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Background and Objectives: Data emerging from the Women's Health Initiative (WHI) study point toward an association between menopausal hormone therapy (MHT) and cardiovascular (CV) risk. However, post hoc subgroup analyses stratifying participants according to their age and time since menopause, have opened the way to a better understanding of the relationship between estrogen and CV risk. The aim of this review was to revise the current literature and evaluate the CV risk or benefit following administration of MHT considering several factors such as MHT timing, dose, route of administration, and formulation. Materials and Methods : An electronic databases search of MEDLINE (PubMed), Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, congress abstracts, and Grey literature (Google Scholar; British Library) was performed, with the date range from each database's inception until June 2019. All the studies evaluating MHT and cardiovascular risk, including thromboembolism or stroke, were selected . Results : Timing of MHT initiation was shown to be a critical factor in CV risk assessment. In concordance with the "timing hypothesis", healthy symptomatic women who initiated MHT when aged younger than 60 years, or who were within 10 years of menopause onset, have demonstrated a reduction in both coronary heart disease (CHD) risk and all-cause mortality. In particular, MHT therapy was associated with improvement of subclinical signs of atherosclerosis. Venous thromboembolism (VTE) risk is reduced when low doses of oral estrogen are used. Moreover, transdermal hormonal application significantly reduces CV risk compared with oral administration. MHT impact on the CV system is influenced by either factors inherent to the specific regimen, or factors inherent to the specific patient. Hence, individualization of care is necessary. Conclusion : CV risk calculation should be considered by clinicians in order to exclude patients with high CV risk, in whom MHT is contraindicated. Assessing risks and benefits in a patient-centered approach according to individual's features, health status, and personal preferences is important in order to realize a safe and effective treatment., Competing Interests: The authors declare no conflict of interest.

Women now live more than a third of their lives after the onset of menopause. The decline in endogenous estrogen production during this period is accompanied by functional disorders that affect quality of life. These symptoms may be relieved by menopausal hormone therapy (MHT) initially based on the administration of equine conjugated estrogens (mainly in the United States, oral route) or the natural estrogen, 17β-estradiol (in Europe, transdermal route). Estrogen receptor α (ERα), but not ERβ, mediates most of the physiological effects of estrogens. ERα belongs to the superfamily of nuclear receptors and regulates the transcription of genes via its activation functions AF1 and AF2. In addition to these classical genomic actions, estrogens can activate a subpopulation of ERα present at the cell membrane and thereby induce rapid signals. In this review, we will summarize the evolution of MHTs in last decades, as well as treatments that use various selective estrogen receptor modulators (SERMs). Next, we will describe recent advances in the understanding of the mechanisms of estrogen action, in particular the respective roles of nuclear and membrane ERα as well as the potential implications for future therapies., (© 2018 médecine/sciences – Inserm.)

Hormone replacement therapy (HRT) plays a large part in maintaining and improving the quality of life (QOL) of postmenopausal women. Despite this obvious role, the use of HRT has stagnated in Japan as well as the United States, since the interim report of the HRT trial of Women's Health Initiative study was published in 2002. The Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health formulated the Guidelines for Hormone Replacement Therapy in 2009, which was subsequently revised in 2012, with the aim of organizing perceptions about HRT and allowing people to provide or receive HRT with a sense of security. Later on, in light of changes in indications for HRT and attitudes toward its impact on cancer risks, amendments were made again in 2017. With the establishment of the 2017 guidelines, practitioners in Japan are able to address various issues related to HRT with more appropriate judgment. Moreover, the practice of reliable, safe and effective HRT is expected to promote further efforts toward improvement or maintenance of QOL in patients., (© 2018 Japan Society of Obstetrics and Gynecology.)

Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied., Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty., Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement., Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.

The worlds of observational, clinical, and basic science collided in 2002 with the publication of results of the Women's Health Initiative (WHI), a large-scale, prospective, blinded, randomized-controlled trial designed to provide evidence regarding use of hormone treatment to prevent cardiovascular disease in menopausal women. The results of the WHI dramatically changed clinical practice, negatively impacted funding for hormone research, and left scientists to unravel the "why" of the results. Now over a decade and a half since the initial publication of the WHI results, basic and clinical scientists often do not interpret the results of the WHI with the precision needed to move the science forward. This review will 1 ) describe the historical background leading up to the WHI, 2 ) list the outcomes from the WHI, and put them in perspective with results of subsequent analysis of the WHI data and results from other prospective menopausal hormone treatment trials addressing cardiovascular effects of menopausal hormone use, and 3 ) articulate how the collective results are influencing current clinical care with the intent to provide guidance for designing and evaluating relevant new hormonal studies., (Copyright © 2017 the American Physiological Society.)

The North American Menopause Society (NAMS) held the 3rd Utian Translational Symposium on October 4, 2016, in Orlando, Florida, to answer questions about the benefits and risks of hormone therapy (HT) for postmenopausal women. This report is a record of the proceedings of that symposium.The maxim about HT for the past 15 years since the publication of the initial results of the Women's Health Initiative (WHI) has been to prescribe the "lowest dose for the shortest period of time." With new clinical trials, observational data, and further analysis of the WHI and the cumulative 13 years' follow-up, it was time to hold a conversation about the state of the evidence and recommendations for HT dose, route, and duration of use.The symposium brought together experts in the field of HT to speak on these topics, organized by session, after which working groups gathered to synthesize the presentations into areas of what still needs to be known and how to proceed with areas of needed research. After the presentations, there was consensus that postmenopausal women aged younger than 60 years or within 10 years of menopause onset without contraindications and who desire to take HT for relief of vasomotor symptoms or prevention of bone loss if at elevated risk can safely do so.The working groups raised the possibility that the use of "Big Data" (pharmacy and cancer databases) would allow answers that cannot be found in clinical trials. This could lead to more appropriate FDA labeling and patient package inserts reflecting the true risks associated with various types and formulations of HT, with differences among estrogen alone, estrogen with a progestogen, and estrogen plus a selective estrogen-receptor modulator for the younger women most likely to initiate these therapies for symptom relief. Differences were found for potential risk among estrogen alone, estrogen with synthetic progestins contrasted to progesterone, lower doses, nonoral doses, and low-dose vaginal estrogen.With all of the available routes and dosages, including vaginal estrogen alone for genitourinary symptoms, there are many options when considering the most appropriate type, dose, formulation, route of administration, and duration of use, taking into account the age of the woman at initiation of HT and the time from menopause.

Objective: Review evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly., Evidence: Randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies., Background: Symptoms and clinical problems associated with estrogen depletion-sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis-confront the estimated 9.3 million breast cancer survivors globally., Recommendations: Following breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind-brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol., Conclusions: Nonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential., (Copyright © 2017 Endocrine Society)

The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees.Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT.For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociación Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d'études de la ménopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Società Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.

Over the past 3 decades, compounds called selective estrogen receptor modulators (SERMs) have been developed that block the estrogen receptor in some tissues (estrogen receptor antagonists) or stimulate the estrogen receptor in other tissues (estrogen receptor agonists). This Practice Pearl focuses on SERMs that clinicians can use for menopausal patients.

As more women are being counseled and tested, clinicians increasingly encounter women with identified BRCA1 and BRCA2 gene mutations. Existing, albeit limited, data indicate that risks of breast cancer are not increased with use of systemic hormone therapy by menopausal BRCA mutation carriers with intact breasts. Young mutation carriers with or without intact breasts should not defer or avoid risk-reducing (and lifesaving) bilateral salpingo-oophorectomy because of concerns that subsequent use of systemic hormone therapy will elevate breast cancer risk.

Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specify on progestogen type, dosage, route of application and duration of safe use. At the same time, the debate on bioidentical hormones including micronized progesterone increases. Based on a systematic literature review on micronized progesterone for endometrial protection, an international expert panel's recommendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesterone provides endometrial protection if applied sequentially for 12-14 days/month at 200 mg/day for up to 5 years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially for at least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3-5 years (off-label use); (3) transdermal micronized progesterone does not provide endometrial protection.

Female aging is a process that involves hypoestrogenism time, the individual impact on each woman, and what we can do as experts to reduce morbidity and provide quality of life. This natural process in the female life cycle has been of concern to women after menopause. Changes in different biophysical and psychosocial aspects, and their individual experiences, have repercussions on the lives of patients seeking specialized and multidisciplinary support to reduce the harmful effects of prolonged hypoestrogenism. Overweight and obesity, inadequate living habits and the presence of multi-morbidities cause damage to the quality of life and impact the functional capacity. Behavioral prescription and hormone therapy are among the treatments given to ease symptoms and reduce morbidity. A better understanding of these factors can help identify groups that require more care after menopause.

Cardiovascular disease (CVD) remains the number one cause of death and morbidity worldwide, and while overall CVD incidence rates declined in both genders between 1999 and 2007, age-specific data suggest that coronary risk factors in women are on the rise. While early observational data favored menopausal hormone therapy's (MHT's) role in primary CVD prevention, the initial interventional study data from the WHI did not. Further detailed analyses of both observational and interventional data have pointed to the possibility that MHT may play a role in primary CVD prevention if initiated within 10 years of menopause and less than 60 years of age (the timing hypothesis). Unanswered questions remain regarding the optimal route and dosage of estrogen in MHT. Data so far, favor transdermal estradiol over conventional-dose CEE with respect to CVD risk and oral estradiol over conventional-dose CEE with respect to stroke risk. Low-dose oral CEE may similarly have benefit over conventional-dose oral CEE for some CVD events. In addition, the transdermal route of delivery may avoid the excess risk of certain CVD events associated with MHT and lower doses of estrogen may have fewer adverse effects than the doses previously tested in WHI. Because questions regarding benefits versus risks remain, MHT is yet to be recommended for CVD prevention. However, it is indicated for menopausal symptom management in women within 10 years of menopause and under the age of 60 years, in whom it does not appear to carry increased cardiovascular risk. Additional research is ongoing and needed to confirm or refute the comparative safety of the various MHT options., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.

There is growing consensus that the benefit to risk profile for hormone therapy is high for healthy, low-risk women initiating therapy within 10 years of menopause or under age 60. However, special considerations are needed for women who are outside those boundaries or for those that have risk factors for cardiovascular disease.

Women who inherit a mutation in either the BRCA1 or BRCA2 gene have greatly elevated lifetime risks of ovarian cancer, fallopian tube cancer and breast cancer. Preventive surgical removal of the ovaries and fallopian tubes (salpingo-oophorectomy) is recommended to these women, often prior to natural menopause, to prevent cancer. The ensuing hormone deprivation may impact on health and quality of life. Most of these women experience menopausal symptoms shortly after surgery; however, there may also be longer term consequences that are less well understood. In this review, we highlight recent studies that examine the implications of salpingo-oophorectomy on health and quality of life in BRCA-positive women and we discuss the care of women following prophylactic surgery.

Background: Reduced circulating estrogen levels around the time of the menopause can induce unacceptable symptoms that affect the health and well-being of women. Hormone therapy (both unopposed estrogen and estrogen/progestogen combinations) is an effective treatment for these symptoms, but is associated with risk of harms. Guidelines recommend that hormone therapy be given at the lowest effective dose and treatment should be reviewed regularly. The aim of this review is to identify the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo., Objectives: The objective of this review is to assess which hormone therapy regimens provide effective protection against the development of endometrial hyperplasia or carcinoma., Search Methods: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2012), The Cochrane Library (Issue 1, 2012), MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), Current Contents (1993 to May 2008), Biological Abstracts (1969 to 2008), Social Sciences Index (1980 to May 2008), PsycINFO (1972 to January 2012) and CINAHL (1982 to May 2008). Attempts were made to identify trials from citation lists of reviews and studies retrieved, and drug companies were contacted for unpublished data., Selection Criteria: Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen-progestogen therapy, sequential estrogen-progestogen therapy with each other or placebo, administered over a minimum period of 12 months. Incidence of endometrial hyperplasia/carcinoma assessed by a biopsy at the end of treatment was a required outcome. Data on adherence to therapy, rates of additional interventions, and withdrawals owing to adverse events were also extracted., Data Collection and Analysis: In this update, 46 studies were included. Odds ratios (ORs) were calculated for dichotomous outcomes. The small numbers of studies in each comparison and the clinical heterogeneity precluded meta-analysis for many outcomes., Main Results: Unopposed estrogen is associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low-dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events)., Authors' Conclusions: Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen to reduce the risk of endometrial hyperplasia.

Objective: The aim of this study was to make an indirect comparison of the results from meta-analyses that evaluated the severity of hot flushes in postmenopausal women exposed to hormone therapy (HT) or soy extracts., Methods: A systematic review and meta-analysis of HT and soy extracts related to the reduction of hot flushes in postmenopausal women versus the same control (placebo) were conducted. In addition, the combination of the overall results obtained from these two meta-analyses (indirect comparison) was adjusted to the common control (placebo)., Results: The indirect standardized mean difference (SMD) obtained from the combination of both individual meta-analyses was calculated by using the following equation: SMD(indirect SOY vs HT) = SMD(soy) - SMD(HT), with a total indirect variance (var) equivalent to the following equation: var(total) = var(soy) + var(HT). These calculations yielded a point estimate of -0.84 (95% CI, -1.33 to -0.35) for the indirect SMD favorable to HT., Conclusions: HT and soy interventions showed a significant difference in efficacy for the reduction of hot flushes in postmenopausal women when each treatment was compared with placebo. However, using indirect comparison, there is a statistically significant difference between HT and soy extracts in their effects on hot flushes.

Premature ovarian failure (POF) is a common cause of infertility in women, and is characterised by amenorrhoea, hypo-oestrogenism and elevated gonadotrophin levels in women under the age of 40. Known causes include iatrogenic agents that cause permanent damage to the ovaries, such as chemotherapy, radiation therapy and surgery, autoimmune conditions, X-chromosome abnormalities and autosomal genetic conditions. However, few genes have been identified that can explain a substantial proportion of cases of POF. Most women with POF are deeply upset by the diagnosis, partly due to the unexpected menopausal symptoms, but also due to infertility. Therefore, early detection would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help to direct potential targets for future treatment.

Objective: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement., Evidence: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence., Consensus Process: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors., Conclusions: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Hormone therapy is still the most commonly used treatment to relieve menopausal symptoms and the consequences of oestrogen deficiency. The decision process is complex and benefits needs to be balanced vs. risks. Not all reported benefits and risks have been as well highlighted by the media throughout recent years, it is therefore important to update regularly the current scientific knowledge. This is an actualization of the last EMAS statement concerning hormone replacement therapy use.

Purpose of Review: In the practice of 'bioidentical hormone therapy', it is our belief that pharmacists are compounding bioidentical hormone therapy with the best intentions. These pharmacists are, however, ill informed regarding the lack of scientific underpinning associated with the efficacy and safety of the practice of bioidentical hormone therapy. It is the purpose of this review to systematically examine the scientific rigor of the arguments posed by the proponents of bioidentical hormone therapy, and to differentiate the practice of bioidentical hormone therapy from the legitimate practice of pharmacy compounding., Recent Findings: Most medical organizations have in essence refuted the bioidentical hormone therapy claims as unsubstantiated. The profession of pharmacy needs to address this issue in an authoritarian, scientific way, outside of the compounding issue., Summary: Bioidentical or natural hormones are expected to have similar efficacy and safety profiles as the commercially available hormonal therapies that have been studied in clinical trials, regardless of whether the active principle hormones are compounded by individual pharmacies or manufactured by large companies. Estriol is a weak estrogen that is not Food and Drug Administration approved for use as a prescription drug in the United States; thus, clinical trials are necessary to demonstrate the efficacy and safety profile for estriol. Further, supplementary clinical trials are necessary to determine whether there are efficacy or safety differences between natural progesterone and synthetic progestin, as studies to date are inconclusive.

Background & Aims: An association between female hormones and symptomatic gastroesophageal reflux disease (GERD) and may be modified by obesity is suggested but not proven. Factors affecting GERD progression, however, are largely unknown., Methods: At 40 US clinical centers, postmenopausal women with hysterectomy (n = 10,739) were randomly assigned to receive 0.625 mg/d of conjugated equine estrogens or placebo. Women without hysterectomy (n = 16,608) were randomly assigned to receive estrogen plus progestin, given as 0.625 mg conjugated equine estrogens/d plus 2.5 mg medroxyprogesterone acetate/d, or placebo. We performed secondary analyses using data from these trials., Results: After 1 year, there was a trend toward a higher incidence of symptomatic GER among women randomly assigned to the estrogen treatment (4.2%) than with placebo (3.1%). The estrogen plus progestin treatment did not affect this risk. Neither treatment affected the progression of existing GER symptom. There was a dose-response association between baseline obesity, particularly as measured by waist circumference, with more than double the risk of incident symptomatic GER at 1 year among women with the largest waist circumference (>or=114 cm) compared with a normal waist circumference (70-80 cm). Weight gain at 1 year was associated with elevated risk of incident symptomatic GER. Weight loss at 1 year alleviated existing GER symptoms. No interaction between hormone therapy and obesity on symptomatic GER was observed., Conclusions: Estrogen treatment alone, but not with progestin, may cause GER symptoms in postmenopausal women. Increasing weight and girth increases the risk of developing GER symptoms, whereas weight loss alleviates existing GER symptoms. This trial was registered at www.clinicaltrials.gov as NCT00000611.

This paper presents information about U.S. Food and Drug Administration (FDA) considerations for intrauterine progestins as part of a hormone replacement therapy strategy. Current U.S.-approved intrauterine systems are reviewed as well as FDA formal guidance to industry regarding clinical evaluation of combination hormone products. The formal guidance is contrasted with FDA actions for approved combination products, and recommendations for proceeding with a development plan for an intrauterine delivery approach are discussed.

These Guidelines summarize the position of an Expert Panel on Menopause in Asian Women regarding the use of hormone replacement therapy (HRT) during the menopausal transition and thereafter. They are intended to aid gynecologists, family physicians and other health-care professionals in providing optimal care to menopausal Asian women who desire HRT.

The announcement in July 2002 in the media of the results of the combined continuous hormone treatment arm of the Women's Health Initiative (WHI) had a profound effect on perceptions about hormone therapy among the lay public and the medical profession. Careful scrutiny of the announcement and the subsequent publications leads to the conclusion that the widespread fear of hormone therapy that was generated was not supported by the facts. WHI was not designed to be, nor can it be, interpreted as a randomised controlled trial of menopausal hormone therapy--rather, it was a trial of chronic disease prevention, particularly aimed at the possible cardiovascular benefits of a specific combination hormone therapy in postmenopausal women. The results, which were consistent with existing data, did not and do not warrant any major change in the previously established guidelines for the use of hormone therapy. Tibolone has emerged as an alternative treatment for menopausal symptoms, but its long-term benefits and risks have yet to be documented.

Aim: A higher risk of premature menopause and osteoporosis has been observed in female kidney-allograft recipients, providing particular indications for hormonal therapy. We have summarized our 10-year-experience with hormonal therapy in menopausal kidney transplant recipients., Materials and Methods: From 1995 to 2004, hormonal therapy was administered to 54 kidney transplant recipients. At onset of therapy the ages of the women ranged from 31 to 52 years, and the period from transplantation from 3 months to 13 years. The mean time on therapy was 4.2 years. All patients received transdermal estradiol (E(2)) in combination with oral progestin., Results: Total regression of climacteric symptoms was reported in 75% of patients. After 3 months of the therapy follicle stimulating hormone (FSH) and E(2) levels normalized: FSH from 129 +/- 30.1 IU/L to 38.3 +/- 26.1 IU/L and E(2) from 18.5 +/- 5.8 pg/mL to 98.6 +/- 33.2 pg/mL. No significant change was noted in serum creatinine. Eleven patients developed abnormal uterine bleeding but none had premalignant or malignant lesions of the uterus on endometrial curettage. No incidence of breast cancer was noted during mean treatment period of 5.2 years. Seventeen patients discontinued therapy for medical indications: one for profound thrombophlebitis and 16 for significant deterioration of liver function. Twelve women made their own decision to discontinue therapy., Conclusion: Hormonal replacement therapy was effective with no negative impact either on graft function or sex organs among kidney transplant recipients. Liver parameter monitoring seemed to be essential for safe continuation of treatment.

Since the publication of several recent randomized trials in the United States, prescriptions for hormonal therapy have dropped precipitously. This has been due, in large part, to the concerns about the increased risk of cardiovascular (CV) disease and breast cancer among the hormone users. This review takes the perspective that the appropriate use of hormones largely alleviates these concerns. The appropriate use of hormones pertains to treating younger, healthy women who have menopausal symptoms as well as using low-doses of hormones. In the randomized trials, suggesting an increased CV risk, the older women were largely asymptomatic and had other CV risk factors. Data are presented to suggest that there is no increased CV risk with hormonal therapy in younger, healthy women within 5 years of menopause. Moreover, a model is presented to attempt to explain the potential of preventing CV disease when estrogen is begun early, and the relative hazard associated with later use. The risk of breast cancer with hormonal therapy is put into perspective with the realization that this risk is related to hormonal dose and duration of use, and that the absolute risk remains small. Use of progestogens, in particular, appears to enhance this risk. The appropriate use of hormones also pertains to using lower-doses. Here data are presented showing efficacy with lower-doses and improved safety. With the use of lower-doses of estrogens, the progestogen dose, as required in women with a uterus, can be minimized.

Estrogens are essential for normal reproductive function. In addition, they exert important, complex, and diverse nonreproductive actions on multiple tissues. Although accumulating evidence from basic science studies using animal models suggests that estradiol plays a critical neuroprotective role against multiple types of neurodegenerative diseases and injuries, recent clinical studies have reported either inconclusive or untoward effects of hormone therapy on the brain. We focus herein on the work that we have done during the past 6 yr that strongly suggests that low levels of estradiol therapy exert dramatic protective actions in the adult injured brain. Our results reveal that 17beta-estradiol slows the progression of this injury and diminishes the extent of cell death by suppressing apoptotic cell death pathways and enhancing expression of genes that optimize cell survival. Furthermore, we have found that estrogen receptors play a pivotal functional role in neuroprotection. Together, these results carry broad implications for the selective targeting of estrogen receptors in the treatment of neurodegenerative conditions resulting from disease or injury, particularly for aging, postmenopausal women.

Objectives: To evaluate the effects of transdermal hormone replacement therapy (HRT) on some biological cardiovascular risk factors, specifically thromboxane B2 level and plasma viscosity. Furthermore, we investigated Doppler flow modifications at the level of the uterine, internal carotid, ophthalmic and bladder wall arteries, and evaluated whether there were significant differences, in the examined parameters, between postmenopausal women who were non-smokers and heavy smokers., Methods: Forty-three postmenopausal women (age 53.6 +/- 3.3 years, mean +/- standard deviation) participated in the study and were divided into two groups (Group I: n = 21, normal controls; and Group II: n = 22, heavy smokers). Patients were treated with continuous estradiol transdermal supplementation and 12-day courses of medroxyprogesterone acetate every 2 months. They were studied at baseline and after 6 months (in the estrogen-only phase of the cycle)., Results: Results showed a beneficial effect of hormone substitution after 6 months of therapy. Plasma viscosity decreased significantly after 6 months of therapy both in non-smokers and heavy smokers (-18% and -14%, respectively). Plasma levels of thromboxane B2, which were similar at baseline, underwent a dramatic reduction in both Group I and Group II (-93% and -88%, respectively). Doppler assessment of pulsatility index at the level of the uterine, internal carotid, ophthalmic and bladder wall arteries showed a significant reduction in vascular impedance at the end of treatment in both groups. However, the treatment was significantly less beneficial, in terms of the analyzed factors, in heavy smokers., Conclusions: Cigarette smoking represents a cardiovascular risk factor that can only partially be modified by the administration of transdermal HRT.

Objective: We sought to understand the relationship among components of residency education about hormone therapy (HT), knowledge about HT, and provider attitudes toward HT during a time of rapidly changing practice guidelines., Methods: We surveyed residents in the University of Pittsburgh Internal Medicine residency programs between February to April 2002 (after the release of the Heart Estrogen/Progestin Replacement Study and prior to the release of preliminary Women's Health Initiative data) regarding demographics, educational (didactic and experiential) exposures to HT and menopause management, knowledge about HT, and attitudes toward HT., Results: Sixty-nine of 92 (75%) eligible residents completed the survey; 38% were women. The race and gender of responders did not differ from nonresponders. Residents had significant didactic exposure to HT and menopause management with 80% reporting more than one didactic exposure. Despite this, HT knowledge was low (mean knowledge score 47 +/- 16%) and only 26% of residents felt prepared to counsel patients about HT. We identified four factors related to provider attitudes toward HT: "persistence" in universally recommending HT, confidence in "HT benefits," concern about "HT cardiac risks," and concern about "HT noncardiac risks." More appropriate attitudes were associated with attending a lecture, having a rotation with a discussion of menopause management (i.e., Women's Health), and a continuity practice including more than 30% women. Pharmaceutical detailing and self-directed study were associated with less appropriate attitudes. Knowledge did not influence attitudes. Strongly held beliefs about the benefits of HT, appropriate or inappropriate, were associated with increasing "persistence.", Conclusions: In an area of rapidly changing information, such as the risks and benefits of HT, knowledge is low. Experiential learning appropriately influences attitudes, while pharmaceutical detailing was associated with inappropriate attitudes toward HT risks.

Recent randomized trials have indicated that the risks of hormone therapy for menopausal women may outweigh the benefits. The purpose of this study was to describe how health plans responded to the findings of the Women's Health Initiative (WHI) estrogen plus progestin trial. We surveyed five health plans affiliated with the HMO Research Network and the Cancer Research Network to document the response of each plan to the WHI in terms of patient and provider education and guidelines. Every health plan issued responses within 3 months of WHI's termination in a variety of formats. Recommendations were relatively consistent across the organizations. Given the documented changes in hormone therapy use in these five health plans in the post-WHI era, we conclude that attempts on the part of each organization to educate patients and providers about the implications of the WHI may have contributed to the observed changes in hormone therapy use.

Objective: To identify the most common perimenopausal symptoms experienced by a group of Australian women and explore the extent to which those symptoms were distressing., Design: A quantitative survey., Setting: All women's health centers listed with the New South Wales Women's Information and Referral Service., Participants: A convenience sample of 200 healthy women, aged 45 to 55 years, drawn from a statewide population of women residing in Australia., Main Outcome Measure: The Women's Health Assessment Scale., Results: Most frequently occurring perimenopausal symptoms included forgetfulness, lack of energy, irritability, and weight gain. The most distressing perimenopausal symptoms included weight gain, heavy bleeding, poor concentration, leaking of urine, and feeling as though life were not worth living. Current use of hormone replacement therapy contributed to the prediction of both symptom occurrence and symptom distress., Conclusion: Perimenopause is marked by more than hot flushes and night sweats; cognitive and affective changes are other distressing symptoms. The relationships between hormone replacement therapy use and both symptom occurrence and symptom distress warrant further investigation. In addition, practitioners should address concerns related to urinary incontinence, weight gain, cognitive and affective dysfunction, and general health status.

Early stopping of clinical trials in favour of a new treatment creates ethical and scientific difficulties, which are different from those associated with early stopping due to toxicity or futility. Two major breast cancer trials have recently taken such a decision, and the problem is relevant for several ongoing trials. Here we argue that such a decision should be taken with the utmost gravity and should be based on a clear overall clinical benefit for the new treatment, and not as an automatic response to crossing a predefined threshold. Predefined rules can be used to trigger a debate within the Independent Data Monitoring and Safety Committee (IDMC) about early stopping, but the IDMC should retain the responsibility of assessing overall clinical benefit in making its recommendation.