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Abstract 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.

Polycystic ovary syndrome is a common endocrine disorder affecting 5–20% of women in association with metabolic disorders and insulin resistance. Patients with PCOS are also at increased risk of developing cardiovascular sound aspects of polycystic ovaries and metabolic complications, a psychosocial impact that exists, which is poorly known, assessed and treated. The delay, sometimes long, for diagnosis and its announcement has a strong impact on the feelings and life projects of these patients. Psychological co-morbidities such as depression, anxiety, eating disorders as well as a decrease in self-esteem and quality of life are frequently described in these patients and must, therefore, be screened and treated.

Abstract 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

BackgroundPolycystic ovary syndrome (PCOS) is linked to an elevated risk of psychological disorders, decreased quality of life and emotional distress. Serum cortisol as a potential stress marker has been found to be increased in women with PCOS. The aim of this study was to evaluate both saliva stress markers and subjective psychological distress in women with PCOS.MethodsIn a prospective case-control study, 31 PCOS women and 31 healthy controls were included. Salivary cortisol, and metanephrines were collected in the morning and in the evening. Emotional distress and quality of life were assessed by means of the Perceived Stress Scale (PSS-10) and the Short Form-36 (SF-36). Multivariable generalized linear models were applied to test the influence of various parameters on numerical outcome parameters.ResultsAfter correction for age and body mass index (BMI), there were no statistically significant differences of salivary biomarkers between PCOS women and healthy controls (p>0.05). PCOS patients revealed significantly higher increased PSS total scores and lower quality of life in all SF-36 modules apart from pain (p< 0.05). The PSS total score was positively correlated to prolactin in PCOS women (r= 0.450; p= 0.011). In overweight/obese PCOS patients, a higher BMI, a higher Ferriman Gallwey score and higher age significantly predicted the PSS total score (p< 0.05).ConclusionStress measured by salivary biomarkers did not differ between PCOS women and healthy controls, whereas stress scores evaluated by questionnaires were significantly greater in women with PCOS. A higher BMI, hirsutism and a higher age seem to be the main modulators of subjective stress in PCOS. Prolactin might serve as a biomarker for chronic stress in PCOS women.

Summary: Background: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood. Methods: We studied brain structure and function in women with and without PCOS using proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging combined with fiber tractography. Then, using a mouse model of PCOS, we investigated by electron microscopy whether AMH played a role on the regulation of hypothalamic structural plasticity. Findings: Increased AMH serum levels are associated with increased hypothalamic activity/axonal-glial signalling in PCOS patients. Furthermore, we demonstrate that AMH promotes profound micro-structural changes in the murine hypothalamic median eminence (ME), creating a permissive environment for GnRH secretion. These include the retraction of the processes of specialized AMH-sensitive ependymo-glial cells called tanycytes, allowing more GnRH neuron terminals to approach ME blood capillaries both during the run-up to ovulation and in a mouse model of PCOS. Interpretation: We uncovered a central function for AMH in the regulation of fertility by remodeling GnRH terminals and their tanycytic sheaths, and provided insights into the pivotal role of the brain in the establishment and maintenance of neuroendocrine dysfunction in PCOS. Funding: INSERM (U1172), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n° 725149), CHU de Lille, France (Bonus H).

Abstract 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.

The two most frequent causes of secondary amenorrhea are polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhea (FHA). Despite several studies showing differences in hormonal profile between these groups, the differential diagnosis remains challenging, in particular between FHA women with polycystic ovarian morphology (FHA-PCOM) and PCOS patients without hyperandrogenism (phenotype D, PCOS-D). In a retrospective case-control study, 58 clearly defined patients with FHA-PCOM were compared to 58 PCOS-D patients, matched 1:1 for age and BMI. Significantly higher levels of LH, estradiol, testosterone, and a higher luteinizing hormone (LH): follicle stimulating hormone (FSH) ratio as well as lower sexual hormone binding globulin (SHBG) levels were found in PCOS-D patients (p< 0.05). Optimized cut-off values for the prediction of FHA-PCOM were calculated by the Youden index. The highest sensitivity was found for an estradiol serum level

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.

Polycystic ovary syndrome (PCOS) and hyperprolactinemia (HPRL) are the two most common etiologies of anovulation in women. Since the 1950s, some authors think that there is a pathophysiological link between PCOS and HPRL. Since then, many authors have speculated about the link between these two endocrine entities, but no hypothesis proposed so far could ever be confirmed. Furthermore, PCOS and HPRL are frequent endocrine diseases and a fortuitous association cannot be excluded. The evolution of knowledge about PCOS and HPRL shows that studies conducted before the 2000s are obsolete given current knowledge. Indeed, most of the studies were conducted before consensual diagnosis criteria of PCOS and included small numbers of patients. In addition, the investigation of HPRL in these studies relied on obsolete methods and did not look for the presence of macroprolactinemia. It is therefore possible that HPRL that has been attributed to PCOS corresponded in fact to macroprolactinemia or to pituitary microadenomas of small sizes that could not be detected with the imaging methods of the time. Recent studies that have conducted a rigorous etiological investigation show that HPRL found in PCOS correspond either to non-permanent increase of prolactin levels, to macroprolactinemia or to other etiologies. None of this recent study found HPRL related to PCOS in these patients. Thus, the link between PCOS and HPRL seems to be more of a myth than a well-established medical reality and we believe that the discovery of an HPRL in a PCOS patient needs a standard etiological investigation of HPRL.

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.

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

BACKGROUND: This study revisited the ovarian volume (OV) as a diagnostic criterion for polycystic ovaries (PCO). Indeed, a threshold of 10 cm3 for the OV, chosen at the polycystic ovary syndrome (PCOS) international consensus held at Rotterdam in 2003, was to date not based on appropriate studies such as receiver operator characteristic (ROC) curve analysis. METHODS: This prospective study included 154 women with PCOS, selected by using the former National Institutes of Health criteria, who were compared with 57 women with normal ovarian function. Ultrasound examination was performed between cycle days 2 and 7 with a 7 MHz transvaginal transducer. RESULTS: Mean OV, ovarian area (OA) and follicle number (FN) values were significantly higher in the PCOS group than in controls. The area under the ROC curve (AUC) was >0.9 for all three criteria, indicating a satisfactory diagnostic potency for each. Concerning the OV, setting the threshold at 7 cm3 offered the best compromise between specificity (91.2%) and sensitivity (67.5%). In comparison, specificity and sensitivity were 98.2 and 45%, respectively, with a threshold at 10 cm3. Nevertheless, the highest AUC was obtained for FN (0.956) and then for OA (0.941). CONCLUSIONS: OV is a good diagnostic criterion for PCO but, on the basis of the present data, we propose to lower its threshold to 7 cm3. The FN >12 still appears as the best diagnostic criterion. The OA could be used as a surrogate for OV in difficult situations. [ABSTRACT FROM AUTHOR]

This review exposes the follicular abnormalities responsible for anovulation in polycystic ovary syndrome (PCOS). The putative pathophysiological explanations involve the principal intra‐ and extra‐ovarian regulators which intervene during normal folliculogenesis to control the initial recruitment and growth and then the cyclic recruitment. We propose the hypothesis that the follicular problem in PCOS is 2‐fold, but with the two abnormalities being linked. First, the intra‐ovarian hyperandrogenism may promote early follicular growth, leading to a 2–5 mm follicle excess. Second, the ensuing excessive number of selectable follicles would inhibit the selection process, presumably through follicle–follicle interaction involving granulosa cell (GC) products such as the anti‐Müllerian hormone (AMH). These factors would induce a reversible refractoriness to the FSH‐induced differentiation of GC. This explanation challenges but does not exclude other hypotheses about the follicular arrest, such as the premature LH action on the GC of selectable follicles. Hyperinsulinism or insulin resistance would act as a second hit, worsening the follicular arrest either through amplification of the intra‐ovarian hyperandrogenism or through dysregulation of the GC. The loss of cyclic rhythm would prevent the inter‐cycle elevation of FSH, thus perpetuating the impairment of the ovulation process. [ABSTRACT FROM AUTHOR]

The polycystic ovary syndrome (PCOS) is a heterogeneous condition, the pathophysiology of which appears to be both multifactorial and polygenic. The definition of the syndrome has been much debated. Key features include menstrual cycle disturbance, hyperandrogenism and obesity. There are many extra-ovarian aspects to the pathophysiology of PCOS, yet ovarian dysfunction is central. At a recent joint ASRM/ESHRE consensus meeting, a refined definition of the PCOS was agreed, encompassing a description of the morphology of the polycystic ovary (PCO). According to the available literature, the criteria fulfilling sufficient specificity and sensitivity to define the PCO should have at least one of the following: either 12 or more follicles measuring 2-9 mm in diameter, or increased ovarian volume (>10 cm3). If there is a follicle >10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area. The presence of a single PCO is sufficient to provide the diagnosis. The distribution of follicles and a description of the stroma are not required in the diagnosis. Increased stromal echogenicity and/or stromal volume are specific to PCO, but it has been shown that the measurement of ovarian volume (or area) is a good surrogate for quantification of the stroma in clinical practice. A woman having PCO in the absence of an ovulation disorder or hyperandrogenism ('asymptomatic PCO') should not be considered as having PCOS, until more is known about this situation. Three-dimensional and Doppler ultrasound studies may be useful research tools but are not required in the definition of PCO. This review outlines evidence for the current ultrasound definition of the polycystic ovary and technical specifications. [ABSTRACT FROM AUTHOR]

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 = − 0.186, P r = − 0.281, P r = − 0.108, P 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. [ABSTRACT FROM AUTHOR]