts ; periodic endometrial biopsies ; and adverse event reporting . Results : Bazedoxifene was not associated with a significant change from baseline in mean endometrial thickness at month 24 . The percentage of participants with a change from baseline in endometrial thickness or endometrial thickness greater than 5 mm at month 24 was similar among groups . There was no consensus diagnosis of endometrial hyperplasia or malignancy in the bazedoxifene or raloxifene groups ; the rates of other histologic findings , including endometrial polyps , were low ( < 5 % ) and similar among groups . No significant between-group differences were found in the change from baseline in ovarian volume , number or size of ovarian cysts , or incidence of ovarian cancer . Reports of breast pain ( < 4 % ) and breast cancer ( < 1 % ) were low and evenly distributed among groups . Conclusion : A favorable endometrial , ovarian , and breast safety profile was found after 2 years of treatment with bazedoxifene in healthy , recently postmenopausal women at risk for osteoporosis With the onset of menopause , women develop increased risk for heart disease , vasomotor instability , and osteoporosis , which is related to estrogen deficiency , and can be corrected with estrogen-replacement therapy ( ERT ) .  Menopausal women with a history of breast cancer are advised against estrogen therapy because of concerns that ERT may adversely affect the course of the disease . There have been no prospect i ve studies that address the issue of risk versus benefit for ERT in women with a history of breast cancer . We have initiated a r and omized , prospect i ve clinical study to define the influence , if any , of ERT on the clinical course of breast cancer ( measure of potential risk ) and the efficacy of ERT in the treatment of metabolic bone derangements ( measure of benefit ) . Changes in serum lipids , cardiovascular events , and indices of psychological well-being are compared but do not constitute statistical end points . Eligible women must have had stage I or stage II breast cancer and must have had no evidence of disease for at least 2 years since therapy if estrogen-receptor-negative disease or for at least 10 years if the estrogen-receptor status is unknown . They were r and omized to receive ERT ( Premarin at 0.625 mg , days 1 - 25 ) versus no intervention ( study control ) . Parameters of benefit and risk will be measured to detect a 10 % change in disease-free rate for up to 5 years , with interim analyses at 20 , 30 , and 36 months of patient accrual . This study will allow us to begin the development of safe and effective strategies for the management of estrogen deficiency in patients with breast cancer . ( ABSTRACT TRUNCATED AT 250 WORDS Objective : To compare the efficacy and tolerability of a new oral estradiol prodrug , estradiol acetate , with micronized estradiol or conjugated equine estrogens for alleviation of postmenopausal vasomotor and urogenital symptoms . Design : A total of 249 postmenopausal women experiencing seven or more moderate or severe vasomotor symptoms daily for 1 week or 60 or more symptoms in 1 week were r and omized to 0.9 mg of estradiol acetate ( n = 79 ) , 1 mg of micronized estradiol ( n = 85 ) , or 0.625 mg of conjugated equine estrogens therapy ( n = 85 ) . Efficacy endpoints were the change in frequency and severity of vasomotor symptoms from baseline to week 12 , participant-assessed urogenital symptoms , and investigator-assessed signs of vaginal atrophy . Efficacy results were considered equivalent if estradiol acetate was at least 80 % as effective as estradiol and conjugated estrogens . Results : At week 12 , frequency of vasomotor symptoms decreased comparably in all groups , and at weeks 4 and 12 , the decrease in frequency of symptoms was statistically equivalent for estradiol acetate and conjugated estrogens .  Severity of vasomotor symptoms also improved comparably for all groups , with least squares mean decreases of 1.05 for estradiol acetate , 1.34 for estradiol , and 1.17 for conjugated estrogens at week 12 . Urogenital symptoms and vaginal signs showed similar improvement in all groups . Overall , the majority of adverse events were mild or moderate and consistent with estrogen therapy . Conclusion : Estradiol acetate 0.9 mg was comparable to 1 mg of estradiol and 0.625 mg of conjugated equine estrogens in reducing the number and severity of vasomotor  and urogenital  symptoms  in postmenopausal women . Oral estradiol acetate was well tolerated Several formulations combining estrogens and progestins for hormone therapy ( HT ) have been approved worldwide for the treatment of menopausal symptoms , yet recent data indicate a decline in their use and an increase in compounded bioidentical HT . Up to now , no single product combining natural 17β-estradiol and progesterone has been approved by the US Food and Drug Administration ( FDA ) or the European Medicines Agency ( EMA ) . A phase 3 trial ( REPLENISH ) is underway to study a novel oral formulation of solubilized 17β-estradiol and natural progesterone combined in a single gelatin capsule ( TX-001HR ; TherapeuticsMD , Inc , Boca Raton , FL ) for treating vasomotor symptoms ( VMS ) in postmenopausal women . The REPLENISH trial evaluates the efficacy and safety of TX-001HR ( 4 doses ) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year . TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones ; further , it does not contain peanut oil , a common allergen . The constituents of TX-001HR , in a pharmacokinetic report , showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together . Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins . This report summarizes the methodology of the REPLENISH trial and review s the evidence suggesting clinical differences between HT containing progesterone or progestins , and estradiol or conjugated equine estrogens OBJECTIVE In some women , hot flashes and other symptoms attributed to menopause persist for many years after the cessation of menses . The frequency and severity of such symptoms and response to hormone therapy in older women have not been well documented . METHODS We used data from the Heart and Estrogen/Progestin Replacement Study , a blinded , clinical trial among 2763 women with documented coronary disease and a uterus who were r and omized to receive either conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg in one tablet or placebo .  Participants were queried at baseline and annually regarding menopausal symptoms . Breast symptoms were self‐reported , and uterine bleeding was recorded on a daily diary . RESULTS Symptoms associated with menopause were relatively common among Heart and Estrogen/Progestin Replacement Study participants , whose average age was 67 years and who averaged 18 years since menopause . At baseline , 16 % of women reported frequent hot flashes , 26 % vaginal dryness , 10 % genital irritation , 55 % trouble sleeping , and 53 % early awakening . Women assigned to hormone therapy reported less frequent hot flashes , vaginal dryness , and trouble sleeping compared with women assigned to placebo , but more frequent vaginal discharge , genital irritation , uterine bleeding , and breast symptoms . The reporting of breast symptoms among women in the hormone group decreased from 40 % at 1 year to 13 % by the 4th year . Uterine bleeding was reported by 31 % and spotting by an additional 33 % of women in the hormone group during the 1st year of treatment ; by the 4th year , these proportions had fallen to 11 % and 20 % , respectively . CONCLUSION Symptoms typically attributed to menopause are common in elderly women .  Postmenopausal hormone therapy  reduces hot flashes , trouble sleeping , and vaginal dryness , but at st and ard doses in elderly women is associated with vaginal discharge , genital irritation , uterine bleeding , and breast symptoms Objective To evaluate the effects of the tissue selective estrogen complex ( TSEC ) pairing bazedoxifene ( BZA ) with conjugated estrogens ( CE ) on sexual function and quality of life in postmenopausal women . Methods In this 12-week , double-blind , placebo-controlled study , postmenopausal , non-hysterectomized women ( n = 652 ) with symptoms of moderate to severe vulvar/vaginal atrophy were r and omized to once-daily treatment with BZA 20 mg/CE 0.45 or 0.625 mg , BZA 20 mg , or placebo . The Arizona Sexual Experiences ( ASEX ) Scale , Menopause-Specific Quality of Life ( MENQOL ) question naire , and Menopause Symptoms Treatment Satisfaction Question naire ( MS-TSQ ) were secondary measures used to assess the effects of BZA/CE on sexual function , menopausal symptoms , and satisfaction with treatment , respectively . Results At week 12 , both BZA/CE doses were associated with significant improvement in ease of lubrication score from baseline compared with placebo ( p < 0.05 ) on the ASEX scale , although there was no difference in the change in total score . The MENQOL question naire results at week 12 showed significant improvements in vasomotor function , sexual function and total scores with both BZA/CE doses vs. placebo or BZA 20 mg ( p < 0.001 ) . The MS-TSQ results showed that BZA/CE-treated subjects reported significantly greater overall satisfaction with treatment , as well as satisfaction with control of hot flushes during the day and night , effect on quality of sleep , and effect on mood or emotions , compared with subjects treated with placebo or BZA 20 mg ( all p < 0.05 ) . Conclusion Treatment with BZA/CE for 12 weeks was shown to significantly improve sexual function and quality -of-life measures in symptomatic postmenopausal women The safety and efficacy of raloxifene , a selective estrogen receptor modulator ( SERM ) , has been studied extensively in large , global clinical trials . However , the effect of raloxifene on bone mineral density ( BMD ) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated . This study was design ed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy . Participants in this multicenter trial were r and omly assigned to receive placebo , raloxifene 60 mg/day ( RLX60 ) , or raloxifene 120 mg/day ( RLX120 ) . Lumbar spine BMD was measured at baseline , 24 , 40 , and 52 weeks , and biochemical markers of bone turnover were assessed at baseline , 12 , 24 , and 52 weeks . Serum lipids were assessed at baseline , 12 , 24 , 40 , and 52 weeks , and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks . Compared with baseline , women taking RLX60 had significant increases in lumbar spine ( L2-L4 ) BMD at 24 weeks ( + 3.3 % , p<0.001 ) through 52 weeks ( + 3.5 % , p<0.001 ) of therapy , and similar results were observed in the RLX120 group . Markers of bone turnover and total cholesterol and LDL-C were significantly reduced , and no significant treatment-group difference was observed for patients reporting at least one adverse event following r and omization . In addition , there were no reported venous thromboembolic events ( VTE ) in any treatment group . The results of this study demonstrate that raloxifene is associated with early increases in lumbar spine BMD , has favorable effects on biochemical markers of bone turnover and lipid profile , and is well tolerated in postmenopausal Japanese women BACKGROUND High mammographic density is associated with increased breast cancer risk . Previous studies have shown that estrogens increase breast density on mammograms , but the effect on mammographic density of selective estrogen receptor modulators , such as raloxifene , is unknown . We assessed changes in mammographic density among women receiving placebo , raloxifene , or conjugated equine estrogens in an osteoporosis prevention trial . METHODS In a 5-year multicenter , double-blind , r and omized , placebo-controlled osteoporosis prevention trial , healthy postmenopausal women who had undergone hysterectomy less than 15 years before the study and had no history of breast cancer received placebo , raloxifene ( at one of two doses ) , or conjugated estrogens ( ERT ) .  Women from English-speaking investigative sites who had baseline and 2-year craniocaudal mammograms with comparable positioning ( n = 168 ) were eligible for this analysis . Changes in mammographic density were determined by digital scanning and computer-assisted segmentation of mammograms and were analyzed with the use of analysis of variance . All statistical tests were two-sided . RESULTS Among the four treatment groups after 2 years on study , the mean breast density ( craniocaudal view ) was statistically significantly greater in the ERT group than it was in the other three groups ( P<0.01 for all three comparisons ) . Within treatment groups , the mean breast density from baseline to 2 years decreased statistically significantly in women receiving the placebo or either the higher or lower raloxifene dose ( P = 0.003 , P = 0.002 , and P<0.001 , respectively ) and showed a nonstatistically significant increase in women receiving ERT . CONCLUSIONS In an osteoporosis prevention trial , raloxifene did not increase breast density after 2 years of treatment . Raloxifene administration should not interfere with , and could even enhance , mammographic detection of new breast cancers Objective : To determine the effects of lower doses of conjugated estrogens ( CE ) alone or in combination with medroxyprogesterone acetate ( MPA ) on body weight and to evaluate the influence of body mass index ( BMI ) on the effect of lower-dose CE or CE/MPA on vasomotor symptoms , vaginal atrophy , bone mineral density ( BMD ) , endometrial safety , and side effects such as endometrial bleeding and breast pain . Design : In this large clinical trial [ the Women 's Health , Osteoporosis , Progestin , Estrogen ( Women 's HOPE ) study ] , 2,673 healthy , postmenopausal women with intact uteri were r and omized for 1 year of CE 0.625 , CE 0.625/MPA 2.5 , CE 0.45 , CE 0.45/MPA 2.5 , CE 0.45/MPA 1.5 , CE 0.3 , CE 0.3/MPA 1.5 ( all doses mg/d ) , or placebo .  Weight , BMI , number and severity of hot flushes , vaginal atrophy ( as determined by the vaginal maturation index ) , bleeding profiles , breast pain , and endometrial biopsies were evaluated . A subset of 822 women was r and omized into a 2-year sub study to evaluate changes in BMD with lower-dose CE or CE/MPA regimens . Results : After 1 year of treatment , a small but significant ( P < 0.05 ) gain in body weight from baseline was observed in all arms of the study , the largest increase in body weight occurring in the placebo group [ 1.15 ± 0.21 ( SE ) kg ] . Body mass index had no significant effect on changes from baseline for vasomotor symptoms , bleeding patterns , vaginal atrophy , BMD , endometrial safety , or breast pain when analyzed both by analysis of covariance with baseline BMI as covariate or when participants were grouped into BMI less than 25 kg/m2 and BMI of 25 kg/m2 or greater . In placebo-treated women , vaginal atrophy was significantly greater ( P < 0.05 ) in women with a BMI less than 25 kg/m2 compared with a BMI of 25 kg/m2 or greater . Conclusions : Lower- and st and ard-dose regimens of CE or CE/MPA are not associated with greater weight gain  than placebo . In addition , BMI does not seem to influence effects of these regimens on vasomotor symptoms , vaginal atrophy , bleeding profiles , BMD , endometrial safety , or breast pain Introduction We previously demonstrated that 1 or 5 mg per day of tamoxifen ( T ) given for four weeks before surgery reduces Ki-67 in breast cancer ( BC ) patients to the same extent as the st and ard 20 mg/d . Given the long half-life of T , a weekly dose ( 10 mg per week ( w ) ) may be worth testing . Also , raloxifene ( R ) has shown Ki-67 reduction in postmenopausal patients in a preoperative setting , but data in premenopausal women are limited . We conducted a r and omized trial testing T 10 mg/w vs. R 60 mg/d vs. placebo in a presurgical model . Methods Out of 204 screened subjects , 57 were not eligible , 22 refused to participate and 125 were included in the study . The participants were all premenopausal women with estrogen receptor-positive BC . They were r and omly assigned to either T 10mg/w or R 60 mg/d or placebo for six weeks before surgery . The primary endpoint was tissue change of Ki-67 . Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers . Results Ki-67 was not significantly modulated by either treatment . In contrast , both selective estrogen receptor modulators ( SERMs ) significantly modulated circulating IGF-I/IGFBP-3 ratio , cholesterol , fibrinogen and antithrombin III . Estradiol was increased with both SERMs . Within the tamoxifen arm , CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen , one of the tamoxifen metabolites , in subjects with reduced CYP2D6 activity . Moreover , a reduction of Ki-67 and a marked increase of sex hormone-binding globulin ( SHBG ) were observed in the active phenotype . Conclusions A weekly dose of tamoxifen and a st and ard dose of raloxifene did not inhibit tumor cell proliferation , measured as Ki-67 expression , in premenopausal BC patients . However , in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki-67 modulation Endocrine treatments of breast cancer patients antagonize estrogen and may lead to consequences of estrogen deprivation including menopausal symptoms . We analyzed the changes in frequency and severity of menopausal symptoms in patients receiving tamoxifen or aromatase inhibitors  and identified factors influencing these symptoms . One hundred and eighty-one consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment  were included in this prospect i ve study . A menopause symptom question naire covering vasomotor , atrophic , psychological , cognitive and somatic symptoms was filled in at baseline , and after 1 and 3 months of therapy . Both first-line tamoxifen and aromatase inhibitors induced an increase in the occurrence and severity of hot flashes ( p<0.0001 and p=0.014 , respectively ) . Musculoskeletal pain and dyspareunia significantly increased under first-line non-steroidal aromatase inhibitors ( p=0.0039 and p=0.001 , respectively ) , while patients under tamoxifen had significant decrease in sexual interest ( p≤0.0001 ) . Younger age was associated with more hot flashes and vaginal dryness at baseline , and after 1 and 3 months of therapy ( all p<0.02 ) . We conclude that there are significant differences between the early effects of tamoxifen and aromatase inhibitors on menopausal symptoms of breast cancer patients . Our results underscore the need for safe and effective non-hormonal interventions to alleviate vasomotor and musculoskeletal symptoms which were the most prevalent and severe symptoms Background At the time of feasibility work and final design of the trial there was no r and omised control trial evidence for the long-term risks and benefits of hormone replacement therapy . Observational studies had suggested that long term use of estrogen was likely to be associated , amongst other things , with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer . Concomitant use of progestogens had been shown to protect against endometrial cancer , but there were few data showing how progestogen might affect estrogen actions on other conditions . Disease specific risks from observational studies suggested that , overall , long-term HRT was likely to be beneficial . Several studies showed that mortality from all causes was lower in HRT users than in non-users . Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women . The WISDOM trial was design ed to compare combined estrogen and progestogen versus placebo , and estrogen alone versus combined estrogen and progestogen . During the development of WISDOM the Women 's Health Initiative trial was design ed , funded and started in the US . Design R and omised , placebo , controlled , trial . Methods The trial was set in general practice s in the UK ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . In these practice s 284175 women aged 50–69 years were registered with 226282 potentially eligible . We sought to r and omise 22300 postmenopausal women aged 50 – 69 and treat for ten years . The interventions were : conjugated equine estrogens , 0.625 mg orally daily ; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ; matched placebo . Primary outcome measures were : major cardiovascular disease , osteoporotic fractures , breast cancer and dementia . Secondary outcomes were : other cancers , all cause death , venous thromboembolism and cerebro-vascular disease . Results The trial was prematurely closed during recruitment following publication of early results from the Women 's Health Initiative . At the time of closure , 56583 had been screened , 8980 entered run-in , and 5694 ( 26 % of target of 22,300 ) r and omised . Those women r and omised had received a mean of one year of therapy , mean age was 62.8 years and total follow-up time was 6491 person years . Discussion The WISDOM experience leads to some simple messages . The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery . When a trial is very costly and beyond the re sources of one country , funders and investigators should make every effort to develop international collaboration with joint funding Objective The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer . Alternative therapies that are effective in the prevention of menopause , having associated morbidities but no unwanted effects , are of primary interest in the pharmacologic research . The aim of this study was to evaluate the effect of two alternative to estrogens drugs , the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone , on the mammographic appearance of the breast . Design The study group comprised 131 postmenopausal women aged 41 to 67 years . The women were at least 2 years postmenopausal , free of climacteric symptoms , and at the time of entry to the study had not had therapy for at least 9 months . Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone ( n = 56 ) or raloxifene ( n = 48 ) therapy . Women with no risk factors and women who either did not qualify for or denied treatment ( n = 27 ) served as controls . The study duration was 12 months . Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period . Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists . Results No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk . Similarly , no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings . In the tibolone group , 10.7 % of the women showed an increase in breast density in the 12-month reevaluation . The respective figure in the raloxifene group was 6.3 % , whereas no woman in the control group showed an increase in breast density . Differences in the increase in breast density between groups did not , however , reach statistical significance . Accordingly , 10.7 % of women in the tibolone group and 18.8 % of women in the raloxifene group exhibited involutionary changes in the repeat mammogram , whereas 25.9 % of women in the control group revealed a decrease in breast density in the 12-month examination . The percentages were not significantly different between groups . Conclusions Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene . In most patients , these drugs are not likely to interfere with mammogram interpretation . Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography
Results of systematic review s and meta-analyses of r and omized controlled trials have shown that both systemic estrogen therapy or hormone therapy ( estrogen combined with a progestin ) are useful to prevent bone loss , and they are the most effective treatment for such climacteric symptoms as hot flushes , sweating , vaginal dryness , and dyspareunia .
The combination of a SERM with estrogen as a tissue selective estrogen complex ( TSEC ) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms .
This combination is particularly interesting from a clinical point of view , taking into account that estrogen alone did not increase breast cancer risk by the Women 's Health Initiative .
TSEC is hypothesized to provide the benefits of estrogen-alone therapy , with an improved tolerability profile because the SERM component can make possible the elimination of progestin .
The conclusion is that effectively , the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women
Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis .
Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition .
Unfortunately , estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer , respectively .
The selective estrogen receptor modulators ( SERMs ) result in positive estrogenic effects on bone , with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms .
The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene ( a third-generation SERM ) in combination with conjugated estrogens in postmenopausal women .