Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials

We conducted meta-analyses to assess the impact of menopausal hormone therapy (MHT) on the risk of incident invasive breast cancer (BC) in cohort studies (CS), case-control studies (CCS) and randomized controlled trials (RCTs) published 1989-2004. We used published data providing information upon unopposed estrogen therapy (ET), estrogen-progestin therapy (EPT) or all MHT combined. Major outcomes were MHT-associated overall risk of BC and change of risk per year used. There is a linear increase of overall risk by midterm year of case ascertainment based upon data of all study types for MHT and to a larger extent for EPT, not for ET. Effects are larger in CS than in CCS. Meta-analyses stratified by <1992 versus > or =1992 as midterm year of case ascertainment indicate larger summary risks for the latter period for all MHT analysed, in particular for EPT. Annual increases in BC risk for EPT across study types are 0-9%, for ET 0-3%. In conclusion, there is evidence that relative risks for BC risks by MHT, in particular EPT, have been increasing in recent years. Given the widespread use of MHT, and often long duration, more detailed knowledge about differential BC risks of both estrogens and progestins are necessary to minimize BC risk in symptomatic women who consider MHT.     

Hormone replacement therapy and the prevention of cardiovascular disease

Cardiovascular disease (CVD) is the primary killer of both men and women in Western societies. The implementation of preventive strategies has led to a fall in the rate of CVD, but there is still much to be achieved. Proven interventional strategies are largely under-utilized, and the search continues for further promising interventions. HRT appears to reduce CVD in post-menopausal women, based on observational data supported by plethora of evidence for the beneficial cardiovascular effects of estrogen. However, a recent controlled trial in post-menopausal women with established CVD has shown that a specific combined oral HRT regimen did not reduce, and may even contribute to, an early increase in cardiovascular events, suggesting that HRT is inappropriate in secondary prevention. HRT may be useful in the primary prevention of CVD, yet observational data that suggested cardiovascular benefit with HRT also suggests that 80% of CVD in women could be eliminated by lifestyle modification, without the attendant risks of HRT including thrombosis and (potentially) breast cancer. At present, it is arguable that the evidence is inadequate to recommend HRT solely for the purpose of CVD prevention, and that the challenge for the health professional should be appropriate utilization of established preventative therapies, with further research into the potential role of HRT and estrogen-receptor modulators.     

Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis

Knowledge about the impact of menopausal hormone therapy (MHT) on the risk of ovarian cancer (OvC) is insufficient, and studies are inconsistent. Mortality from OvC ranks highest among cancer sites in female reproductive organs. We performed meta-analyses to assess the impact of specified types of MHT on the risk of OvC in cohort studies (CS), case-control studies (CCS), randomized controlled trials (RCT) and cancer registry studies (CRS). We used data published 1966-2006 on estrogen therapy (ET), estrogen/progestin therapy (EPT) or MHT (unspecified regimen) identified by a structured, computerized and manual literature search. We identified 42 studies (30CCS, 7CS, 1 RCT and 4 CRS) with 12 238 cases. The risk of OvC (ever-use, annual risk) is increased 1.28-fold by ET [confidence interval (CI) 1.18-1.40] and 1.11-fold by EPT (CI 1.02-1.21) with a suggestion of greater risks with ET. There appears to be no differential impact of any therapy on histological subtypes. Risks were greater in European than North American studies for both ET and EPT. In conclusion, ET as well as EPT, are risk factors for OvC. Given the widespread use of MHT, known benefits should be weighed against the increased risk of OvC, and more studies are warranted, particularly on factors with the greatest apparent risks.     

Prevention of postmenopausal osteoporosis with oestrogen replacement therapy and associated compounds: update on clinical trials since 1995

Hormonal replacement therapy (HRT) is generally regarded as first choice for pharmacological prevention of osteoporosis in women. We reviewed recent studies of HRT regimens and selective oestrogen receptor modulators (SERMs), including controlled trials of at least one-year duration published since 1995 until February 2000 providing data on bone mineral density (BMD) or fractures. Natural and synthetic oestrogens exert a continuum of positive effects on BMD in a dose-dependent, though non-proportional, fashion independent of age and mode of administration. Bone loss may be largely prevented by 25 microg transdermal patch oestradiol, 0.3 mg conjugated equine or 0.3 mg esterified oestrogens. Progestogens neither attenuate nor augment the effect of oestrogens; sole use of tibolone prevents bone loss. Both the SERMs, tamoxifen and raloxifene, slightly increase BMD. There are no adequately powered fracture trials for any HRT regimen. Raloxifene 60 mg daily decreases the relative risk of vertebral fractures by at least 30%, as demonstrated by one 3-year fracture study of osteoporotic women. In conclusion, the recommendation to use oestrogen for postmenopausal osteoporosis, given both the lack of fracture trials and the rare trials on long-term use of HRT in (late) postmenopausal women, is not well supported. Fracture trials could overcome shortcomings of the current level of evidence.     

Cytohormonal and morphological alterations in cervicovaginal smears of postmenopausal women on hormone replacement therapy

The objective of the study was to study the cytohormonal and morphological alterations in cervicovaginal smears associated with the use of hormone replacement therapy (HRT) and to assess the utility of vaginal cytology in determining the response to HRT. Ninety postmenopausal women (30 on estrogen-progesterone combination (HRT) for 1 to 24 mo (user 1), 30 on estrogen therapy (ERT) for 1 to 44 mo (user 2), and 30 not on any hormones (nonusers)) were included in the cross-sectional study. Their lateral vaginal wall smears and cervical smears were examined for hormonal and morphological assessments, respectively. The smear pattern showed predominance of parabasal cells in 46.6% of nonusers, while none of the users had >70% parabasal cells. A high percentage (>70%) of intermediate cells was found in 46.6% of users and only in 16.6% of nonusers. A high maturation value (MV) was found in more than 75% of users but in only 16.6% of nonusers. The women with high MV (>50) were significantly less symptomatic than did nonusers. Atrophic changes were present in cervical smears of 14/20 (46.6%) nonusers when compared with 1/60 (1.66%) users. Atypical squamous cells of undetermined significance (ASC-US) were diagnosed in seven users and three nonusers. It persisted on follow-up in four users and one nonuser. Histology revealed one mild dysplasia among users. Lactobacilli were more frequently observed in users. The cytohormonal pattern on vaginal smears correlates well with the response to hormonal therapy and clinical symptoms. Awareness of the morphological alterations associated with the use of replacement hormones would enable the cytologists to reduce the false-positive diagnoses while evaluating postmenopausal smears.     

New findings from non-linear longitudinal modelling of menopausal hormone changes

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.     

Attitudes towards and level of information on perimenopausal and postmenopausal hormone replacement therapy among Norwegian women

In order to investigate women's attitudes towards and level of information on perimenopausal and postmenopausal hormone replacement therapy (HRT) 1019 women over 17 years of age constituting a representative sample of the Norwegian female population were interviewed in 1990 as part of a monthly national opinion poll (response rate 96.5%). Women's magazines proved to be the most important source of information on hormone therapy. Only in the over-45 age group were doctors mentioned frequently as information sources. A high self-assessed information level was associated with a positive attitude towards hormone therapy. Those who had obtained information from a doctor were more positive than those who had not. More than half of those who expressed an opinion believed that hormone therapy increased the risk of heart infarction, stroke, breast cancer and cancer in general. There was a strong association between a negative attitude, towards using hormones and belief in an increased risk of serious disease. The women were more positive towards the use of HRT for the prevention of osteoporosis and for postmenopausal urogenital complaints than for the alleviation of climacteric symptoms.     

Oral contraceptives, menopause hormone replacement therapy, and risk of stroke

Objectives: To review available evidence from observational and intervention studies on oral contraceptives (OC), menopause hormone replacement therapy (HRT) and stroke. Methods: Qualitative literature review. Results: High dose OC were associated to elevated risk of stroke. However, the use of low oestrogen OC preparations by non-hypertensive women not at high baseline risk is not related to an appreciable risk of stroke. With reference to HRT, randomised clinical trials showed an excess risk of stroke among users of combined therapy. Conclusions: In non-hypertensive women below age 35 stroke is not materially related to the use of low dose OC. HRT is associated to a moderate excess risk in randomised studies, and should therefore not be used for the prevention of stroke.     

Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing

The improved long-term survival of adolescents and young women treated for cancer has resulted in an increased focus on the effects of chemotherapy on ovarian function and its preservation. These women may seek advice and treatment regarding their reproductive status, including ways of preserving their fertility and preventing a premature menopause--factors that can have a profound impact on their quality of life. This article comprehensively reviews ovarian reserve testing (ORT) in general. Special emphasis is placed on patients with cancer, including the pathophysiology of gonadal damage following chemotherapy, fertility preservation and the potential role of ORT. Baseline parameters of ovarian reserve [FSH LH, estradiol, inhibin B and anti-Mullerian hormone (AMH)] have not yet performed sufficiently well in predicting poor outcome in assisted reproduction, but biochemical markers of ovarian reserve appear to be better than chronological age. Inhibin B and AMH show potential for future use. Dynamic testing appears to show much promise, especially stimulated levels of inhibin B and estradiol. The most promising tests of ovarian reserve are the biophysical markers, where total antral follicle count was found to be most discriminatory followed by ovarian volume. Combination of biochemical, biophysical and clinical markers of ovarian reserve may also improve predictive capacity. However, there is a lack of data pertinent to ORT in cancer. As yet there is no single clinically useful test to predict ovarian reserve accurately. Patients with cancer represent a distinct cohort who have particular concerns about their future fertility and the possibility of a premature menopause, they can benefit greatly from knowledge of their functional ovarian reserve. Large, prospective, randomized, adequately controlled studies specific to different geographical areas are required in a control population of comparable reproductive age to determine the potential role of ORT in clinical practice.     

Effects of alendronate and hormone replacement therapy, alone or in combination, on bone mass in postmenopausal women with osteoporosis: a prospective, randomized study

The effectiveness of hormone replacement therapy (HRT) and alendronate, alone and in combination, was evaluated in 120 postmenopausal patients with osteoporosis with bone mineral density (BMD) measurements at least 2 SD below the mean value for young premenopausal subjects. They had no contra-indications to HRT or alendronate use and were randomized to three different treatment groups. Group I was treated with micronized 17 beta-oestradiol 2 mg and norethisterone acetate 1 mg/day per os, group II received alendronate 10 mg/day per os and group III received micronized 17 beta-oestradiol 2 mg, norethisterone acetate 1 mg/day per os and alendronate 10 mg/day per os for 1 year. Elementary calcium 1500 mg/day was supplied to patients in all three groups. Spinal and femoral neck BMD and markers of bone mineral metabolism were measured on each patient before treatment and 6 and 12 months after treatment in 95 patients. At the end of the 12th month, significant increases in spinal and femoral neck BMD were found in all groups. Increases in spinal BMD were significantly higher in patients treated with alendronate and alendronate with HRT when compared with patients treated with HRT only. No significant difference was found in femoral neck BMD changes between the groups. Significant decreases in bone resorption and markers of bone formation were observed in all groups. Alendronate was found to be more effective than HRT and could have a very beneficial effect when added to the HRT regimen in patients with postmenopausal osteoporosis. Alendronate might also be used in postmenopausal patients with osteoporosis when HRT is contra-indicated or when there is reluctance to use hormonal treatment.     

Heterogeneity of follicle stimulating hormone: control and physiological function

The existence of a heterogeneous population of follicle stimulatinghormone (FSH) was described many years ago. Other pituitaryglycoproteins, such as thyroid stimulating hormone (TSH) andluteinizing hormone (LH) as well as placental human chorionicgonadotrophin (HCG) also exhibit heterogeneity. Because FSHplays a significant role in a variety of ovarian activitiessuch as follicular maturation, selection of the dominant follicleand ovulation, the possible role of sub-populations of FSH withdistinct physicochemical characteristics is of great interest.After a great deal of investigation, the physiological significanceof this biochemical phenomenon has yet to be fully understood.Investigators have employed immunoassays, in-vitro bioassaysand radioreceptor assays to study the biological activity ofthe individual isoforms ofFSH. As more informations has accumulated,it has become clear that some ofthe initial assumptions usedto interpret data may be incorrect. This review is Providedto Update the reader with availableinformation on the topicas it relates to FSH and to pointout issues that require re-evaluationin this area.     

Human choriogonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights

BACKGROUND: Human chorionic gonadotrophin (hCG) is measured in serum andurine for the early detection of ectopic pregnancy, patientswith higher risk of miscarriage, embryos or fetuses with chromosomeabnormalities, prediction of pre-eclampsia or fetal growth restrictionand identification or follow-up of trophoblast neoplasia. Thisreview examines basic knowledge on the heterogeneity of hCGprotein core and sugar branches and its relevance to assaysused in a clinical setting. METHODS: The databases Scielo and Medline/Pubmed were consulted for identificationof the most relevant published papers. Search terms were gonadotrophin,glycoprotein structure, hCG structure and molecular forms ofhCG. RESULTS: The synthesis of alpha (hCG) and beta (hCGβ) peptide chainsand their further glycosylation involve the complex action ofdifferent enzymes. After assembly, hCG reaches the cell surfaceand is secreted as a bioactive heterodimer. The complex cascadeof enzymes acting in hCG secretion results in heterogeneousmolecular forms. The hCG molecules are differently metabolizedby the liver, ovary and kidney, but the majority of hCG formsare excreted in the urine. Intact hCG, hCG, hCGβ, hyperglycosylated(hCGh), nicked (hCGn) and core fragment of hCGβ (hCGβcf)forms have relevant clinical use. The immunogenicity of eachhCG variant, their epitopes distribution and the available antibodiesare important for the development of specific assays. Dependingon the prevalent form or proportion in relation to the intacthCG, the choice of assay for measurement of a specific moleculein a particular clinical setting is paramount. CONCLUSIONS: Measurement of hCG and/or its related molecules is useful inclinical practice, but greater awareness is needed worldwideregarding the use of new sensitive and specific assays tailoredfor different clinical applications.     

The Anti-Mullerian hormone and ovarian cancer

The Anti-Mullerian hormone (AMH), which is produced by fetal Sertoli cells, is responsible for regression of Mullerian ducts, the anlagen for uterus and Fallopian tubes, during male sex differentiation. Ovarian granulosa cells also secrete AMH from late in fetal life. The patterns of expression of AMH and its type II receptor in the post-natal ovary indicate that AMH may play an important role in ovarian folliculogenesis. Recent advances in the physiological role of AMH has stimulated interest in the significance of AMH as a diagnostic marker and therapeutic agent for ovarian cancer. Currently, AMH has been shown to be a circulating marker specifically for granulosa cell tumour (GCT). Its diagnostic performance seems to be very good, with a sensitivity ranging between 76 and 93%. In patients treated for GCT, AMH may be used post-operatively as marker for the efficacy of surgery and for disease recurrence. Based on the physiological inhibitory role of AMH in the Mullerian ducts, it has been proposed that AMH may inhibit epithelial ovarian cancer cell both in vitro and in vivo. These observations will be the basis for future research aiming to investigate the possible clinical role of AMH as neo-adjuvant, or most probably adjuvant, therapy for ovarian cancer.     

Turner's syndrome and fertility: current status and possible putative prospects.

Women with Turner's syndrome should be carefully followed throughout life. Growth hormone therapy should be started at age 2-5 years. Hormone replacement therapy for the development of normal female sexual characteristics should be started at age 12-15 years and continued for the long term to prevent coronary artery disease and osteoporosis. Most women with Turner's syndrome have ovarian dysgenesis; therefore, they are usually infertile, and in very rare cases have spontaneous menses followed by early menopause. Only 2% of the women have natural pregnancies, with high rates of miscarriages, stillbirths and malformed babies. Their pregnancy rate in oocyte donation programmes is 24-47%, but even these pregnancies have a high rate of miscarriage, probably due to uterine factors. A possible future prospect is cryopreservation of ovarian tissue containing immature follicles before the onset of early menopause, but methods of replantation and in-vitro maturation still need to be developed. Should these autologous oocytes indeed be used in the future, affected women would need to undergo genetic counselling before conception, followed by prenatal assessment.     

Sex steroids and bone: current perspectives

Although the process of bone remodelling or its control has not yet been fully elucidated there is, at present, sufficient information available to conclude that ovarian steroids (estrogens, androgens, progesterone) play an essential role in skeletal homeostasis. The mechanism of action of sex steroids on the skeleton is still not entirely clear, but it has traditionally included indirect effects on systemic hormones that regulate calcium balance and a direct receptor-mediated action. More recently, changes in cytokine production within the bone marrow, as well as pro-apoptotic and anti-apoptotic effects in the osteoblastic cells, have been proposed as new perspectives on the cellular and molecular mechanisms by which sex steroids influence adult bone homeostasis. Mechanical loading, when combined with estrogens or androgens, results in a greater osteogenic response than either condition separately. Women are especially at risk for osteoporosis if they have had a premature or surgical menopause and have not received hormone replacement therapy (HRT). Other reproductive factors that can help to identify women with osteopenia and emphasize the role of sex steroids in preserving bone mass in premenopausal women include: age at menarche, menstrual history and irregularities (including those associated with excessive exercise), age at menopause, previous hysterectomy, hyperprolactinaemia, anorexia nervosa, scoliosis, ovarian dysgenesis, pregnancy and lactation, and pharmacological ovarian suppression. The prevention of osteoporosis starts with the onset of the menarche. A combination of exercise, appropriate nutrition and a healthy lifestyle all maximize bone mineral accrual and result in optimal peak bone mass; normal ovarian function is essential to this process. Unfortunately, many women actually become aware of the need for osteoporosis prevention much later in life, usually after they have already become menopausal. HRT, however, has important limitations for prevention of fractures in post-menopausal women. Future perspectives for treatment of osteoporosis include androgen therapy and anabolic agents. Specifically, synthetic ligands of the estrogen receptor that can evoke the non-genotrophic but not the genotrophic signal of the receptor may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are anti-resorptive agents. The same ligands may circumvent the side effects associated with conventional HRT.     

Testosterone replacement therapy: current trends and future directions

Male hypogonadism is characterized by abnormally low serum testosterone levels associated with typical symptoms, including mood disturbance, sexual dysfunction, decreased muscle mass and strength, and decreased bone mineral density. By restoring serum testosterone levels to the normal range using testosterone replacement therapy, many of these symptoms can be relieved. For many years, injectable testosterone esters or surgically implanted testosterone pellets have been the preferred treatment for male hypogonadism. Recently, newer treatment modalities have been introduced, including transdermal patches and gels. The development of a mucoadhesive sustained-release buccal tablet is the latest innovation, which will provide patients with an additional option. The availability of new treatment modalities has helped to renew interest in the management of male hypogonadism, highlighting the need to address a number of important but previously neglected questions in testosterone replacement therapy. These include the risks and benefits of treatment in different patient populations (e.g. the elderly) and the need for evidence-based diagnosis and treatment monitoring guidelines. While some recommendations have been developed in individual countries, up-to-date, internationally accepted evidence-based guidelines that take into account national differences in clinical practice and healthcare delivery would optimize patient care universally.     

The effect of hormone replacement therapy on the immunoreactive concentrations in the endometrium of oestrogen and progesterone receptor, heat shock protein 27, and human beta-lactoglobulin

We determined the expression of oestrogen receptor (ER), progesterone receptor (PR), heat shock protein 27 (HSP27) and human beta-lactoglobulin in the endometrium under hormone replacement therapy (HRT). The immunohistochemical expression during the late progestogenic phase of sequential HRT was compared semi-quantitatively and using image analysis, to the early, mid-, and late luteal phase of the physiological cycle. Under sequential HRT, smaller glands were positive for the ER but larger glands with more advanced secretory features were negative. ER expression was lower in the stroma under HRT, and the difference was statistically significant compared with the early luteal phase (P < 0.05). Expression of HSP27 under HRT was lower in the epithelium but higher in the stroma compared with the physiological luteal phase. Epithelial PR expression was lower under HRT compared with the early, but not the mid- or the late luteal phase. The number of PR-positive stromal cells under HRT was lower compared with the physiological cycle, and the difference was statistically significant in comparison with the early luteal phase (P < 0.05). The glandular area expressing human beta-lactoglobulin during the late progestogenic phase was statistically significantly higher compared with the early, but lower in comparison with the mid- or the late luteal phase (P < 0.05). The study demonstrates a sub-physiological progestogenic response superimposed on evidence of a hypo-oestrogenism, and a differential response in the epithelium and stroma.     

Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications

The relationship between chronic pelvic pain symptoms and endometriosis is unclear because painful symptoms are frequent in women without this pathology, and because asymptomatic forms of endometriosis exist. Our comprehensive review attempts to clarify the links between the characteristics of lesions and the semiology of chronic pelvic pain symptoms. Based on randomized trials against placebo, endometriosis appears to be responsible for chronic pelvic pain symptoms in more than half of confirmed cases. A causal association between severe dysmenorrhoea and endometriosis is very probable. This association is independent of the macroscopic type of the lesions or their anatomical locations and may be related to recurrent cyclic micro-bleeding in the implants. Endometriosis-related adhesions may also cause severe dysmenorrhoea. There are histological and physiopathological arguments for the responsibility of deeply infiltrating endometriosis (DIE) in severe chronic pelvic pain symptoms. DIE-related pain may be in relation with compression or infiltration of nerves in the sub-peritoneal pelvic space by the implants. The painful symptoms caused by DIE present particular characteristics, being specific to involvement of precise anatomical locations (severe deep dyspareunia, painful defecation) or organs (functional urinary tract signs, bowel signs). They can thus be described as location indicating pain. A precise semiological analysis of the chronic pelvic pain symptoms characteristics is useful for the diagnosis and therapeutic management of endometriosis in a context of pain.     

Screening before and during the use of oral contraceptives and hormone replacement therapy. The ESHRE Capri Workshop Group

Most users of oral contraceptives (OC), and many users of hormone replacement therapy (HRT) are apparently healthy, using a preparation for preventative purposes. It is understandable, therefore, that many clinicians feel that they should screen women using these preparations for hidden disease. Sometimes this has resulted in women being subjected to a variety of procedures. This medicalization of the provision of care can inhibit women from availing themselves of these services. All screening programmes must have evidence that: early detection will affect the natural history of the disease; the performance characteristics of the test must be known; the test should be cost-effective, acceptable to users and providers, should influence clinical decisions, and treatment should exist for abnormal results. The tests time to time suggested before and during the use of OC and HRT do not fulfill these needs. Whether any of the contraindications for OC use are present can be determined simply by taking a history and performing a physical examination including measurement of blood pressure. The same policy applies to the women who will start HRT. If facilities are available for screening mammography this test should be performed prior to starting HRT as the oestrogen can promote the growth of an existing subclinical breast cancer. It is not cost effective to perform an endometrial biopsy in women without abnormal genital bleeding prior to starting HRT. Routine measurement of bone density is also not cost effective or necessary since no current available agent reduces the risk of fractures in women with osteoporosis more than HRT.     

Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy

A great deal of new information has arisen in the recent years concerning inhibin physiology and clinical relevance in reproductive medicine. It is now recognized that the two inhibin isoforms, named inhibin A and inhibin B, are produced by the gonads in the course of gamete maturation and in women have a different pattern of secretion throughout the menstrual cycle. Since inhibins are also produced by placenta and fetal membranes, it has been suggested that there is an involvement in physiological adaptation of pregnancy. Evidence from several sources has underlined the clinical usefulness of the measurement of inhibin-related proteins in the diagnosis and follow-up of different fertility disturbances and early pregnancy viability. In the male, inhibin B is produced in the testis, principally by the Sertoli cells. Inhibin B expression and secretion are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH. This review covers the most recent advances on the role of inhibins in human reproductive function. Considerable progress in the understanding of inhibin physiology has resulted from selective measurement of the two inhibin molecular forms, named inhibin A and B. Newly recognized alterations of inhibin levels in gynaecological diseases as well as in normal and pathological pregnancy are discussed, with particular emphasis on the potential clinical usefulness of assessing inhibin levels in serum and other biological fluids.