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Background: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'., Objectives: To evaluate those claims., Methods: Epidemiological criteria of causation were applied to the evidence., Results: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor., Conclusions: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

Background: After publication of the Women's Health Initiative study in 2002, use of menopausal hormone therapy (HT) has declined by nearly 80% worldwide and internists now play only a limited role in menopause management. Over the past decade, new data have increased our knowledge of the multiple effects and mechanisms of HT., Methods: Existing literature was reviewed., Results: A consensus has emerged that the benefits of HT outweigh the risks for the relief of symptoms in women who have recently undergone menopause and are not at excess risk of breast cancer and cardiovascular disease. Non-hormonal agents, selective estrogen receptor modulators (SERMs), and tibolone are also useful in management. Factors entering into the decision-making process regarding menopause management are increasingly complex and involve consideration of effects on multiple systems and potential disease-related events. These considerations suggest that internists trained to evaluate and integrate factors influencing multiple organ systems should re-engage in menopause management. Most internists currently lack the core competencies and experience necessary to address menopausal issues and meet the needs of women who have completed their reproductive years. We believe that this situation is detrimental to women's health, leads to fragmented care, and should change., Conclusions: We propose that the multidimensional expertise that characterizes the internist may provide the most comprehensive approach to menopause management. For the internist to meet this need, a set of core competencies must be attained, which will require new didactic programs to be developed for medical students, residents and practicing physicians.

Vitex agnus-castus L. (chaste tree; chasteberry) is a popular herbal treatment, predominantly used for a range of female reproductive conditions in Anglo-American and European practice. The objective of this systematic review was to evaluate the evidence for the efficacy and safety of Vitex extracts from randomised, controlled trials investigating women's health.Eight databases were searched using Latin and common names for Vitex and phytotherapeutic preparations of the herb as a sole agent, together with filters for randomised, controlled trials or clinical trials. Methodological quality was assessed according to the Cochrane risk of bias and Jadad scales, as well as the proposed elaboration of CONSORT for reporting trials on herbal interventions.Thirteen randomised, controlled trials were identified and twelve are included in this review, of which eight investigated premenstrual syndrome, two premenstrual dysphoric disorder, and two latent hyperprolactinaemia. For premenstrual syndrome, seven of eight trials found Vitex extracts to be superior to placebo (5 of 6 studies), pyridoxine (1), and magnesium oxide (1). In premenstrual dysphoric disorder, one study reported Vitex to be equivalent to fluoxetine, while in the other, fluoxetine outperformed Vitex. In latent hyperprolactinaemia, one trial reported it to be superior to placebo for reducing TRH-stimulated prolactin secretion, normalising a shortened luteal phase, increasing mid-luteal progesterone and 17β-oestradiol levels, while the other found Vitex comparable to bromocriptine for reducing serum prolactin levels and ameliorating cyclic mastalgia. Adverse events with Vitex were mild and generally infrequent. The methodological quality of the included studies varied, but was generally moderate-to-high. Limitations include small sample sizes in some studies, heterogeneity of conditions being treated, and a range of reference treatments.Despite some methodological limitations, the results from randomised, controlled trials to date suggest benefits for Vitex extracts in the treatment of premenstrual syndrome, premenstrual dysphoric disorder and latent hyperprolactinaemia. Further research is recommended, and greater transparency in reporting for future trials., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study, it is claimed that hormone replacement therapy (HRT) is an established cause of breast cancer. The authors have previously reviewed those studies (Parts 1-4). The WHI findings were first published in 2002, following which the use of HRT rapidly declined. A correspondingly rapid decline in the incidence of breast cancer has been reported, and attributed to the drop in the use of HRT. The evidence, however, is conflicting., Methods: Using generally accepted causal criteria, in this article (Part 5) the authors evaluate reported trends in the incidence of breast cancer., Results: The evidence to suggest a correlated decline in the incidence of breast cancer following a decline in the use of HRT has not adequately satisfied the criteria of time order, detection bias, confounding, statistical stability and strength of association, internal consistency, and external consistency; biological plausibility is difficult to assess., Conclusions: Based on the observed trends in the incidence of breast cancer following the decline in HRT use, the ecological evidence is too limited either to support or refute the possibility that HRT causes breast cancer.

Following the announcement of the first results of the Women's Health Initiative (WHI) to the media in 2002, prior to their scientific publication, the resulting panic headlines had an immediate and lasting negative effect on use of menopausal hormone replacement therapy (HRT) around the world. Rates of use dropped by 40-80%. Symptomatic women then sought multiple alternative therapies but the majority of these have no greater effect than the effect seen from placebo in well-conducted trials of HRT. Some of these therapies have risks. Although anecdotally most menopause practitioners after 2002 can attest to having to counsel large numbers of women with debilitating menopausal symptoms who were too frightened to consider HRT, it is difficult to document loss of health-related quality of life in large population studies as they were not conducted. Similarly, the positive or negative effects of the marked decline in HRT on long-term morbidities and mortality have yet to be fully assessed. Recent studies have shown an increase in postmenopausal fractures and in some, but not all, populations a small temporary decline in breast cancer. Cardiovascular outcomes may not be apparent for another decade. Short-term, randomized, placebo-controlled trials confirm that HRT is the only therapy that effectively improves health-related quality of life in symptomatic women through a reduction in vasomotor and urogenital symptoms, joint pains and insomnia, while improving sexuality. The results of the re-analyses of the WHI data and new data from other studies do not justify the continuing negative attitude to HRT in symptomatic women who start HRT near menopause.

Background: Based principally on findings in three studies, the collaborative reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1-3)., Objective: To evaluate the evidence for causality in the MWS., Methods: Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET., Results: Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50-55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported., Conclusion: HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.

The approach to menopause can be divided into the early (E) and late (L) menopausal transitions (MT) on the basis of menstrual irregularity (EMT) and subsequent observation of at least one episode of 60 or more days amenorrhoea (LMT). In total, 40-60% of cycles in the LMT are anovulatory, often with low oestradiol (E2) and high follicle-stimulating hormone concentrations. The ovulatory cycles have variable endocrine characteristics, none of which is specific to EMT or LMT. Hormonal measurements of FSH and E2 are thus of little diagnostic value because of their unpredictable variability. Symptoms during the transitions may result from high or low E2 and can often be satisfactorily managed with low-dose oral contraceptives, which suppress pituitary-ovarian function.

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.

Background: It has been suggested that some of the symptoms typically attributed to menopause may be more related to premenstrual syndrome (PMS) than menopause, as perimenopausal women appear to be more prone to PMS-like symptoms, or at least to tolerate them less well., Objective: The objective of this study was to evaluate the effectiveness of a phytotherapeutic intervention comprising a combination of Hypericum perforatum (St. John's wort) and Vitex agnus-castus (chaste tree/berry) in the management of PMS-like symptoms in perimenopausal women., Design: A double-blind, randomized, placebo-controlled parallel trial was conducted over 16 weeks on menopause-related symptoms. Data on PMS-like symptoms were collected at 4-weekly intervals from a small subgroup of late-perimenopausal women (n = 14) participating in this study. The primary endpoint was PMS scores measured on the Abrahams Menstrual Symptoms Questionnaire, comprising the subclusters of PMS-A (anxiety), PMS-D (depression), PMS-H (hydration), and PMS-C (cravings). Herbal combination therapy or placebo tablets were administered twice daily., Results: At the end of the 16-week treatment phase, analyses of covariance showed the herbal combination to be superior to placebo for total PMS-like scores (p = 0.02), PMS-D (p = 0.006), and PMS-C clusters (p = 0.027). The active treatment group also showed significant reductions in the anxiety (p = 0.003) and hydration (p = 0.002) clusters, using paired-samples t tests. Results of trend analyses showed significant treatment group effects across the five phases for total PMS and all subscales, all in the clinically expected direction. No significant trends were evident in the placebo group., Conclusions: These results suggest a potentially significant clinical application for this phytotherapeutic combination in PMS-like symptoms among perimenopausal women. Further research is warranted through a randomized, controlled trial dedicated to investigation of these symptoms.

Background: The origin of the current practice of administering Vitex agnus-castus in menopause-related complaints is uncertain, but appears to be relatively recent. Here we review the evidence for this application of Vitex based on evidence from pharmacological studies and clinical research., Methods: The mechanisms of potential relevance in the context of menopause are explored with reference to the current understanding of the endocrinology and neuroendocrinology of menopause and associated symptoms., Conclusions: We conclude that, while evidence from rigorous randomized controlled trials is lacking for the individual herb in this context, emerging pharmacological evidence supports a role for V. agnus-castus in the alleviation of menopausal symptoms and suggests that further investigation may be appropriate.

Background: Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms., Methods: A post hoc analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects., Results: Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, low anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm., Conclusion: This study was a post hoc analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported., Trial Registration: International Clinical Trials Registry ISRCTN98972974.

Context: Ovarian hormones regulate pituitary gonadotropin secretion across the menstrual cycle via negative and positive feedback mechanisms. The contribution of individual hormones is complex and is a continuing area of research., Objective: The aim of the study was to identify relationships between LH/FSH and estradiol, progesterone, inhibin A, inhibin B, and anti-Mullerian hormone (AMH) in ovulatory menstrual cycles across reproductive age., Design: Serum ovarian and pituitary hormones were studied in a group of young (<35 yr; n = 21) and older (>45 yr; n = 55) women. The slopes of the regression lines relating the ovarian and pituitary hormones were determined by multiple linear regression analysis and expressed with 95% confidence intervals for each ovarian hormone, with FSH and LH as independent variables. Both simultaneous and delayed (time lagged) relationships were examined., Results: Clear associations were evident for the lagged prediction of FSH, with significant negative associations being evident with inhibin B and AMH in the follicular phase and with estradiol, inhibin B, progesterone, and AMH in the luteal phase. For the lagged prediction of LH, significant positive and negative associations were observed with estradiol and inhibin B, respectively, in the follicular phase and a negative association with progesterone and inhibin B in the luteal phase., Conclusions: It is concluded that in the follicular phase, inhibin B is a major feedback regulator of FSH and may also be a negative feedback regulator of LH. AMH may be indirectly involved in FSH regulation.

Plants contain compounds with oestrogen--like action called phytoestrogens. Soy contains daidzin, a potent phytoestrogen, and wheat flour contains less potent enterolactones. We aimed to show in 58 postmenopausal women (age 54, range 30-70 years) with at least 14 hot flushes per week, that their daily diet supplemented with soy flour (n = 28) could reduce flushes compared with wheat flour (n = 30) over 12 weeks when randomised and double blind. Hot flushes significantly decreased in the soy and wheat flour groups (40% and 25% reduction, respectively < 0.001 for both) with a significant rapid response in the soy flour group in 6 weeks (P < 0.001) that continued. Menopausal symptom score decreased significantly in both groups (P < 0.05). Urinary daidzein excretion confirmed compliance. Vaginal cell maturation, plasma lipids and urinary calcium remained unchanged. Serum FSH decreased and urinary hydroxyproline increased in the wheat flour group.

Background: Trials of testosterone therapy in aging men have demonstrated increases in fat-free mass (FFM) and skeletal muscle and decreases in fat mass (FM) but have not reported the impact of baseline body composition., Objective: The objective of the study was to determine the effect, in nonobese aging men with symptoms of androgen deficiency and low-normal serum testosterone levels, of testosterone therapy on total and regional body composition and hormonal and metabolic indices., Methods: Sixty healthy but symptomatic, nonobese men aged 55 yr or older with total testosterone (TT) levels less than 15 nm were randomized to transdermal testosterone patches or placebo for 52 wk. Body composition, by dual-energy x-ray absorptiometry (FM, FFM, skeletal muscle) and magnetic resonance imaging (abdominal sc and visceral adipose tissue, thigh skeletal muscle, and intermuscular fat) and hormonal and metabolic parameters were measured at wk 0 and 52., Results: Serum TT increased by 30% (P = 0.01), and LH decreased by 50% (P < 0.001). Relative to placebo, total body FFM (P = 0.03) and skeletal muscle (P = 0.008) were increased and thigh skeletal muscle loss was prevented (P = 0.045) with testosterone therapy and visceral fat accumulation decreased (P = 0.001) without change in total body or abdominal sc FM; change in visceral fat was correlated with change in TT levels (r2 = 0.36; P = 0.014). There was a trend to increasing total and low-density lipoprotein cholesterol with placebo., Conclusion: Testosterone therapy, relative to placebo, selectively lessened visceral fat accumulation without change in total body FM and increased total body FFM and total body and thigh skeletal muscle mass. Further studies are needed to determine the impact of these body compositional changes on markers of metabolic and cardiovascular risk.

The menopause, defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity, marks the end of natural female reproductive life. It is preceded by a period of menstrual cycle irregularity, the menopausal transition, which usually begins in the mid-40s and is conventionally divided into early and late phases. The endocrine changes, which underlie the transition, are predominantly the consequence of a marked decline in ovarian follicle numbers. The most significant changes include a decrease in early cycle inhibin B and in anti-Mullerian hormone (AMH) levels. The decline in inhibin B results in an increase in FSH, which appears to be an important factor in the maintenance of estradiol (E2) concentrations until late in reproductive life. In the post-menopause, FSH levels are markedly raised, E2 levels are low, whereas inhibin B and AMH are undetectable. The menopausal transition is a time of marked hormonal instability. The Melbourne Women's Midlife Health Project has been an extremely productive study in which it has been possible to describe longitudinal changes in hormone levels throughout the menopause transition and to separate the effects of hormone change from the effects of ageing on a number of endpoints. This review provides the background for an accompanying manuscript in which a novel approach to modelling the hormonal changes during the transition is described.

Changes in FSH and estradiol (E2) across the menopausal transition are clearly not linear. The present study utilizes data from 204 women who completed the 13-year prospective Melbourne Women's Midlife Health Project. E2, FSH, symptoms, self-rated health, mood, sexual function and coronary heart disease (CHD) risk were measured longitudinally. We presumed an s-shaped curve for each hormone and estimated five parameters for each hormone curve for each woman: baseline, final value, range, slope at inflexion point and age at inflexion point. These parameters were found to adequately estimate the curve for each hormone. The median age of transition observed for E2 occurs >1 year later than the median age of transition observed for FSH. FSH parameters did not affect any of the health outcomes analysed. Hot flushes, night sweats, sleeping problems, vaginal dryness and to a lesser extent self-rated health were highly significantly associated with E2 range and slope. Sexual response and CHD risk were highly significantly associated with final E2 level (post-menopausally). These findings have clinical relevance in identifying which symptoms will be triggered by steep transitions of E2 such as sudden withdrawal and which health parameters may require a maintenance level of E2.

Context: Female reproductive aging based on changes in menstrual cycle length and frequency progresses through a number of stages as defined by the Stages of Reproductive Aging Workshop (STRAW) staging criteria., Objective: This paper provides a comprehensive description of the endocrine features associated with the STRAW stages., Design: Healthy women aged 21-35 and 45-55 yr submitted three blood samples a week over a single menstrual cycle. They were classified as mid-reproductive age (n = 21), late-reproductive age (n = 16), early menopause transition (n = 16), and late menopause transition (n = 23)., Results: There were nine, one, zero, and two anovulatory cycles identified in the late menopause transition, early menopause transition, late-reproductive age, and mid-reproductive age groups, respectively. Ovulatory cycle FSH, LH, and estradiol levels increased with progression of STRAW stage (P = 0.001, P < 0.01, and P < 0.05, respectively), and mean luteal phase serum progesterone decreased (P < 0.01). Early cycle (ovulatory and anovulatory) inhibin B decreased steadily across the STRAW stages (P < 0.01) and was largely undetectable during elongated ovulatory and anovulatory cycles in the menopause transition. Anti-Mullerian hormone decreased markedly (10- to 15-fold) and progressively across the STRAW stages (P < 0.01 and P < 0.001, respectively)., Conclusions: Progression through the STRAW stages is associated with elevations in serum FSH, LH, and estradiol and decreases in luteal phase progesterone. The marked fall in inhibin B and particularly anti-Mullerian hormone indicate that they may be useful in predicting STRAW stage but future analyses of early cycle measurements on larger cohorts are needed to draw predictive conclusions.

Two randomised controlled trials of hormone therapy (HT) were conducted within the US Women's Health Initiative. Both were chronic disease prevention trials, undertaken to determine whether HT reduced cardiovascular risk and increased breast cancer risk. Because the majority of subjects in both trials were asymptomatic and many years postmenopausal, and because substantial numbers had received HT prior to recruitment to the trials, care must be taken in drawing conclusions that the observed risks are applicable to women for whom HT is conventionally prescribed. Each of the reported risks must be examined critically to determine its likely applicability to symptomatic women treated for two to three years to relieve symptoms, but sometimes for substantially longer periods. Further, the risks reported in each of the two trials must be considered separately. Concerning cardiovascular disease, many subjects in the trials were at increased baseline risk because of their age, body mass index, smoking status, blood pressure and years since menopause, in contrast to the usual situation for symptomatic perimenopausal women. Therefore the reported overall cardiovascular risks in WHI, in both treatment arms, should be regarded as irrelevant to menopause management. In contrast, breast cancer risk is relevant, providing that proper note is taken of the fact that there was no increased risk after five years of combined hormone therapy in non-prior HT users and there was a tendency to a decreased risk in oestrogen only treated individuals. Other risks are analysed similarly.

In 2001, the Stages of Reproductive Aging Workshop (STRAW) proposed bleeding and endocrine criteria for defining the early and late menopausal transition stages. Based on expert consensus, STRAW recommended a shorter interval of amenorrhea than the commonly used 90-day amenorrhea criteria for late transition and a >7-day change in cycle length for early transition. The ReSTAGE collaboration used prospective menstrual calendar data from four cohorts (TREMIN, Melbourne Women's Midlife Health Project, Seattle Midlife Women's Health Study, and Study of Women's Health Across the Nation) to quantitatively evaluate STRAW's recommendations. This empirical assessment supported the STRAW recommendations that (1) > or =60 days of amenorrhea be used to define the late menopausal transition and (2) that early transition is consistent with a persistent 7 or more day difference in length of consecutive cycles. Serum follicle stimulating hormone (FSH) values > or =40 IU/l was an independent marker of the transition and, when occurring together with a bleeding marker, increased prediction of final menstrual period. Such a FSH criterion could be incorporated into the STRAW paradigm to facilitate prediction of proximity of the final menstrual period.

Objective: To determine the influence of obesity on the diagnosis of age-related androgen deficiency (AD) in symptomatic men according to current Australian guidelines., Design, Setting and Participants: A community-based cohort of healthy ageing men with symptoms suggestive of AD was studied between May 2001 and February 2003. Men were classified as obese or non-obese according to body mass index (BMI) or waist circumference (WC)., Main Outcome Measure: Diagnosis of AD according to Endocrine Society of Australia (ESA) guidelines., Results: 223 men aged 54-86 years with mean BMI 27.3 +/- 0.2 kg/m2 (range 20.5-36.2 kg/m2) were recruited; 99 men were obese (BMI > or = 30.0 kg/m2 or WC > or = 102 cm) and 124 men were non-obese. Obese men had lower total testosterone (TT) (12.7 +/- 0.4 v 15.0 +/- 0.4 nmol/L); P < 0.001) and calculated free testosterone (275.7 +/- 7.8 v 299.3 +/- 7.4 pmol/L); P = 0.03) levels than non-obese men. TT levels < 8 nmol/L were recorded in 12% of obese men and 1% of non-obese men. Applying the ESA guidelines for the diagnosis of age-related AD, 15 obese men (15%) and 4 non-obese men (3%) were classified as being eligible for androgen therapy supported by the Pharmaceutical Benefits Scheme (PBS); the relative risk in obese men was 1.92 (95% CI, 1.44-2.55; P < 0.001)., Conclusion: Obesity is an important determinant of serum TT levels in ageing men. Almost one in seven obese men but only one in 30 non-obese men in our study were eligible for PBS-supported androgen therapy according to Australian guidelines. Although obese men are more likely to have biochemical hypoandrogenism, the clinical implications of this remain uncertain. Studies of testosterone therapy in this group of ageing men are needed to determine whether androgen replacement is beneficial.

The diagnosis of female androgen deficiency syndrome is suggested by complaints of a diminished sense of well being, persistent unexplained fatigue and decreased sexual desire, sexual receptivity and pleasure in a woman who is oestrogen-replete and in whom no other significant contributing factors can be identified. The diagnosis is supported by the finding of low circulating concentrations of free testosterone. Barriers to its recognition include the non-specificity of the symptoms and methodological problems due to insensitive testosterone assays. Barriers to its treatment include the unavailability of satisfactory forms of testosterone for administration to women and lack of data regarding long-term safety. Although several conditions lead to clear-cut androgen deficiency, such as hypopituitarism, adrenal and ovarian insufficiency, glucocorticoid therapy and use of oral contraceptives and oral oestrogens, it is important for clinicians to recognise that in normal women, androgen levels decline by 50% from the early 20s to the mid 40s, and hence age-related androgen insufficiency may occur in women in their late 30s and 40s, as well as postmenopausally. Satisfactory measurements of free testosterone requires a sensitive and reliable assay for total testosterone, and quantitation of sex hormone binding globulin, from which free testosterone is readily calculated. Adverse effects of testosterone treatment are few if replacement is monitored to achieve physiological circulating testosterone concentrations. Currently, available methods include testosterone implants and testosterone creams, and transdermal patches and sprays are in development.

Objective: To investigate the associations between C-reactive protein (CRP), homocysteine levels, use of hormone therapy (HT) and other factors., Methods: A 12-year prospective study of 438 Australian-born women (Melbourne Women's Midlife Health Project), who at baseline were aged 45-55 years, had menstruated in the previous 3 months and were not taking HT. Fasting blood was collected in the 11th follow-up year for CRP, homocysteine, estradiol and follicle stimulating hormone (FSH) levels. Physical measurements and face-to-face interviews obtained information on health and lifestyle variables., Results: A total of 258 women (mean age 60 years) participated in the 11th follow-up year. Multiple regression analysis found that CRP levels were positively associated with body mass index (p < 0.001), HT use (p < 0.01), and negatively associated with statin use (p < 0.005) and exercising (p < 0.05). In postmenopausal women currently not using HT (n = 173) and after adjusting for body mass index, exercise and smoking, CRP was negatively associated with FSH levels (beta = -0.32, p < 0.05). Homocysteine levels were positively associated with smoking (p < 0.001) and negatively associated with HT use (p < 0.05)., Conclusion: In middle-aged Australian-born women, HT use was associated with increased CRP and decreased homocysteine levels. High CRP levels were also associated with high relative weight, low exercise levels and no statin medication.

The fourth Amsterdam Menopause Symposium (2-4 October 2004) was dedicated to practical recommendations to guide clinicians after the confusion, concerns, and controversies generated by study results over the previous several years. Those recommendations are summarized in this deliberately concise and user-friendly document, always recognizing that each clinician must help women with their decision-making according to individual needs, desires, and understanding of benefits and risks.

Objective: The aim of this study was to assess the relative strength of the association of endogenous estradiol and androgens with bone loss at the lumbar spine and femoral neck during the menopausal transition., Design: A longitudinal study of a population-based cohort of 159 Australian-born women who at baseline had a mean age of 50.0 years (SD=2.4) and had menstruated in the prior 3 months. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck on up to three occasions., Results: Of the 159 participants, 50 had two BMD measurements and 109 had a third measure. The mean time between the first and final measures for the whole group was 39 months and at the time of the final measures 49% of the participants had become postmenopausal. The mean percentage change/year in lumbar spine BMD was -0.9% (95% CI, -1.1 to -0.6) and at the femoral neck, -0.5% (95% CI, -0.7 to -0.2). A highly significant association with estradiol at the final time point was found, whereas the contribution of estradiol at baseline was negligible. The variance explained by estradiol levels was 19% and 11% for change in BMD at the LS and FN, respectively. Excluding baseline estradiol values and using the average of change in BMD at the LS and FN, the final regression equation estimated that an estradiol level of 330 pmol/l (95% CI, 274 to 386) and 245 pmol/l (95% CI, 194 to 296) is required for preservation of LS and FN BMD, respectively. A stepwise linear regression model was used to assess the effect of age, BMI, estradiol, testosterone, DHEAS, SHBG, and free testosterone index on changes in BMD and found that only the final estradiol level had a significant association with change in BMD., Conclusion: Endogenous estradiol was the only hormone among those investigated to have a significant effect on bone mineral density during the menopausal transition.

The inhibins are produced and secreted by several ovarian cancers. Monitoring serum levels by immunoassay may be a useful diagnostic aid in the initial assessment of this disease and in monitoring its potential recurrence following surgery. The assays are applicable to women after menopause when the majority of ovarian cancers are detected, and when the normal ovarian production of inhibin is low to negligible. A new inhibin immunoassay (total inhibin ELISA) has been developed with the intention of widespread clinical application. The assay readily detects granulosa cell and mucinous tumours. CA125, a widely used ovarian cancer marker, detects the other main ovarian cancer types (serous, endometrioid, undifferentiated) with high sensitivity. The combination of the two tests detects the majority of ovarian cancers with high specificity (95%) and sensitivity (95%). Studies have been undertaken to assess its application to women in the perimenopausal stage and to younger women during normal reproductive life. These studies are providing a platform for the introduction of the test into clinical practice.

The proposed key symptoms of the female androgen insufficiency syndrome (FAIS) include reduced libido, diminished well being and lowered mood. The diagnosis of FAIS is made on the basis of these symptoms in the setting of a low serum free testosterone level. However, there is currently no readily available inexpensive assay which reliably measures free testosterone levels in the female range. The diagnosis of FAIS is further complicated by the lack of data demonstrating a minimum serum free testosterone level which, if below this, correlates with the symptoms of FAIS. Despite the complexities involved with defining FAIS, the symptoms have been reported to respond well to testosterone replacement. There is a need for formulations of testosterone therapy specifically designed for use in women, along with clear guidelines regarding optimal therapeutic doses and long-term safety data.

To examine the hormonal characteristics of menstrual cycles in healthy women approaching menopause, serum hormone profiles were investigated annually in this longitudinal study of 13 healthy women between 4 and 9 yr before menopause and the year of the menopause. Serum FSH, LH, estradiol, progesterone, total inhibin, inhibins A and B, and prolactin were determined in blood samples collected annually three times weekly for 4 wk beginning with the onset of menses. Menstrual bleeding diaries covering this 4- to 9-yr period were also collected allowing the prospective identification of the final menstrual period. A change in serum hormone patterns was observed in cycles approaching menopause, exemplified by an increasing number of cycles of prolonged length with a prolonged follicular phase resulting in a failure to detect a luteal phase rise in serum progesterone within the 4-wk collection period. These prolonged cycles (designated B cycles based on a previous work) were analyzed separately and compared with the remaining ovulatory (D) cycles. No B cycles were identified in any women earlier than 27 cycles from menopause. The proportion of B cycles increased as menopause approached, reaching 62% in the last 10 cycles. The proportion of D cycles decreased accordingly. The B cycles during the initial 4-wk collection period were characterized by elevated FSH, LH, FSH/inhibin A and FSH/inhibin B ratios, and longer duration, although cycle length/subject was not significantly different presumably due to the small number of B cycles. The D cycles showed no changes in hormonal profiles over the 4- to 9-yr time period. These data indicate that there is a time-related change in the character of menstrual cycles as menopause approaches, with an increasing proportion of cycles observed with prolonged follicular phases that may either be delayed ovulatory cycles or anovulatory cycles. The increase in the proportion of B cycles with elevated early follicular phase FSH levels and low inhibin/FSH ratios toward menopause provides a basis for the apparent early increase in serum FSH and decrease in serum inhibins observed previously in studies of the menopause transition based on sampling confined to the follicular phase only. The data amplify and clarify current concepts of the endocrine basis of the menopause transition.

A multicenter, open-label, randomized efficacy and safety study was performed with combined human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) (Puregon(R)) treatment to induce spermatogenesis in hypogonadotropic hypogonadal male patients. Patients were pretreated for 16 weeks with hCG to normalize testosterone levels. A total of 30 of 49 (61%) subjects had normalized testosterone levels but were still azoospermic after the hCG-alone phase. These patients were randomized into 2 treatment schemes with recFSH (2 x 225 IU recFSH per week [group A] or 3 x 150 IU recFSH per week [group B]), in combination with hCG for a period of 48 weeks. Total testosterone increased during the hCG-alone period from 1.08 and 1.22 ng/mL to 6.26 and 4.52 ng/mL for groups A and B, respectively. Combined gonadotropin treatment was effective in inducing spermatogenesis (sperm count >/=1 x 10(6)/mL) in 14 of 30 subjects (47%) and this was achieved after a median duration of treatment of approximately 5.5 months. Treatment time necessary for first sperm cells to appear in the ejaculate was related to the initial testicular volume. Subjects with a history of maldescended testes (11 of 30 subjects, 37%) showed a lower mean response to treatment as indicated by the relatively lower number of subjects reaching levels of at least 1 x 10(6) sperm cells per milliliter. Combined testicular volume increased during combined gonadotropin treatment from 11.4 to 24.0 mL. Although subjects with a history of maldescended testes had a lower starting testicular volume, subjects with and without a history of maldescended testes showed approximately the same relative increase in testicular volume. Total testosterone levels showed only a minor further increase during the combined gonadotropin treatment period. In conclusion, a weekly dose of 450 IU (3 x 150 IU or 2 x 225 IU) recFSH, in addition to hCG, was able to induce spermatogenesis in many hypogonadotropic azoospermic men who failed to respond to treatment with hCG alone.

Objective: To investigate the effect of endogenous hormone levels on central abdominal fat during the menopausal transition in a population-based cohort of Australian-born women., Design: Prospective observational study., Setting: Population-based sample. Body composition was assessed in the Royal Melbourne Hospital, and interviews were conducted at the patient's home., Subject(s): One hundred two women from the Melbourne Women's Midlife Health Project. Data, physical measures, and blood were obtained by interview when the longitudinal study commenced (baseline) and at the time of the total body scan approximately 5 years later. Body composition was measured using dual-energy X-ray absorptiometry., Intervention(s): None., Main Outcome Measures: Total body fat and central abdominal fat., Result(s): The 102 women were either premenopausal or in the early menopausal transition at baseline. At the time of their dual-energy X-ray absorptiometry scan, 31 were in the early menopausal transition, 22 were in the late menopausal transition, and 49 were postmenopausal. Multiple regression analysis found that total percentage of body fat was associated with weight measures, whereas central abdominal fat was also positively associated with baseline free T index (FTI) and with the increase in FTI since baseline., Conclusion(s): The major hormonal change associated with central adiposity during the menopausal transition is the increase in the FTI. This effect is significant even after allowing for baseline and final weight.

Background: Testicular regulation of inhibin B may be influenced by the germ cell complement., Methods: We examined the effects of gonadotrophin stimulation on serum inhibin B and pro-alphaC in 25 normal men at (i) control (stimulation test 1), (ii) after spermatogenic suppression induced by testosterone plus progestin treatment (stimulation test 2), and (iii) during spermatogenic recovery induced by FSH and/or hCG treatment (stimulation test 3). For each test, subjects received a single injection of 1200 IU FSH or 5000 IU hCG or both., Results: Inhibin B and pro-alphaC fell with spermatogenic suppression (75 and 51% of pre-treatment baseline respectively, P < 0.05). Inhibin B response to FSH (130-144%) was similar in controls and after germ cell suppression. Pro-alphaC response after germ cell suppression compared with control was significantly increased (P < 0.05) with both FSH (210-229% versus 140-185%) and hCG (254-261% versus 145%). All treatments partially restored spermatogenesis with no clear relationship apparent between inhibin B and sperm count., Conclusions: We conclude that: (i) serum inhibin B and pro-alphaC are only partially gonadotrophin dependent, (ii) spermatogenic suppression does not modify inhibin B response to FSH but enhances pro-alphaC response to both FSH and hCG, and (iii) inhibin B is a poor marker of spermatogenesis in this model of gonadotrophic manipulation in normal men.

The concept of a female androgen insufficiency syndrome, although not new, remains somewhat controversial. Androgens are quantitatively the predominant sex steroid in women, circulating in the micromolar and nanomolar concentration range, compared with picomolar levels of oestrogens. The most significant biologically active androgen is testosterone (T), which circulates bound tightly to sex-hormone-binding globulin (SHBG) and loosely to albumin. It is generally held that the non-SHBG-bound fraction is the bioavailable moiety. Hence, clinically useful T measurements require data on total concentrations as well as SHBG level. Testosterone insufficiency occurs in a number of circumstances, including hypopituitarism, premature ovarian failure, adrenal failure, exogenous corticosteroid use and oral oestrogen therapy (causing elevation of SHBG and suppression of gonadotrophins). Clinical symptoms of androgen insufficiency include loss of libido, diminished well-being, fatigue and blunted motivation and have been reported to respond well to T replacement, generally without significant side-effects.

Background: Most studies examining the potential cardioprotective effects of postmenopausal estrogen have been undertaken in healthy women, with doses that may not be appropriate for long-term intervention. New low-dose estrogen-progestin regimens alleviate postmenopausal symptoms with a favorable side-effect profile; however, little is known of the impact of such regimens in women at increased risk of cardiovascular disease. Hence, we have evaluated the effects of low-dose oral estrogen-progestin therapy on serum lipoprotein lipids, brachial artery reactivity and fibrinogen in hypercholesterolemic postmenopausal women in direct comparison with the effects of pravastatin, a lipid-lowering agent known to reduce cardiovascular events in women., Methods: In a randomized, double-blind, double-dummy, parallel trial, we studied the effects of continuous combined estrogen-progestin therapy (1 mg 17beta-estradiol with 500 micro g norethisterone acetate daily) or pravastatin (20 mg daily) in 72 postmenopausal women with fasting serum low-density lipoprotein (LDL) cholesterol levels greater than 124 mg/dl after an 8-week run-in diet, over a 24-week period. The primary end-point was percentage change in LDL cholesterol from baseline., Results: The intention-to-treat population comprised 65 women, mean age 59 +/- 6.3 years, and 29 in each group completed the trial. Diet alone reduced LDL cholesterol significantly in both treatment groups, in association with a reduction in weight during this period. Compared with respective baseline values, pravastatin decreased LDL cholesterol and total cholesterol to a greater extent than hormone therapy (p = 0.0001 and 0.003 for difference between treatments, respectively). High-density lipoprotein (HDL) cholesterol levels decreased with hormone therapy, but did not change with pravastatin (p = 0.01). Lipoprotein(a) decreased significantly with hormone therapy only (-14%, 95% confidence interval (CI) -21 to -6%, p = 0.01 for difference between groups). Brachial artery flow-mediated dilatation (FMD) was impaired at baseline, and this increased with hormone therapy (absolute mean change in artery diameter as percentage units 2.07, 95% CI 0.57-3.57, p = 0.009) versus no change with pravastatin (0.19, 95% CI -1.1 to 1.5, p = 0.78), with a near-significant difference between the two groups (p = 0.058). A significant correlation between improved brachial artery FMD and reduction in LDL cholesterol was not observed. Fibrinogen decreased significantly in both treatment groups with no difference between treatments., Conclusions: In postmenopausal hypercholesterolemic women, pravastatin and hormone therapy exhibited divergent effects. The former lowered total and LDL cholesterol more effectively, whereas hormone therapy lowered lipoprotein(a) significantly and improved brachial artery endothelium-dependent dilatation, independent of the reduction in LDL cholesterol. The modest increase in brachial artery FMD seen is consistent with hypercholesterolemia compromising endothelial integrity, and suggests that the important effect of estrogen on the endothelial microenvironment may be attenuated in women with endothelial dysfunction.

This review explores the pituitary-ovarian hormones involved with ageing and the onset of menopause. The serum patterns of pituitary-ovarian hormones throughout the menstrual cycle alter as menopause approaches. The increase in follicular phase FSH prior to menopause is attributed to an early decline in the ovarian hormone, inhibin B, which negatively regulates follicle-stimulating hormone (FSH) secretion. Serum inhibin B is believed to reflect the age-related decrease in ovarian follicle reserve, which is the primary source of serum inhibin B. The later rise in serum luteinizing hormone (LH) during the menopause transition is due to a cessation of ovarian follicle development. Hormonal patterns during the luteal phase of the menstrual cycle also show changes with age but these changes are poorly understood.

The concept of an androgen deficiency syndrome in women is a relatively old one, although it has gained substantially increased attention in recent years. Androgens are quantitatively the predominant sex steroid in women, circulating in the micro- and nanomolar concentration range, compared with picomolar levels of oestrogen. The most significant biologically active androgen is testosterone, which circulates bound tightly to sex hormone-binding globulin (SHBG) and loosely to albumin. It is generally held that the non-SHBG bound fraction is the bioavailable moiety. Hence interpretable testosterone measurements require data on total concentrations as well as the SHBG level. Testosterone deficiency occurs in a number of situations such as hypopituitarism, primary ovarian and adrenal failure, exogenous corticosteroid use and oral oestrogen therapy (due to the elevation of SHBG and suppression of gonadotrophins). Clinical symptoms of androgen deficiency include lethargy, tiredness and loss of sex drive and interest, and have responded well to androgen replacement, generally without significant side-effects., (Copyright 2002 Elsevier Science Ltd.)

Granulosa cell tumours (GCT) of the ovary arise from granulosa cells of the ovary on morphological, biochemical and molecular criteria. In order to understand the molecular pathogenesis of these tumours better we have sought to define their molecular phenotype, to identify activating mutations of the FSH-signalling pathway, to characterise their estrogen receptor expression and to explore the hypothesis that GCT may be resistant to inhibin. The pattern of gene expression observed in GCT suggests a phenotype which is similar to that of late preovulatory granulosa cells which would be consistent with activation of the FSH receptor signalling pathway, however, there is no evidence for activating mutations of either the FSH receptor or the associated trimeric G-proteins. Estrogen receptor beta is abundantly expressed in GCT. The various subunits and isoforms of the activin-inhibin receptor are expressed in GCT. These observations provide a basis for future studies of GCT, including further characterisation of signalling pathways known to be important in the regulation of granulosa cell growth and differentiation.

It is widely recognised that the early detection and subsequent assessment of recurrence of ovarian cancers are key steps for successful treatment. Available serum markers (e.g. CA125) are sensitive for some epithelial carcinomas (e.g. serous, endometrioid, clear cell), however, these markers are less sensitive for granulosa cell tumours and mucinous carcinomas. Serum inhibin is an ovarian product which decreases to non detectable levels after menopause, however, certain ovarian cancers (mucinous carcinomas and sex cord stromal tumours such as granulosa cell tumours) continue to produce inhibin which provides a basis for a serum diagnostic test. Studies from this and other laboratories have investigated the suitability of inhibin as a diagnostic marker by identifying which inhibin (inhibin A (alphabetaA), inhibin B (alphabetaB), free alpha subunit) or activin (betaAbetaA) form is associated with these cancers. Available data show that inhibin assays which detect all inhibin forms, i.e. assays which detect the alpha subunit both as the free form and as an alphabeta subunit dimer provide the highest sensitivity/specificity characteristics as an ovarian cancer diagnostic test. This review will discuss the data supporting these observations and show recent studies in which a new alpha subunit monoclonal antibody-based ELISA is used as a potential diagnostic test. Furthermore, based on the high sensitivity/specificity characteristics of the respective assays for the various types of ovarian cancer, the combination of the inhibin assay with CA125 detects the majority of all ovarian cancers.

Development, growth and function of the ovary are controlled by endocrine and paracrine signals. These may also influence the development of ovarian cancer. The aim of this study was to identify the key molecular markers of the unregulated growth and hormone synthesis seen in ovarian tumours, particularly in granulosa cell tumours (GCT). Genes used in this study were chosen on the basis of our understanding of growth and differentiation in the normal ovary. We sought to define the patterns of gene expression in a panel of epithelial and stromal ovarian tumours. Expression was determined by RT-PCR using gene-specific primers for the FSH receptor (FSHR); the FSH early response genes: regulatory subunit of protein kinase A (RII-beta), cyclin D2 (cycD2) and sgk; and late response markers: cyclooxygenase-2 (COX-2) and the LH receptor (LHR). The GCT had high expression of FSHR compared with normal ovaries and the other tumours. cycD2 and RII-beta and COX-2 genes were also highly expressed in the GCT. sgk and LHR expression was lower in all of the tumours than in normal ovaries. Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. Comparison of the gene expression profiles between each tumour group suggests a molecular phenotype for GCT that is similar to that reported for FSH stimulated pre-ovulatory granulosa cells.

Objective: To describe the sources, production rates, circulating concentrations, and regulatory mechanisms of the major androgen precursors and androgens in women., Design: Review of the major published literature., Result(s): Quantitatively, women secrete greater amounts of androgen than of estrogen. The major circulating steroids generally classified as androgens include dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone in descending order of serum concentration, though only the latter two bind the androgen receptor. The other three steroids are better considered as pro-androgens. Dehydroepiandrosterone is primarily an adrenal product, regulated by adrenocorticotropic hormone (ACTH) and acting as a precursor for the peripheral synthesis of more potent androgens. Dehydroepiandrosterone is produced by both the ovary and adrenal, as well as being derived from circulating DHEAS. Androstenedione and testosterone are products of the ovary and the adrenal. Testosterone circulates both in its free form, and bound to protein including albumin and sex steroid hormone-binding globulin (SHBG), the levels of which are an important determinant of free testosterone concentration., Conclusion(s): The postmenopausal ovary is an androgen-secreting organ and the levels of testosterone are not directly influenced by the menopausal transition or the occurrence of menopause. Dihydrotestosterone (DHT) is primarily a peripheral product of testosterone metabolism. Severe androgen deficiency occurs in hypopituitarism, but other causes may lead to androgen deficiency, including Addison's disease, corticosteroid therapy, chronic illness, estrogen replacement (leads to elevated SHBG and, therefore, low free testosterone), premenopausal ovarian failure, or oophorectomy.

Granulosa cell tumors of the ovary (GCT) express the inhibin subunit genes and secrete dimeric inhibin. Transgenic mice null for the alpha-inhibin gene develop GCT. It has been suggested that this apparent contradiction may be reconciled if the human GCT are resistant to the tumor-suppressive effects of inhibin. Inhibin receptors have recently been characterized as consisting of either betaglycan or p120 in association with the type II or type I activin receptor subunits (ActR), respectively. To test the hypothesis that GCT may exhibit loss of inhibin receptor expression we have examined the expression of the receptor subunits in a cohort of GCT and in mucinous and serous cystadenocarcinomas and normal ovary. Expression was determined by RT-PCR using gene-specific primers and probes combined with Southern blot analysis of the PCR products. The ActRI subunits and ActRIIA exhibited widespread albeit variable expression across tissues, with the highest levels in the serous tumors. ActRIIB expression was relatively low in the mucinous tumors and high in the GCT. Betaglycan expression was abundant, widespread, and variable across all tissues; highest mean levels occurred in the GCT and normal ovary. p120 expression was low or absent in all tissues except the GCT. Within the GCT there was parallel expression of the ActR subunits, betaglycan and p120; the levels, however, varied considerably between tumors. Expression of betaglycan and p120 in most GCT argues against the hypothesis, but does not exclude the possibility that low or absent expression of p120 might be significant in a subset of these tumors.

The aim of this study was to characterize the molecular wt forms of inhibins A and B and its free alpha-subunit present in serum from women with ovarian cancer as a basis for developing improved monoclonal antibody-based inhibin assays for monitoring ovarian cancer. Three new inhibin alpha-subunit (alphaC) ELISAs were developed using monoclonal antibodies directed to three nonoverlapping peptide regions of the alphaC region of the inhibin alpha-subunit. To characterize serum inhibin molecular wt forms present in women with ovarian cancer, existing inhibin immunoassays (inhibin A, inhibin B, and pro-alphaC) and the new alphaC ELISAs were applied to sera from women with granulosa cell tumors and mucinous carcinomas previously fractionated using a combined immunoaffinity chromatography, preparative SDS-PAGE, and electroelution procedure. The distribution and molecular size of dimeric inhibins and alpha-subunit detected were consistent with known mol wt forms of inhibins A and B and inhibin alpha-subunit and their precursor forms present in serum and follicular fluid from healthy women. The alphaC ELISAs recognized all known forms of inhibin and the free inhibin alpha-subunit, although differences between alphaC ELISAs were observed in their ability to detect high mol wt forms. To assess which of the alphaC ELISAs was preferred in application to ovarian cancer, the alphaC ELISAs were applied to serum from a range of normal postmenopausal women (n = 61) and postmenopausal women (n = 152) with ovarian (serous, mucinous, endometrioid, clear cell carcinomas, and granulosa cell tumors) and nonovarian (breast and colon) cancers. Despite differences in their ability to detect high mol wt forms of inhibin, the alphaC ELISAs showed similar sensitivity (i.e. proportion of cancer patients correctly detected) and specificity (proportion of controls correctly detected) indexes in the detection of mucinous carcinomas (84% and 95%) and granulosa cell tumors (100% and 95%) compared with earlier inhibin RIA or polyclonal antibody-based immunofluorometric assays. A combination of the alphaC ELISAs with the CA125 assay, an ovarian tumor marker that has a high sensitivity and specificity for other ovarian cancers (serous, clear cell, and endometrioid), resulted in an increase in sensitivity/specificity indexes (95% and 95%) for the all ovarian cancer group. These new monoclonal antibody-based inhibin alphaC ELISAs now provide practical and sensitive assays suitable for evaluation as diagnostic tests for monitoring ovarian cancers.

With the availability of laparoscopic ovarian cautery, there has been a resurgence in interest in the surgical treatment of clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Comparison of ovulation and pregnancy rates has found no difference in success rates between ovarian cautery and gonadotropin ovulation induction for such women. We have therefore compared the cost of laparoscopic ovarian cautery with that of a typical cycle of gonadotropin ovulation induction, and also found that there is little difference. Because of the potential advantages of ovarian cautery, we recommend this surgery as the next line of treatment if clomiphene citrate fails to induce ovulation in PCOS patients, before gonadotropins are introduced.

The menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is heralded by the menopausal transition, a period when the endocrine, biological, and clinical features of approaching menopause begin. A common initial marker is the onset of menstrual irregularity. The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the ovary, the most striking of which is a profound decline in follicle numbers. Follicle-stimulating hormone (FSH) is an established indirect marker of follicular activity. In studies of groups of women, its concentration, particularly in the early follicular phase of the menstrual cycle, begins to increase some years before there are any clinical indications of approaching menopause. The rise in FSH is the result of declining levels of inhibin B (INH-B), a dimeric protein that reflects the fall in ovarian follicle numbers, with or without any change in the ability of the lining granulosa cells to secrete INH-B. Estradiol levels remain relatively unchanged or tend to rise with age until the onset of the transition and are usually well preserved until the late perimenopause, presumably in response to the elevated FSH levels. During the transition, hormone levels frequently vary markedly - hence, measures of FSH and estradiol are unreliable guides to menopausal status. Concentrations of testosterone have been reported to fall by about 50% during reproductive life, between the ages of 20 and 40. They change little during the transition and, after menopause, may even rise. Dehydroepiandrosterone (DHEA) and DHEAS, its sulphate, on the other hand, decline with age, without any specific influence of the menopause. Symptoms of the menopause can be interpreted as resulting primarily from the profound fall in estradiol, occurring over a 3- to 4-year period around final menses, a fall that presumably contributes importantly to the beginning, in the late perimenopause, of loss of bone mineral density.

We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty; inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the Galpha(s) gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER beta genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells; the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.