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Background Women with functional hypothalamic amenorrhea (FHA) reveal polycystic ovarian morphology (PCOM) in up to 50%. If stress sensitivity in women with polycystic ovary syndrome (PCOS) is the reason why PCOS women are prone to develop FHA, patients with FHA caused by stress should reveal PCOM more often. Methods In a retrospective cohort study, 38 stress-associated and 38 excessive exercise-induced FHA women were included. The main outcome parameter was PCOM. In addition, the focus was on general patient characteristics as well as on prolactin, dehydroepiandrosterone-sulphate (DHEAS), and anti-Mullerian hormone (AMH). Results PCOM was found in 34/76 patients (44.7%). The stress group showed a higher prevalence of PCOM than the excessive exercise group (57.9% versus 31.6%, p = 0.019) as well as higher prolactin levels (median 13.2ng/mL versus 11.7ng/mL, p = 0.008) and a trend towards higher DHEAS levels (p = 0.058). Conclusions In FHA women, the PCOM prevalence was significantly higher in the stress-group than in the excessive exercise-group. The well-known stress sensitivity in women with PCOS might explain why PCOS women are prone to develop FHA as well as the high PCOM prevalence in FHA women.

Background To evaluate in women with functional hypothalamic amenorrhea (FHA), whether there is a difference between patients with and without polycystic ovarian morphology (PCOM) concerning the response to a gonadotropin releasing hormone (GnRH) stimulation test and to pulsatile GnRH treatment. Methods In a retrospective observational study, 64 women with FHA who underwent a GnRH stimulation test and 32 age-matched controls without PCOM were included. Pulsatile GnRH treatment was provided to 31 FHA patients and three-month follow-up data were available for 19 of these. Results Serum levels of gonadotropins and estradiol were lower in FHA women than in controls (p p p p = 0.002). Conclusions In women with FHA without PCOM, the phenomenon of low AMH levels seems to be based on relative gonadotropin deficiency rather than diminished ovarian reserve. AMH tended to rise after three months of pulsatile GnRH treatment. The differences found between patients with and without PCOM suggest the former the existence of some PCOS-specific systemic and/or intra-ovarian abnormalities.

Purpose The primary objective of the present study of women participating in an ICSI program was to determine whether the morphologic quality of oocytes was related to the polycystic ovary syndrome (PCOS) phenotype. Methods We performed a retrospective cohort study in the IVF unit at the Lille University Medical Center (Lille, France) between 2006 and 2015. Oocyte morphology (fragmented first polar body, abnormal zona pellucida, large perivitelline space, material in perivitelline space, abnormal shape of oocyte, granular cytoplasm and intracytoplasmic vacuoles) was evaluated in PCOS women and according to different subgroup (depending on the presence or absence of the cardinal features polycystic ovarian morphology (PCOM), hyperandrogenism (HA), and oligo-anovulation (OA)). Results A total of 1496 metaphase II oocytes (n = 602 for phenotype A combining PCOM + HA + OA, n = 462 oocytes for phenotype C: PCOM + HA, and n = 432 for phenotype D: PCOM + OA) were assessed. The phenotypes A, C and D did not differ significantly with regard to the proportion of normal oocytes (adjusted percentages (95%CI): 35.2% (31.5 to 39.1%), 25.8% (21.9 to 29.9%) and 34.0% (29.7 to 38.6%), respectively: adjusted p = 0.13). Likewise, there were no significant intergroup differences in oocyte morphology. The ICSI outcome was not significantly associated with the PCOS phenotype. Conclusion The present study is the first to show that the PCOS phenotype (notably the presence vs. absence of OA and/or HA) is not significantly associated with the morphological quality of oocytes.

International audience

Research question Which clinical features, along with biological features, ultrasound features, or both, are the most strongly associated with either high or low anti-Mullerian hormone (AMH) levels in patients with polycystic ovary syndrome (PCOS)? Design A retrospective cross-sectional study conducted within a university-affiliated reproductive endocrinology unit in Lille, France. A total of 639 patients with PCOS according to the Rotterdam Criteria and 137 control women were included. A comparison of clinical, hormonal, metabolic and ultrasound data in patients with PCOS and controls belonging to the first (Q1) and fourth (Q4) quartiles of their respective AMH ranges (discriminant analysis) was conducted. Results In the PCOS group, patients in Q4 had higher LH levels and a more severe phenotype, but they were thinner and had lower levels of hyperinsulinaemia than patients in Q1. In the PCOS group, discriminant analysis yielded a highly significant model in which follicle number per ovary (FNPO) and serum LH were strongly and equally discriminating between Q4 and Q1 (R2 at 0.371 and 0.304, respectively, both P Conclusion High serum AMH levels are associated with high serum LH levels and more severe features of PCOS. Conversely, the effect of hyperinsulinism may be greater in patients with lower serum AMH levels, suggesting independent effects of AMH and insulin on the phenotypic expression of PCOS.

Besides its interest for diagnosis, the finding of an elevated serum AMH level in PCOS has open major pathophysiological issues. This review addresses the three most important issues: 1- the role of AMH in the disturbed folliculogenesis of PCOS; 2- the role of AMH in the gonadotropin dysregulation of PCOS and 3- the role of AMH in the trans-generational transmission of PCOS. For each of those issues, the clinical and experimental evidences currently available are discussed and pathophysiological hypothesis are proposed.

STUDY QUESTION Are serum levels of anti-Müllerian hormone (AMH) normal in patients with functional hypothalamic anovulation (FHA)? SUMMARY ANSWER Our study confirms that in the general FHA population, serum AMH levels are not decreased, but if patients with polycystic ovarian morphology (PCOM) are excluded, levels become significantly lower, as in other situations of gonadotropic insufficiency. WHAT IS KNOWN ALREADY In most situations of low LH (physiological, pharmacological or pathological), serum AMH levels are low. However, paradoxically, many publications have reported normal or even increased serum AMH levels in FHA patients. STUDY DESIGN, SIZE, DURATION Retrospective observational study conducted in an academic centre. The data concerning the study population was collected between 2006 and 2015 from a database including clinical, biological and ultrasound information. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 45 FHA patients were compared to 37 controls matched based on age and body mass index (BMI). Serum LH, FSH, androstenedione, total testosterone, prolactin and AMH levels were measured by immunoassay. We defined PCOM with strict criteria: a follicle number per ovary (FNPO) ≥ 12 or ≥ 19 per ovary, depending on the date on which the assessment was carried out and the ultrasound device. An AMH level ≥ 35 pmol/l could be a substitute for an excess FNPO. Controls meeting these criteria were not included in this study. MAIN RESULTS AND THE ROLE OF CHANCE There was no significant difference in the ranges of AMH levels between FHA and controls. Using strict criteria to define PCOM status, 46.7% of FHA patients had PCOM. After excluding these patients, the levels of AMH were significantly lower (P < 0.002) in FHA patients compared to controls. Within the FHA group, patients with PCOM had significantly higher ranks of AMH levels and BMI than those without PCOM. However, within the PCOM+ subgroup, the ranks of LH, FSH and A levels were still lower than in controls (P LIMITATIONS, REASONS FOR CAUTION This is a retrospective study; our controls did not represent the general population as they were recruited in an ART centre; we used a modified classification for PCOM using follicle count and/or AMH level with in-house thresholds to define the follicle excess; the AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS Besides biasing the results of AMH assay in FHA patients, the presence of PCOM in FHA patients despite low gonadotropin and androgen levels raises the issue of epigenetically acquired amplification of androgen and/or FSH sensitivity within granulosa cells from polycystic ovaries. In terms of clinical practice, it seems important not to diagnose a low ovarian reserve in FHA patients too quickly on the basis of a decreased AMH level alone. On the contrary, a high AMH level in the context of a menstrual disorder and PCOM should not lead to a misdiagnosis of polycystic ovary syndrome (PCOS) if the basal LH is low. STUDY FUNDING/COMPETING INTEREST(S) None TRIAL REGISTRATION NUMBER N/A

This review details the physiologic roles of two insulin sensitizers, myo-inositol (MI) and d-chiro-inositol (DCI). In the human ovary, MI is a second messenger of follicle-stimulating hormone (FSH) and DCI is an aromatase inhibitor. These activities allow a treatment for polycystic ovary syndrome (PCOS) to be defined based on the combined administration of MI and DCI, where the best MI:DCI ratio is 40:1. Moreover, MI enhances the effect of metformin and clomiphene on the fertility of PCOS women seeking pregnancy. As impaired intestinal transport may lead to unsuccessful inositol treatment, we also discuss new data on the use of alpha-lactalbumin to boost inositol absorption. Overall, the physiological activities of MI and DCI dictate the dosages and timing of inositol supplementation in the treatment of PCOS.

International audience; No abstract available

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference?SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist.STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength.PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels.MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management.LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided.WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

The relationship between serum anti-Mullerian hormone (AMH) levels, body mass index (BMI) and related metabolic factors were investigated in women with polycystic ovary syndrome (PCOS). A total of 691 women aged between 18 and 35 years, referred to the Department of Gynaecological Endocrinology at the University Hospital of Lille between 2009 and 2014 were included: 137 controls and 554 women with PCOS. Mean serum AMH levels were slightly but significantly lower in women with PCOS who were overweight or obese (BMI ≥25) compared with women of normal weight (BMI

It is well known that myo-inositol (MI) and D-chiro-inositol (DCI) are insulin-sensitizing agents, and MI is of proven utility in polycystic ovary syndrome (PCOS). In addition, MI plays a pivotal role in the physiology of reproduction, and has beneficial effects on the development of oocytes, spermatozoa, and embryos. By contrast, DCI has little effect on spermatozoa, but high concentrations in the ovary can negatively affect the quality of oocytes and the blastocyst. Overall, the evidence in the literature supports the beneficial effects of MI in both female and male reproduction, warranting clinical use of MI in assisted reproductive treatment (ART).

The prevalence of ovulation disorder (OD) is 3-fold higher in obese than normal-weight women. Most ODs are associated with concomitant polycystic ovary syndrome (PCOS), but obesity by itself can cause OD, through mechanisms that remain poorly documented. The literature on obese non-PCOS women with OD is sparse. The aim of the present study was to analyze a population of obese non-PCOS women with OD to shed further light on the mechanism of ovulation disorder.This retrospective observational study of infertile obese women without PCOS compared a control group without OD (n=45) to a study group with OD (n=30) (OD group). Clinical, hormonal, and ultrasound characteristics were collected between cycle days 2 and 5. Women older than 37 years and women with PCOM (polycystic ovarian morphology) or hormonal disorder were excluded.Body mass index (BMI) was significantly higher in the OD group, as were waist circumference and insulin and leptin serum levels. Conversely, serum follicle stimulating hormone (FSH) levels were significantly lower. After adjustment for BMI, only serum FSH level remained significantly different between the 2 groups. Discriminant analysis suggested that FSH may have a much stronger effect on OD than BMI.Low serum FSH level may contribute to OD in some obese women, independently of BMI. The pathophysiological mechanism of this finding and its impact on therapeutic strategies must be clarified.

In women, the anti-Müllerian hormone (AMH) is secreted by the granulosa cells of growing follicles. Its measurement is strongly correlated with antral follicle count and represents a reliable marker of ovarian reserve. It also has the advantage of being highly reproducible since it has little variation within and between cycles. However, although it seems to be a good quantitative reflection of the ovarian reserve, it does not assess oocyte or embryo quality. This drawback precludes any good prediction of female fertility in the general population as well as in specific subgroups of patients. However, the AMH assay can become an indirect marker of the remaining female fertile years in some cases such as in those women who are at risk for premature ovarian failure or in those suffering from polycystic ovary syndrome. Its interest is no more to be proven in assisted reproductive technology where it is a valuable aid to the choice of the proposed techniques, ovarian stimulation protocols and gonadotropin dosage. AMH is finally very informative in monitoring cancer patients having received gonadotoxic drugs or having undergone mutilating ovarian surgeries. In conclusion, although it cannot be considered as a reliable predictor of pregnancy in women, AMH is now a useful tool in the management and treatment of female infertility.

Low vitamin D serum level has been reported in women with polycystic ovary syndrome (PCOS) compared to controls. A few in vitro studies showed that the bioactive form of vitamin D is able to modulate the expression of the anti-Müllerian hormone (AMH) gene. However, in vivo studies failed to demonstrate clearly whether low vitamin D3 serum level is involved in the AMH excess of PCOS. This prospective study evaluates serum vitamin D3 and AMH levels in women with PCOS and in controls, before and after vitamin D supplementation.Among vitamin D deficient patients, 23 patients with PCOS were compared to 27 women with normal ovarian reserve (NOR). The vitamin D deficient patients received a vitamin D supplementation according to the depth of their insufficiency. For the 23 patients with PCOS and the 27 controls, serum AMH assay and serum calciotropic hormone assays [25-hydroxyvitamin D (25[OH]D), 1,25 dihydroxyvitamin D (1,25[OH]Serum 25(OH)D levels before treatment were statistically lower in PCOS women than in NOR patients (P0.05), even after adjustment for BMI, age and AMH level, but not after adjustment for waist circumference measurement. No difference in the serum AMH levels before and after treatment was observed neither in PCOS patients nor in NOR patients. In both groups, 25(OH)D serum levels were not related to serum AMH levels, serum 1,25(OH)We found no evidence that serum calciotropic hormones are linked to circulating AMH levels, particularly in PCOS.

To compare the suppressive effect of anti-androgen therapy by cyproterone acetate (CPA) and by oral contraceptive pill (OCP) on anti-müllerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) in order to detect a putative direct anti-androgen effect on AMH excess.This is a prospective longitudinal study including 58 women with PCOS between January 2010 and April 2014 at the Lille University Hospital. A total of 47 women with clinical hyperandrogenism were treated by CPA (50 mg/d was administered 20 days out of 28) and 11 women with PCOS but without clinical hyperandrogenism received OCP.Serum AHM levels at baseline were similar in CPA and OCP groups (median [5-95th percentiles]: 60.4 pmol/l [25.1-200.2] versus 58 pmol/l [27.6-100], respectively, p = 0.39). After 3 months of treatment, serum AMH levels decreased significantly by 28% ± 20% and by 22% ± 27% in CPA and OCP groups, respectively. The decrease under both treatments was similar (p = 0.48).That any anti-androgen effect could be observed on AMH in our CPA group in addition to the gonadotropin-suppressing effect suggests that either androgens are not involved in AMH regulation or that they act by interfering with gonadotropin effects on granulosa cells.

Polycystic ovary syndrome (PCOS) affects 8–13% of women. The Rotterdam diagnostic criteria include polycystic ovarian morphology (PCOM) on ultrasound, but given recognized challenges, serum anti-Müllerian hormone (AMH) is proposed as an alternative. To inform international PCOS guidelines, a systematic review was completed. Key identified gaps include large international studies in well-defined populations across the lifespan, clustering of AMH with PCOS features, relationships to long-term health outcomes, and improved quality, assay standardization, and sample handling, all needed to determine cut offs. Here we identify research priorities to address these gaps and enhance AMH utility in PCOS. Once issues are addressed, AMH levels could replace more costly and less accessible ultrasound in PCOS diagnosis.

International audience; Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.

STUDY QUESTION: Do patient-specific features contribute to the differences between measured serum anti-Müllerian hormone (AMH) concentrations and AMH values expected from the corresponding antral follicle count (AFC)? SUMMARY ANSWER: Patient-specific features contribute to the differences between measured AMH values and AMH values expected from the corresponding AFC (AMHp), potentially through their effect on follicular AMH production. WHAT IS KNOWN ALREADY: Both patient counselling and patient management could be hampered by finding of disagreement between AFC and AMH if both are used for the prediction of ovarian response. The difference between measured AMH concentrations and AMH values expected according to the corresponding AFC cannot be entirely explained by the technical limitations of counting of antral follicles and analytical variability of the AMH assay used. STUDY DESIGN, SIZE, DURATION: This retrospective study analysed medical records of 1097 IVF patients collected between March 2011 and July 2013. PARTICIPANT/MATERIALS, SETTING, METHODS: The study population (N = 1097) included 705 (64.3%) women with normal ovarian morphology and 392 (35.7%) women with polycystic ovarian morphology, aged 20-44 years, who underwent their first IVF cycle in a single clinical centre. AMH was measured by a routine laboratory method and predicted AMH (AMHp) values were calculated using the linear regression equation (AMHp = -4.4 + 1.5 × AFC). The absolute value of the difference between AMH and AMHp was considered to be the measure of the degree of AMH-AFC agreement. The association of the difference between AMH and AMHp with clinical and biochemical parameters was investigated in both the higher-than-predicted (HTP) group comprising patients with AMH higher than AMHp (N = 466) and the lower-than-predicted (LTP) group comprising patients with AMH lower than AMHp (N = 631). MAIN RESULTS AND THE ROLE OF CHANCE: Patients in the HTP group had significantly longer menstrual cycle length and higher AMH and LH concentrations but lower AFC and FSH concentration than their counterparts in the LTP group. There was a significant association of absolute value of the difference between AMH and AMHp with age, menstrual cycle length, AFC, FSH and testosterone in both groups (P < 0.001). The difference between AMH and AMHp was exclusively correlated to LH in the HTP group (r = 0.159, P < 0.001) and to BMI in the LTP group (r = 0.231, P < 0.001), respectively. Multiple regression analysis revealed that only LH was significantly related to the difference between AMH and AMHp in the HTP group, independently from AFC. In the LTP group, BMI, menstrual cycle length, FSH and testosterone were found associated with the difference between AMH and AMHp, independently from AFC. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is selection bias. Data analysed in this study were collected from medical records of patients undergoing IVF treatment in a single department of human reproduction which precludes generalization of the results to women of different geographic origin, ethnicity, race and reproductive status. WIDER IMPLICATION OF THE FINDINGS: AMH higher than expected for a given AFC could suggest up-regulated AMH secretion (a typical feature of polycystic ovary syndrome) while AMH lower than expected from the corresponding AFC suggest down-regulated AMH secretion that could be seen as an early symptom of diminished ovarian reserve and premature ovarian insufficiency. In other words, when challenged against AFC, the serum AMH level is not only a quantitative but also a qualitative follicle marker, in relation with clinical and endocrine parameters. STUDY FUNDING/COMPETING INTEREST(S): No study funding was obtained for this study. The authors have no conflict of interest(s) to declare. TRIAL REGISTRATION NUMBER: Non-applicable.

Polycystic ovarian syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women and represents a true public health concern and an economic burden.The pathophysiology of PCOS is still not fully understood, but progresses have been made and the relationships between anti mullerian hormone (AMH), follicle stimulating hormone, luteinizing hormone, E2 and androgens have been explored. The follicle excess plays a central role in the syndrome and AMH is definitively a major component of this phenomena.The aim of this chapter is to present the recent work studying the role of AMH in the pathophysiology of PCOS and to discuss the improvement that serum AMH assay brings in the diagnosis of PCOS.

STUDY QUESTION Is intrinsic dysregulation of granulosa cells (GC) and consequent increases in the per-follicle production of anti-Müllerian hormone (AMH), correlated with the phenotypic presentation of women with polycystic ovaries? SUMMARY ANSWER Involvement of intrinsic GC dysregulation in oligo-anovulation associated with polycystic ovary syndrome (PCOS) is likely because among women with PCOS, those with oligo-amenorrhea have higher per-follicle AMH production than those who ovulate normally, irrespective of their androgen and/or metabolic status. WHAT IS KNOWN ALREADY Women with PCOS have higher serum AMH level than non-PCOS women due to an increased follicle number and excessive AMH production per follicle, the latter reflecting a putative GC dysfunction that may vary between PCOS phenotypes. STUDY DESIGN, SIZE, DURATION This is a retrospective analysis of data collected from 1021 women undergoing infertility evaluation from March 2011 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS The study included women with polycystic ovarian morphology (PCOM) who met the Rotterdam criteria for PCOS (n = 272), women with PCOM only (n = 168) and controls (n = 581). MAIN RESULTS AND THE ROLE OF CHANCE We used serum AMH to antral follicle count (AFC) ratio (AMH/AFC) as a marker of per-follicle AMH production and checked whether this ratio was associated with the PCOS phenotype and to the menstrual, androgen and metabolic status in women with PCOS, women with PCOM only and in controls. AMH/AFC was significantly higher in oligo-amenorrheic women with PCOS than in eumenorrheic women with PCOS or PCOM (P < 0.001) but also in the latter group compared with controls (P < 0.001) regardless of androgen status. Stepwise discriminant analysis yielded a significant score for the menstrual status with a discriminant power of 26.5% (P < 0.001). This score included AFC, AMH/AFC, waist circumference and LH with partial R2 of 0.172, 0.042, 0.024 and 0.023, respectively. LIMITATIONS, REASONS FOR CAUTION The AMH to AFC ratio as a surrogate marker for average AMH may be subject to error because follicles below the sensitivity limit of the ultrasonography used may also contribute to serum AMH concentration and secondly, AFC can be subjective. WIDER IMPLICATIONS OF THE FINDINGS The higher AMH/AFC in women with PCOM only than in controls suggests that isolated PCOM may represent a PCOS-like phenotype in which an inherent dysfunction of GC exists but is too mild to affect the ovulatory process. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained for this study. There are no conflicts of interest to be declared. TRIAL REGISTRATION NUMBER Non-applicable.

STUDY QUESTION Does the use of the serum anti-Mullerian hormone (AMH) assay to replace or complement ultrasound (U/S) affect the diagnosis or phenotypic distribution of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Combining U/S and the serum AMH assay to define polycystic ovarian morphology (PCOM) diagnoses PCOS (according to the Rotterdam classification) in more patients than definitions using one or the other of these indicators exclusively. WHAT IS KNOWN ALREADY Since 2003, PCOM, as defined by U/S, is one of the three diagnostic criteria for PCOS. As it is closely correlated with follicle excess seen at U/S, an excessive serum AMH level could be used as a surrogate for PCOM. STUDY DESIGN, SIZE, DURATION Single-center retrospective study from a database of prospectively collected clinical, laboratory and ultrasound data from patients referred for oligo-anovulation (OA) and/or hyperandrogenism (HA) between January 2009 and January 2016. PARTICIPANTS/MATERIALS, SETTING, METHOD The standard Rotterdam classification for PCOS was tested against two modified versions that defined PCOM by either excessive serum AMH level alone (AMH-only) or a combination (i.e. 'and/or') of the latter and U/S. The PCOS phenotypes were defined as A (full phenotype, OA+HA+PCOM), B (OA+HA), C (HA+PCOM) and D (OA+PCOM). MAIN RESULTS AND THE ROLE OF CHANCE PCOS was more frequently diagnosed when PCOM was defined as the combination 'positive U/S' and/or 'positive AMH' (n = 639) than by either only U/S-only (standard definition, n = 612) or by AMH-only (n = 601). With this combination, PCOM was recognized in 637 of the 639 cases that met the Rotterdam classification, and phenotype B practically disappeared. In this population, U/S and AMH markers were discordant for PCOM in 103 (16.1%) cases (9% U/S-only, 7.1% AMH-only, P = 0.159). The markers used had no other significant impact on the phenotypic distribution (except for phenotype B). However, the percentage of cases positive by U/S-only was significantly higher in phenotype D than in phenotype A (14.1% vs. 5.8%, P < 0.05). Furthermore, in the discordant cases, plasma LH levels were significantly higher in the AMH-only group than in the concordant cases, and fasting insulin serum levels tended to be higher in the U/S-only group. LIMITATIONS, REASONS FOR CAUTION This is a retrospective study. A referral bias explains the relatively high proportion of patients with phenotype D (28%). PCOM was defined by in-house thresholds. The AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that ideally both U/S data and serum AMH level should be integrated to define PCOM in the Rotterdam classification. In a cost-effectiveness approach, the choice of one or the other has little impact on the diagnosis and the phenotyping of PCOS. STUDY FUNDING/COMPETING INTEREST(S) No external funding. The authors have no conflict of interest to declare.

International audience; Patients with very low sperm count through direct sperm examination can exhibit extreme oligozoospermia or cryptozoospermia (after centrifugation). The management of these patients is a real challenge for both clinicians and biologists. In this retrospective and comparative cohort study, we compared the andrological phenotype of patients with extreme alterations of spermatogenesis and assessed whether the origin of spermatozoa (testicular or ejaculate) had any influence on intracytoplasmic sperm injection (ICSI) outcomes. A total of 161 ICSI cycles were performed using ejaculated spermatozoa from 75 patients with extreme oligozoospermia (EOS) or cryptozoospermia (CS) and 150 ICSI cycles using extracted testicular spermatozoa from 74 patients with non-obstructive azoospermia (NOA). Physical, hormonal, ultrasound assessments, and ICSI outcomes were performed in each group. Cryptorchidism was significantly more frequent in the NOA group (60.8% vs. 22.6%, p = 0.001). FSH levels were significantly higher [18.9 IU/L (5.9-27.0) vs. 15.3 IU/L (9.0-46.5), p = 0.001] and the majority of inhibin B levels measured were found mostly undetectable in the NOA group as compared to EOS/CS group (31.1% vs. 10.7%, p = 0.0004). Moreover, we found no significant differences in the respect to the fertilization rates (48.9% and 43.3%, p = 0.43), implantation rates (17.4% and 15.9%, p = 0.77), and percentage of top quality embryo (22.4% and 20.4%, p = 0.73) between the two groups. The clinical pregnancy rates per embryo transferred were comparable in both groups (28.3% and 27.4%, p = 0.89). In this study, we showed for the first time a different andrological phenotype between EOS/CS and NOA groups. Indeed, cryptorchidism was significantly more frequent with more severe endocrine parameters found in the NOA group. These results reflect a more profound alteration in spermatogenesis in NOA patients. However, there was no difference in ICSI outcomes between NOA and EOS/CS groups.

Objective To describe a case of falsely elevated serum antimullerian hormone (AMH) level in an infertile 37-year-old woman with rheumatoid arthritis. Design Case report. Setting Lille University IVF center. Patient(s) A 37-year-old woman with rheumatoid arthritis demonstrating a high serum AMH level (74.5 ng/mL) and a low antral follicle count. Intervention(s) Assay with a Heterophilic Blocking Tube (HBT) to avoid heterophilic interference. Main Outcome Measure(s) Serum AMH level, ultrasound antral follicle count, hormonal assays on the 4th day of a spontaneous cycle. Result(s) The results of the infertility workup were as follows: serum AMH: 74.5 ng/mL (15-fold the upper limit of normal) (immunoassay: Immunotech); LH: 3.2 IU/L; FSH: 4.5 IU/L; E 2 : 27 pg/mL; PRL: 10 ng/mL. The antral follicle count (follicles from 2 to 9 mm) at ultrasound was 7 for both ovaries. Because there were discrepancies between the serum AMH level and the results of the infertility workup using the bioassays, we suspected a case of falsely elevated AMH level due to heterophilic interference. An HBT tube revealed a serum AMH level of 0.63 ng/mL. Conclusion(s) This case illustrates, for the first time, the possibility of a falsely high serum AMH level due to heterophilic interference.

Background Pulsatile GnRH therapy is the gold standard treatment for ovulation induction in women having functional hypothalamic amenorrhea (FHA). The use of pulsatile GnRH therapy in FHA patients with polycystic ovarian morphology (PCOM), called “FHA-PCOM”, has been little studied in the literature and results remain contradictory. The aim of this study was to compare the outcomes of pulsatile GnRH therapy for ovulation induction between FHA and “FHA-PCOM” patients in order to search for an eventual impact of PCOM. Methods Retrospective study from August 2002 to June 2015, including 27 patients with FHA and 40 “FHA-PCOM” patients (85 and 104 initiated cycles, respectively) treated by pulsatile GnRH therapy for induction ovulation. Results The two groups were similar except for markers of PCOM (follicle number per ovary, serum Anti-Müllerian Hormone level and ovarian area), which were significantly higher in patients with “FHA-PCOM”. There was no significant difference between the groups concerning the ovarian response: with equivalent doses of GnRH, both groups had similar ovulation (80.8 vs 77.7 %, NS) and excessive response rates (12.5 vs 10.6 %, NS). There was no significant difference in on-going pregnancy rates (26.9 vs 20 % per initiated cycle, NS), as well as in miscarriage, multiple pregnancy or biochemical pregnancy rates. Conclusion Pulsatile GnRH seems to be a successful and safe method for ovulation induction in “FHA-PCOM” patients. If results were confirmed by prospective studies, GnRH therapy could therefore become a first-line treatment for this specific population, just as it is for women with FHA without PCOM.

Background Oocyte donation is a medical technique used principally for woman with ovarian failure. Optimizing donor recruitment is essential to obtain the best results with this technique. Understanding how donor parameters influence outcome for the recipients is fundamental. The aim of this study was to determine whether clinical and/or biological parameters in the donors influence the chance of pregnancy in recipients. Our objective was also to verify whether the outcomes of controlled ovarian stimulation (COS) are predictive of pregnancy in the recipients. Methods A retrospective observational study was conducted in the Department of Reproductive Medicine in the Lille University Hospital. Between September 2005 and April 2014, COS was performed in 145 donors for 308 recipients’ cycles. We compared the cycles whose outcome was pregnancy to the cycles without pregnancy. Quantitative variables were compared using the nonparametric Mann–Whitney test. Qualitative variables were compared using a Chi-2 test or Fisher exact test, according to the numbers. Covariance analysis was performed to adjust for potential confounding factors. Results The donors who produced at least one pregnancy had a mean baseline serum anti-Müllerian hormone (AMH) level significantly higher than those who did not (p = 0.001). The mean antral follicle count did not differ between the 2 groups. After covariance analysis controlling for the number of couples attributed to a given donor, this difference remained significant (p = 0.029). Mature follicle number, estradiol serum level at the trigger day, number of mature oocytes and embryo number were significantly higher in the donors who produced pregnancy. Conclusion Serum AMH level is associated with pregnancy outcome after oocyte donation.

The stimulation of spermatogenesis is the best treatment of infertility for male hypogonadotropic-hypogonadism. The results are very pleasing because a real improvement of semen is sometimes obtained with spontaneous pregnants describing in the literature but after a long duration of treatment, often many months. Sometimes, the treatment improves the technical conditions of ICSI for the embryologists. Stimulation of spermatogenesis by gonadotrophins rFSH and/or hCG is the most used but others treatments, like pulsatile GnRH therapy or clomifene citrate can be used. The purpose of this review is to described the different protocols of stimulation of spermatogenesis and explain their results and finally to see if others indications of stimulation of spermatogenesis are existing.

Ovulation induction in patients having both functional hypothalamic amenorrhea (FHA) and polycystic ovarian morphology (PCOM) has been less studied in the literature. As results remain contradictory, no recommendations have yet been established.To compare pulsatile GnRH therapy versus gonadotropins for ovulation induction in "FHA-PCOM" patients and to determine if one treatment strikes as superior to the other.A 12-year retrospective study, comparing 55 "FHA-PCOM" patients, treated either with GnRH therapy (38 patients, 93 cycles) or with gonadotropins (17 patients, 53 cycles).Both groups were similar, defined by low serum LH and E2 levels, low BMI, excessive follicle number per ovary and/or high serum AMH level. Ovulation rates were significantly lower with gonadotropins (56.6% versus 78.6%, p = 0.005), with more cancellation and ovarian hyper-responses (14% versus 34% per initiated cycle, p 0.005). Pregnancy rates were significantly higher with GnRH therapy, whether per initiated cycle (26.9% versus 7.6%, p = 0.005) or per patient (65.8% versus 23.5%, p = 0.007).In our study, GnRH therapy was more successful and safer than gonadotropins, for ovulation induction in "FHA-PCOM" patients. If results were confirmed by prospective studies, it could become a first-line treatment for this population, just as it is for FHA women without PCOM.

International audience; In the management of azoospermia, a combination of testicular sperm extraction and intracytoplasmic sperm injection (ICSI) is usually the most successful option for fatherhood. However, an outstanding question remains: How can at least a few spermatozoa be obtained from the ejaculate, thus avoiding the need for a surgical procedure? A 36-year-old man presented to Assisted Reproduction Unit with his 26-year-old wife. The ultrasound assessment revealed bilateral microlithiasis. Two spermograms revealed absolute azoospermia. Levels of follicle-stimulating hormone (FSH) and luteinising hormone were normal-low. The patient underwent 10 months of treatment with clomiphene citrate. A bilateral testicular sperm extraction failed to retrieve spermatozoa and revealed a maturation arrest at spermatocyte/spermatid stages depending on the tubules. Clomiphene citrate was replaced with recombinant FSH (rFSH). After 9-month treatment with rFSH, motile spermatozoa from droplets of ejaculate pellet were cryopreserved as a single straw. Ovarian stimulation was provided using classic antagonist protocol, and five mature oocytes were collected. Two consecutive fresh semen samples on the day of ICSI yielded seven motile spermatozoa, and fertilisation was achieved in all five oocytes. On day 3, two embryos were transferred, yielding positive beta-human chorionic gonadotropin and a healthy delivery of a boy and a girl.

Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic–pituitary–gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS., Anti-Müllerian hormone (AMH) plays a role in sexual differentiation and gonadal function, but extra-gonadal effects of AMH are not known. Here Cimino et al. show that AMH activates a subset of gonadotrophin-releasing hormone (GnRH)-releasing neurons, contributing to luteinizing hormone secretion from the pituitary gland.

Objective To verify whether a variable number of days beyond the menses of estrogen (E) pretreatment may impact on controlled ovarian hyperstimulation (COH) outcomes and birth rate using a GnRH antagonist protocol. Design Single center, prospective, nonrandomized study. Setting Nonacademic fertility unit. Patient(s) A total of 1,080 women, aged 25–38 years, consecutively included (1,603 cycles). Intervention(s) Given 4 mg/d E 2 valerate, started 3 days before the theoretical date of the next menses up to the first day of stimulation (S1). Main Outcome Measure(s) Hormone serum levels, drug exposure, and main IVF outcomes. Result(s) The cancellation rate was similar in the six similarly sized groups according to the number of days with E 2 pretreatment beyond the menses (1–8 days). The mean serum E 2 and LH levels at S1 gradually increased along with E 2 exposure, whereas the mean serum P level decreased. The mean serum E 2 level on the day of hCG administration gradually increased along with E 2 exposure. Serum LH level at S1 correlated significantly and positively to the length of E 2 exposure and to E 2 level on the day of hCG administration. No significant difference was observed for the number of oocytes retrieved and the number of embryos obtained. Women exposed the longest to exogenous E 2 tended to have higher pregnancy rates (PR). Conclusion(s) Extending E 2 pretreatment beyond the menses had no deleterious effect on the main COH outcomes and proved to be slightly beneficial.

Anti-Mullerian hormone (AMH) is known to be secreted in women by granulosa cells of growing follicles from the primary to the large antral follicle stage. Serum and intrafollicular AMH levels are elevated in patients with polycystic ovary syndrome (PCOS) due to increased number of small follicles and an increased secretion within each of these small follicles. This excess of AMH is strongly suspected to play a role in the follicular arrest of PCOS by a negative action on aromatase expression and on action of FSH. The interest of serum AMH assay is also clinically important because AMH level is more sensitive, more specific and reproducible from one center to another as the follicle count. Rates above 5ng/ml or 35pmol/l may be considered as a diagnostic criterion for PCOS.

It is still debated whether clinical and/or biological indices of hyperandrogenism (HA) should be present to qualify a patient as having polycystic ovary syndrome (PCOS). We hypothesized that excessive follicle number (FN) assessed by ovarian ultrasonography and/or serum anti-Müllerian hormone (AMH) concentrations may be used as surrogates for the classical markers of HA.Data were obtained from a database of clinical, hormonal, and ultrasound features that were consecutively recorded in 270 women with PCOS (defined using the Rotterdam Criteria) and 217 infertile nonhyperandrogenic normoovulatory women. These variables were submitted to principal component analysis, a multivariable statistical procedure that transforms a number of possibly correlated variables into a smaller number of uncorrelated variables called principal components (PC). Variables that aggregate in the same PC capture the same information.In the control group, as expected, three independent PCs were identified: 1) the markers of the metabolic (i.e. insulin resistance) status; 2) those of the androgen status; and 3) those of the follicle status. In the PCOS group, the metabolic variables also aggregated in a first PC. Ovarian androgen and follicle markers aggregated in a second independent PC, with FN and serum AMH having the strongest correlation coefficients. A third PC summarized the adrenal contribution to the HA of PCOS. In both groups, the free androgen index correlated equally to the first and second PCs.The similarity of the first PC between controls and PCOS supports the hypothesis that the metabolic anomaly of PCOS is neither intrinsic nor specific. Conversely, by gathering the androgen and follicle variables, the second PC in PCOS may be viewed as summarizing a specific ovarian anomaly. Because both FN and/or serum AMH were strongly correlated to the second PC along with androgens, they may be used equally as surrogates for the classical markers of ovarian HA. This reconciles the Rotterdam Consensus and other definitions for PCOS, especially in women having the Rotterdam PCOS phenotype without HA. We thus propose a simple strategy for the diagnosis of PCOS in clinical practice.

Polycystic ovary syndrome (PCOS) is the most common etiology of menstrual disorders and hyperandrogenism. It is characterized by an excess of ovarian follicles. The mechanisms that underlie folliculogenesis disorder in PCOS appear to arise from primitive ovarian hyperandrogenism. This can be modulated by hormonal factors, such as LH or insulin. Ovarian hyperandrogenism results from a real theca cells dysfunction, whose origin is still poorly understood. It seems that complex genetic factors may be involved, but these have not yet been clearly identified. PCOS also results from granulosa cells dysfunction. For example, intra-ovarian factors, such as anti-mullerian hormone, are possibly involved in ovulation's disorders by blocking the physiological process of follicular recruitment. In turn, the oocyte could also be one of the actors possibly involved in the follicular excess in PCOS.

Resume Le besoin d’une imagerie calibree des ovaires polykystiques (OPK) est plus fort que jamais depuis la conference de consensus qui s’est tenue a Rotterdam du 1er au 3 mai 2003. Cependant, imager les ovaires polykystiques n’est pas une procedure facile et requiert un certain savoir-faire technique et medical. L’echographie en deux dimensions reste l’examen standard d’imagerie des OPK et la definition des OPK dans le consensus actuel retenue a la conference de consensus ASRM/ESHRE repose sur cette technique : 12 ou davantage de follicules mesurant 2 a 9 mm de diametre et/ou un volume ovarien augmente au-dela de 10 cm3. Cependant, ces seuils necessitent d’etre revus avec les nouveaux appareils possedant une meilleure resolution spatiale et avec l’apparition de l’echographie 3-D. Les etudes en doppler et en imagerie par resonance magnetique (IRM) sont rarement utiles au diagnostic mais peuvent etre interessantes en recherche clinique.

Resume 1. La classification dite de Rotterdam doit etre utilisee pour la definition du SOPMK: existence d’une anomalie du cycle menstruel : amenorrhee, oligospaniomenorrhee ou cycles longs ; existence d’une hyperandrogenie clinique et/ou biologique ; presence d’ovaires polykystiques (OPK) a l’echographie. Deux criteres sur trois suffisent, apres exclusion des autres diagnostics. 2. La classification de Ferriman et Gallway ne doit pas etre utilisee pour faire le diagnostic d’hirsutisme. 3. La definition echographique de l’OPK repond a des criteres precis qui doivent figurer dans le compte-rendu : presence d’au moins 12 follicules mesurant 2–9 mm de diametre dans chaque ovaire ; et/ou volume ovarien augmente > a 10 ml. 4. L’elevation de la LH plasmatique ne doit plus etre recherchee. Le test a la GnRH est inutile. 5. La recherche d’anomalies metaboliques doit etre systematique et repose sur les criteres suivants: poids, taille, calcul de l’IMC, tour de taille, pression arterielle ; biologie: glycemie, triglycerides, cholesterol HDL. 6. En cas d’obesite (IMC > 30 kg/m2), l’hyperglycemie par voie orale (HPGO) est recommandee si la glycemie a jeun est normale. 7. Le Citrate de Clomiphene (CC) demeure le traitement de premiere intention pour l’induction de l’ovulation. Si l’IMC est > 30, il doit etre precede d’une amelioration de l’etat metabolique par des mesures hygieno-dietetiques.

Serum androgen levels correlate with ovarian sensitivity to follicle-stimulating hormone (FSH) but in practice, standard baseline serum testosterone (T) levels prior to in-vitro fertilization (IVF) may not be the most appropriate marker for determination.Infertile women enrolled in an IVF programme were included in this study. Serum T and Delta4-androstenedione (A), and the androgen precursor 17-hydroxyprogesterone (17-OHP) were measured before and 24 h after a gonadotrophin-releasing hormone agonist stimulation test (GAST). An early follicular phase antral follicle count (AFC) was also performed. Patients were subsequently enrolled in a long gonadotrophin-releasing hormone agonist protocol with a standard FSH dose (150 IU) for 7 days to assess the association between androgen levels and ovarian responsiveness to FSH.The GAST elicited a significant increase in serum androgen levels that was well correlated with AFC. 17-OHP showed the greatest response to GAST and strongest correlation with AFC. The 17-OHP response to GAST differentiated patients with high ovarian reserve (OR) from those with low or normal OR as assessed by AFC, whereas only the estradiol response could differentiate those with low AFC. GAST-stimulated serum levels of 17-OHP were also correlated with ovarian response to FSH. Using receiver operating characteristic curve analysis, stimulated 17-OHP levels were predictive of the ovarian response to controlled ovarian stimulation, with similar power to that observed with AFC but lower power than with anti-Müllerian hormone.Serum androgen levels following GAST are correlated with AFC and ovarian response to FSH. Serum T is a less sensitive marker of theca cell function than 17-OHP.

Please cite this paper as: Dewailly D, Contestin M, Gallo C, Catteau-Jonard S. Metabolic syndrome in young women with the polycystic ovary syndrome: revisiting the threshold for an abnormally decreased high-density lipoprotein cholesterol serum level. BJOG 2010;117:175–180. Objective To verify whether the adult threshold for an abnormally decreased high-density lipoprotein cholesterol (HDL-C) serum level (0.5 g/l) is appropriate in young women with polycystic ovary syndrome (PCOS). Design Retrospective analysis of a database. Setting Academic Hospital. Population A total of 854 women aged 16–40 years having PCOS according to Rotterdam criteria. Methods Criteria defining the metabolic syndrome (MetS) (increased waist circumference, systolic and/or diastolic blood pressure, triglycerides, fasting glycaemia and decreased HDL-C) were separately analysed and compared in three different subgroups (16–20 years, 20–30 years and 30–40 years). The prevalence of the MetS was calculated using two different thresholds (0.5 and 0.4 g/l) for HDL-C in the 16–20 years group. Main outcomes measures Prevalence of MetS. Results The prevalence of an abnormal HDL-C (

Although treatment and survival are the primary focus of health-care patients, with cancer survivors living longer it is now appropriate to consider their quality of life after treatment, including the possibility of becoming parents. There are several options for fertility preservation in cancer patients. Even though most of them are still experimental and their efficacy and reliability have not been determined, especially in women. The most successful alternative for female survivors is embryo cryopreservation, an approach not suitable for many single or virgin women or even possible for prepubertal girls. Reports of live birth after transplantation of human ovarian tissue have reinforced the clinical potential of ovarian tissue banking for fertility preservation. Many exciting studies are underway to improve the efficacy and solve the problems with current fertility preservation strategies, especially for in vitro culture of cryopreserved tissue or follicles. Continuous efforts to improve current strategies and to develop new strategies will benefit many women and children who are facing premature ovarian failure and sterility.

Background Recent studies suggest a role for luteinizing hormone and human chorionic gonadotrophin receptor (LH/hCGR) signalling in the regulation of the oocyte-cumulus oophorus cell interplay. The present study aimed at assessing the LH/hCGR gene expression in cumulus cells (CCs) surrounding oocytes in patients undergoing controlled ovarian hyperstimulation (COS) before ICSI and to relate the LH/hCGR expression to other COS quality parameters. Methods CCs from single oocytes of normal responder patients were analysed by DNA microarrays. Concomitantly, estradiol levels on the day of hCG administration, CC morphology, total collected oocyte and metaphase II oocyte number were assessed in relation to LH/hCGR gene expression in CC. Results The transcriptome analysis of CC indicated a variable expression of LH/hCGR among the patients and intra-patients. LH/hCGR mRNA expression was negatively correlated with serum estradiol level on the day of hCG administration. Eighty-five genes were significantly modulated between CCs from patients with a high and a low LH/hCGR expression. These genes are involved principally in steroid metabolism and in the ovulation process and include TNFAIP6, a gene expressed during CC-oocyte complex (COC) expansion. There were no significant differences in LH/hCGR gene expression profile between COS protocols. Conclusions LH/hCGR is expressed in CC under COS conditions. LH/hCGR expression level is associated with TNFAIP6 gene expression and negatively correlated with serum estradiol level on the day of hCG administration.

Ectopic prolactin secretion remains exceptional and originates mainly from malignant tumors. We report the case of a 47-year-old woman who presented amenorrhea leading to unravel important hyperprolactinaemia (269 ng/mL) with no hypothalamo-pituitary mass on magnetic resonance imaging (MRI). Pelvic imaging revealed the presence of a large pelvic mass that originated from the mesocolon. After complete surgical extraction, histological examination was in favour of a "perivascular epithelioid cell tumor" (PEComa). Prolactin levels normalized after surgical extraction and remained normal after a 3-year follow-up, totally free of tumour recurrence and/or metastasis. This suggests that hyperprolactinaemia was most likely related to the PEComa, despite negative reactions with antiprolactin antibodies at immunohistochemistry. Alternatively to a direct prolactin secretion by the tumor, one could hypothesize that the tumour secreted a prolactin stimulating factor or a dopamine antagonist that could not be identified. In conclusion, in face of an important hyperprolactinaemia without any hypothalamic-pituitary mass, it remains important to search for an ectopic prolactin production, such as a PEComa.

BACKGROUND: We previously hypothesized that the excess of 2–5 mm follicles seen at ovarian ultrasonography might be involved in the follicular arrest (FA) of polycystic ovary syndrome (PCOS), independently from the main putative contributors of FA, namely hyperandrogenism and hyperinsulinism. METHODS: A multivariate statistical analysis was applied retrospectively to clinical, biological and ultrasound data that were consecutively collected during 5 years in 457 patients with polycystic ovaries and in 188 age-matched non-hyperandrogenic and regularly cycling controls without PCO at ultrasound. RESULTS: Stepwise discriminant analysis indicated that in PCOS the 2–5 mm follicle number (FN) gave the strongest correlation to severity of the FA, followed by age and then by fasting insulin level. The other variables [waist circumference (WC), 6–9 mm FN, serum testosterone, FSH, LH and ovarian area] were rejected by the analysis. Multiple linear regression indicated a significant and independent negative relationship between the 2–5 and 6–9 mm FN in the PCOS (r 52 0.186, P< 0.01) and control groups (r 52 0.281, P< 0.01). In PCOS only, the 6–9 mm FN was negatively and independently related to the WC (r 52 0.108, P< 0.05). CONCLUSIONS: The size of the 2–5 mm follicle pool is an independent and important contributor to the FA of PCOS. This result could be explained by an exaggerated physiological inhibitory effect from this pool on the terminal follicle growth. The metabolic derangement of PCOS that also contributes to the FA would act through a different mechanism.

Background Androgens, FSH, anti-Mullerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood. Objectives and rationale The purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS). Search methods A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980-2015 and the databases interrogated were PubMed and Web of Science. Outcomes During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS. Wider implications Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS.

International audience; Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women. Excessive ovarian production of Anti-Müllerian Hormone, secreted by growing follicles in excess, is now considered as an important feature of PCOS. The aim of this review is first to update the current knowledge about the role of AMH in the pathophysiology of PCOS. Then, this review will discuss the improvement that serum AMH assay brings in the diagnosis of PCOS. Last, this review will explain the utility of serum AMH assay in the management of infertility in women with PCOS and its utility as a marker of treatment efficiency on PCOS symptoms. It must be emphasized however that the lack of an international standard for the serum AMH assay, mainly because of technical issues, makes it difficult to define consensual thresholds, and thus impairs the widespread use of this new ovarian marker. Hopefully, this should soon improve.

ObjectiveAlthough an inhibin B assay may be useful in the assessment of testicular function in a number of genital conditions, reliable reference ranges are still lacking. The present study sought to establish the reference range for serum inhibin B by applying the updated Gen II assay.DesignThis prospective study included 818 men referred for semen analysis: 377 were normozoospermic (reference group) and 441 presented at least one abnormal semen parameter (case group).MethodsSemen parameters were interpreted according to the 2010 World Health Organization manual and David's modified classification for normal morphology. The inhibin B concentration was determined with the current ELISA.ResultsIn the reference group, the 2.5th percentile for inhibin B was 92 pg/ml and the 97.5th percentile for FSH was 7.8 IU/l. In the overall population, an inhibin B level PPP=0.0026). The combination of a FSH >7.8 IU/l and an inhibin B PConclusionsA new reference range for serum inhibin B was established by the use of updated immunoassay. The correlations between hormone levels and semen parameters highlighted the importance of establishing these values with respect to the spermogram. When combined with FSH assay, the inhibin B range may be of value in the evaluation of spermatogenesis in a number of male genital conditions.

International audience; Context: Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men.Objective: The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility.Methods: From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men.Results: Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children.Conclusion: We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.

Objective: The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. Participants: Participants included expert investigators in the field. Evidence: Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. Consensus Process: The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. Conclusions: Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that there should be acceptance of the original 1990 National Institutes of Health criteria with some modifications, taking into consideration the concerns expressed in the proceedings of the 2003 Rotterdam conference. A principal conclusion was that PCOS should be first considered a disorder of androgen excess or hyperandrogenism, although a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism but recognized that more data are required before validating this supposition. Finally, the task force recognized, and fully expects, that the definition of this syndrome will evolve over time to incorporate new research findings.

Background and objective: Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF). Subject and methods: We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child. Results: We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions. Conclusions: We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.