Functional hypothalamic amenorrhoea and polycystic ovarian morphology: a narrative review about an intriguing association.

BACKGROUND: Functional hypothalamic amenorrhoea (FHA) is responsible for 20-35% of all cases of secondary amenorrhoea and, thus, is the second most common cause of secondary amenorrhoea after polycystic ovary syndrome (PCOS). A high number of patients with FHA reveal polycystic ovarian morphology (PCOM) on ultrasound. The combination of amenorrhoea and PCOM can lead to confusion. First, amenorrhoeic women with PCOM fulfil the revised Rotterdam criteria and, thus, can easily be misdiagnosed with PCOS. Moreover, it has been claimed that some women with FHA and concomitant PCOM differ from those without PCOM in terms of endocrine regulation and metabolic traits. OBJECTIVE AND RATIONALE: The main focus of this article was on studies about FHA, which differentiated between patients with or without PCOM. The aim was to estimate the prevalence of PCOM and to look if it has an impact on pathophysiologic, diagnostic and therapeutic issues as well as on long-term consequences. SEARCH METHODS: Peer review original and review articles were selected from PubMed searches for this review. Searches were performed using the search terms 'polycystic AND functional hypothalamic amenorrhoea'. The reference lists of publications found were searched for relevant additional studies. The inclusion criteria for publications were: English language, patients' age ≥ 18 years, year of publication >1980, original studies, validated diagnosis of FHA, and validated diagnosis of PCOM using transvaginal ultrasound. OUTCOMES: The prevalence of PCOM in women with FHA varied from 41.9% to 46.7%, which is higher than in healthy non-PCOS controls. Hypothetically, the high prevalence might be due to a mixture of silent PCOM, as in the general population, and pre-existing PCOS. Several differences in metabolic and hormonal parameters were found between FHA-PCOM and FHA-non-PCOM patients. While oestrogen deficiency is common to both groups of patients, FHA-PCOM patients have a higher BMI, higher levels of anti-Müllerian hormone (AMH) and testosterone, a higher increase in LH in the course of a GnRH test, and lower sex hormone binding globulin (SHBG) levels than FHA-non-PCOM patients. The differential diagnosis between FHA-PCOM and PCOS, especially PCOS phenotype D (PCOM and oligo-/anovulation without hyperandrogenism), can be challenging. Several parameters have been suggested, which are helpful though not absolutely reliable. They include the typical causes for FHA (excessive exercise, energy deficit, and/or psychological stress), the serum levels of LH, testosterone, and SHBG, as well as the progestin challenge test. Whether FHA-PCOM has a different risk profile for long-term consequences concerning patients' metabolic and cardiovascular situation as well as their bone mass, is unclear. Concerning therapeutic aspects, there are only few data about FHA-PCOM compared to FHA-non-PCOM. To treat anovulation, the use of pulsatile GnRH treatment seems to be equally effective in both groups. Similar to FHA-non-PCOM patients, pulsatile GnRH therapy would be more efficient than exogenous gonadotropins in FHA-PCOM patients. WIDER IMPLICATIONS: Women with FHA-PCOM present a special sub-population of FHA patients. The diagnostic pitfall of FHA-PCOM should be emphasized in clinical guidelines about FHA and PCOS. The fact that almost half of the women with FHA have an ovarian follicle excess (i.e. PCOM) in face of low gonadotropin serum levels suggests that the intra-ovarian regulation of folliculogenesis is subject to individual variations, for unknown reasons, either genetic or epigenetic. Further studies are needed to investigate this hypothesis. REGISTRATION NUMBER: Not applicable.

Pulsatile gonadotropin-releasing hormone therapy: comparison of efficacy between functional hypothalamic amenorrhea and congenital hypogonadotropic hypogonadism.

OBJECTIVE: To compare the ongoing pregnancy rate per initiated cycle between patients with functional hypothalamic amenorrhea (FHA) and patients with congenital hypogonadotropic hypogonadism (CHH) treated with pulsatile gonadotropin-releasing hormone (GnRH) administration. DESIGN: Retrospective monocentric cohort study conducted at the University Hospital of Lille from 2004 to 2022. SETTING: Lille University Hospital, Department of Endocrine Gynecology. PATIENT(S): A total of 141 patients diagnosed with central suprapituitary amenorrhea during infertility evaluation and subsequently treated with pulsatile GnRH therapy. 111 and 30 patients were diagnosed with FHA or CHH, respectively. INTERVENTION(S): Pulsatile GnRH administration. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate per initiated cycle. RESULT(S): Ongoing pregnancy rates per initiated cycle were comparable between groups: 21.5% in the FHA group vs. 22% in the CHH group. Comparison of baseline characteristics showed a more pronounced follicle-stimulating hormone (FSH) deficiency in patients with CHH than in those with FHA: 2.55 (0.6-4.92) vs. 4.80 (3.90-5.70) UI/L. Within the CHH group, basal FSH level was positively associated with the occurrence of ongoing pregnancies (odds ratio, 1.57; 95% confidence interval, 1.11-2.22). In the CHH group, the duration of treatment was higher than in the FHA group: 23.59 (± 8.02) vs. 18.16 (± 7.66) days. CONCLUSION(S): The baseline FSH level is lower in patients with CHH than in patients with FHA. The lower the FSH, the lower the chance of pregnancy in patients with CHH. These patients also require more days of GnRH administration. However, the rate of ongoing pregnancies is comparable between the two groups.

Prevalence of functional hypothalamic amenorrhea in a cohort of women referred because of polycystic ovary syndrome.

In this unselected population of women referred to a center specialized in gynecologic endocrinology for suspicion of PCOS, a minimum rate of misdiagnosed FHA patients of about 2% was found. It is necessary to evaluate reliable markers for the differential diagnosis between PCOS and FHA to avoid incorrect treatment, which might lead to negative long-term effects in women with undiagnosed FHA.

The LH:FSH Ratio in Functional Hypothalamic Amenorrhea: An Observational Study.

BACKGROUND: In functional hypothalamic amenorrhea (FHA), luteinizing hormone and follicle-stimulating hormone levels show high interindividual variability, which significantly limits their diagnostic value in differentiating FHA from polycystic ovary syndrome (PCOS). Our aim was to profile the LH:FSH ratio in a large sample of patients with well-defined FHA. METHODS: This observational study included all consecutive patients with FHA presenting to the Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, between January 2017 and August 2023. The main parameters of interest were the LH level, the FSH level, and the LH:FSH ratio. In a subgroup analysis, we compared the LH:FSH ratio of patients with PCO morphology (PCOM) on ultrasound with that of patients without PCOM. RESULTS: A total of 135 patients were included. Only a minority of patients revealed FSH and LH levels ≤ 2.0 mIU/mL (13% and 39%, respectively). Most patients (81.5%) had an LH:FSH ratio ≤ 1.0, while a minority (2.2%) had a ratio ≥ 2.1. The LH:FSH ratio was similar in patients with and without PCOM. CONCLUSION: In a well-defined FHA sample, the LH:FSH ratio was ≤ 1 in most patients. The LH:FSH ratio may prove useful in distinguishing FHA from PCOS but needs further investigation.

d-Chiro-Inositol in Clinical Practice: A Perspective from the Experts Group on Inositol in Basic and Clinical Research (EGOI).

BACKGROUND: d-Chiro-inositol is a natural molecule that, in association with its well-studied isomer myo-inositol, may play a role in treating various metabolic and gynecological disorders. OBJECTIVES: This perspective seeks to explore the mechanisms and functions of d-chiro-inositol, laying the foundations to discuss its use in clinical practice, across dysmetabolism, obesity, and hormonal dysregulation. METHODS: A narrative review of all the relevant papers known to the authors was conducted. OUTCOME: d-Chiro-inositol acts through a variety of mechanisms, acting as an insulin sensitizer, inhibiting the transcription of aromatase, in addition to modulating white adipose tissue/brown adipose tissue transdifferentiation. These different modes of action have potential applications in a variety of therapeutic fields, including PCOS, dysmetabolism, obesity, hypoestrogenic/hyperandrogenic disorders, and bone health. CONCLUSIONS: d-Chiro-inositol mode of action has been studied in detail in recent years, resulting in a clear differentiation between d-chiro-inositol and its isomer myo-inositol. The insulin-sensitizing activities of d-chiro-inositol are well understood; however, its potential applications in other fields, in particular obesity and hyperestrogenic/hypoandrogenic disorders in men and women, represent promising avenues of research that require further clinical study.

Prolactin levels in functional hypothalamic amenorrhea: a retrospective case-control study.

PURPOSE: Functional hypothalamic amenorrhea (FHA) is due to hypothalamic dysregulation. Literature lacks data about prolactin in FHA women, although both prolactin levels and FHA are associated with stress. Moreover, polycystic ovarian morphology is common in FHA and there is an association between FHA and polycystic ovary syndrome. Thus, the aim of this study was to assess prolactin levels in FHA patients and controls with a special focus on factors influencing prolactin levels, that could be considered as "sensors" of the hypothalamic-pituitary dysregulation. METHODS: In a retrospective cohort study, 140 women with clearly defined FHA were compared to 70 healthy, normally ovulating women matched for age. The main outcome parameter was prolactin. Factors associated with prolactin levels > 12 µg/L were tested using a multivariable binary logistic regression model. RESULTS: The median prolactin level was 11.5 µg/L (interquartile range, IQR 7.5-14.4), which was similar to the control group (median 10.7, IQR 8.3-14.5; p = 0.065). Only two women had hyperprolactinemia (prolactin > 25 µg/L; 1.4%). In a multivariable binary logistic regression model eating disorder (odds ratio, OR 0.206; p = 0.040), excessive exercise (OR 0.280; p = 0.031) and TSH (OR 1.923; p = 0.020) were significantly associated with prolactin levels > 12 µg/L. CONCLUSION: Women with FHA have similar prolactin levels to healthy age-matched individuals. Eating disorders and excessive exercise where associated with prolactin levels < 12 µg/L, in contrast to TSH.

How to Choose the Optimal Starting Dose of Clomiphene Citrate (50 or 100 mg per Day) for a First Cycle of Ovulation Induction in Anovulatory PCOS Women?

RESEARCH QUESTION: Clomiphene citrate (CC) is one of the first-line treatments for ovulation induction in women with anovulatory polycystic ovary syndrome (PCOS). However, nearly 1 out of 2 women is resistant to 50 mg/day of CC. The objective of this study is to investigate the clinical, biological, and/or ultrasound factors that may predict the resistance to 50 mg/day of CC in the first cycle of treatment in women with anovulatory PCOS. This would make it possible to identify PCOS patients to whom the dose of 100 mg/day would be offered as of the first cycle. DESIGN: A retrospective and monocentric study was conducted on 283 women with anovulatory PCOS who required the use of ovulation induction with CC (903 cycles). RESULTS: During the first cycle of treatment, 104 patients (36.8%) were resistant to 50 mg/day of CC. Univariate regression analysis showed that patients who resisted 50 mg/day of CC had significantly higher BMI, waist circumference, serum levels of AMH, total testosterone, Δ4-androstenedione, 17-OHP, and insulin (p < 0.05), compared to patients ovulating with this dose. Serum levels of SHBG were significantly lower in patients resistant to 50 mg/day (p < 0.05). After multivariate analysis, only AMH and SHBG remained statistically significant (p = 0.01 and p = 0.001, respectively). However, areas under the ROC curves were weak (0.59 and 0.68, respectively). CONCLUSION: AMH and SHBG are the only two parameters significantly associated with the risk of resistance to 50 mg/day of CC. However, no satisfactory thresholds have been established to predict resistance to 50 mg CC.

Using serum anti-Müllerian hormone levels to predict the chance of live birth after spontaneous or assisted conception: a systematic review and meta-analysis.

STUDY QUESTION: Is serum anti-Müllerian hormone (AMH) level predictive of cumulative live birth (CLB) rate after ART or in women trying to conceive naturally? SUMMARY ANSWER: Serum AMH level is linked to CLB after IVF/ICSI but data are lacking after IUI or in women trying to conceive without ART. WHAT IS KNOWN ALREADY: Serum AMH level is a marker of ovarian reserve and a good predictor of ovarian response after controlled ovarian stimulation. It is unclear whether AMH measurement can predict CLB in spontaneous or assisted conception. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis was undertaken to assess whether serum AMH level may predict chances of CLB in infertile women undergoing IVF/ICSI or IUI and/or chances of live birth in women having conceived naturally. PARTICIPANTS/MATERIALS, SETTING, METHODS: A systematic review and meta-analysis was performed using the following keywords: 'AMH', 'anti-mullerian hormone', 'live-birth', 'cumulative live birth'. Searches were conducted from January 2004 to April 2021 on PubMed and Embase. Two independent reviewers carried out study selection, quality, and risk of bias assessment as well as data extraction. Odds ratios were estimated using a random-effect model. Pre-specified sensitivity analyses and subgroup analyses were performed. The primary outcome was CLB. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 32 studies were included in the meta-analysis. Overall, 27 articles were included in the meta-analysis of the relation between AMH and CLB or AMH and LB after IVF/ICSI. A non-linear positive relation was found in both cases. A polynomial fraction was the best model to describe it but no discriminant AMH threshold was shown, especially no serum AMH level threshold below which live birth could not be achieved after IVF/ICSI. After IVF-ICSI, only four studies reported CLB rate according to AMH level. No statistically significant differences in mean serum AMH levels were shown between patients with and without CLB, but with a high heterogeneity. After exclusion of two studies with high risks of bias, there was no more heterogeneity [I2 = 0%] and the mean AMH level was statistically significantly higher in women with CLB. There were not enough articles/data to assess the ability of AMH to predict CLB rate or find an AMH threshold after IUI or in women without history of infertility trying to conceive without ART. LIMITATIONS, REASONS FOR CAUTION: The systematic review and meta-analysis had some limitations owing to the limits and bias of the studies included. In the present meta-analysis, heterogeneity may have been caused by different baseline characteristics in study participants, different stimulating protocols for ART, different serum AMH level thresholds used and the use of various assays for serum AMH. This could explain, in part, the absence of a discriminating AMH threshold found in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Serum AMH level is linked to CLB rate after IVF/ICSI but no discriminating threshold can be established, therefore low serum AMH level should not be used as the sole criterion for rejecting IVF treatment, especially in young patients. Data are lacking concerning its predictive value after IUI or in women trying to conceive without ART. Our findings may be helpful to counsel candidate couples to IVF-ICSI. STUDY FUNDING/COMPETING INTERESTS: No external funding was obtained for this study. There are no conflicts of interest. REGISTRATION NUMBER: PROSPERO CRD42021269332.

Outcome of Gastric Bypass Surgery on Patients with Polycystic Ovary Syndrome: A Review.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is associated with obesity. The most effective method to achieve and maintain long-term weight loss is by the Roux-en-Y gastric bypass (RYGB). In this review, an overview about metabolic and PCOS-specific outcomes after RYGB in obese PCOS women is provided. The RYGB leads to an adequate excess weight loss and reduction in BMI in this patient population. Testosterone levels decline significantly at 6- and 12-months follow-up, as does the incidence of hirsutism and cycle irregularities. Data about fertility are scarce in this patient population. In conclusion, RYGB surgery seems to be an efficient treatment option for obese PCOS patients and leads to weight loss and improvements in metabolic parameters as well as in an improvement of PCOS-specific characteristics. However, larger prospective studies are warranted, which include all PCOS-specific outcome data in one patient population at the same time.

A case-control study about markers of stress in normal-/overweight women with polycystic ovary syndrome and in controls.

Background: Polycystic 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. Methods: In 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. Results: After 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). Conclusion: Stress 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.

Stress and polycystic ovarian morphology in functional hypothalamic amenorrhea: a retrospective cohort study.

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.

Serum LH levels are associated to serum insulin and Anti-Müllerian hormone levels in women with both functional hypothalamic amenorrhoea and polycystic ovarian morphology.

OBJECTIVE: The aim of the study was to investigate whether serum Luteinizing Hormone (LH) levels in women with Functional Hypothalamic Amenorrhoea (FHA) and Polycystic Ovarian Morphology (PCOM) are still associated to Body Mass Index (BMI) and/or serum insulin and/or Anti-Müllerian Hormone (AMH) levels using a larger population of FHA. DESIGN: Retrospective observational study (2006-2020). PARTICIPANTS: Data from 62 FHA patients were used for this study using strict criteria to define them. MEASUREMENTS: Serum LH, FSH, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulphate (DHEA-S), androstenedione, total testosterone, prolactin, Sex Hormone Binding Globulin (SHBG) and AMH levels were measured by immunoassay. To homogenize the AMH values, we converted those obtained after 2015. We defined PCOM with strict criteria: a follicle number per ovary (FNPO) ≥12 or ≥20 per ovary, depending on the date on which the assessment was carried out and the ultrasound device. RESULTS: Forty-two percentage of our FHA population had PCOM. The PCOM+ group had significantly higher ranks of BMI (p = .024) and serum AMH levels (p = .0001) and significantly lower ranks of serum FSH levels (p = .002). LH was positively correlated with fasting insulin (p = .011) and with AMH (p = .035) in the PCOM+ group only but not with BMI. There was a positive correlation between LH and FSH in both groups. CONCLUSION: Our study suggests that GnRH insufficiency in women with PCOM unravels some mechanisms of LH regulation that are poorly documented in the literature and may involve a direct pituitary effect, as suggested by our results with serum insulin and AMH levels.

Hypothalamic neuroglial plasticity is regulated by anti-Müllerian hormone and disrupted in polycystic ovary syndrome.

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).

Basal and dynamic relationships between serum anti-Müllerian hormone and gonadotropins in patients with functional hypothalamic amenorrhea, with or without polycystic ovarian morphology.

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 < 0.05). FHA patients revealed PCOM in 27/64 cases (42.2%). FHA patients without PCOM revealed lower anti-Müllerian hormone (AMH) levels than controls (median 2.03 ng/mL, IQR 1.40-2.50, versus 3.08 ng/mL, IQR 2.24-4.10, respectively, p < 0.001). Comparing FHA patients with and without PCOM, the latter revealed lower AMH levels, a lower median LH increase after the GnRH stimulation test (240.0%, IQR 186.4-370.0, versus 604.9%, IQR 360.0-1122.0; p < 0.001) as well as, contrary to patients with PCOM, a significant increase in AMH after three months of successful pulsatile GnRH treatment (median 1.69 ng/mL at baseline versus 2.02 ng/mL after three months of treatment; 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.

Polycystic Ovary Syndrome Phenotype D Versus Functional Hypothalamic Amenorrhea With Polycystic Ovarian Morphology: A Retrospective Study About a Frequent Differential Diagnosis.

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 <37.5 pg/mL (84.5%, 95% confidence interval, CI: 72.6-92.6), whereas a LH : FSH ratio <0.96 had the highest specificity (94.8, 95% CI: 85.6-98.9). A linear discriminant analysis including testosterone, SHBG and LH was able to correctly classify 87.9% of FHA-PCOM patients (bootstrap 95% CI: 80.2 - 94.0%). In conclusion, this model including serological parameters could be an easy and reliable tool to distinguish between FHA-PCOM and PCOS-D patients, especially in situations where the clinical profile is not obvious.

Comparison of two endometrial preparation methods for frozen-thawed embryo transfer in anovulatory PCOS patients: Impact on miscarriage rate.

OBJECTIVE: Some studies have suggested that patients with polycystic ovary syndrome (PCOS) are at high risk of miscarriage. However, this still remains controversial. Several potential factors might explain this association: obesity, hyperinsulinemia and hyperandrogenism. Artificial and stimulated cycles appear to be comparable for endometrial preparation in frozen-thawed embryo transfer (FET) in PCOS patients. Only a few studies have assessed miscarriage rates specifically in PCOS. We have evaluated the impact of endometrial preparation on FET outcomes in anovulatory PCOS patients. METHODS: A retrospective cohort study was conducted at the Lille University Hospital, including 255 FET cycles in 134 PCOS patients between January 2011 and December 2017. PCOS was defined by the presence of at least two of the three Rotterdam's criteria. Patients were under 35 years old. Two endometrial preparation protocol were studied: stimulated cycle (gonadotropins on the second day of the cycle and luteal phase support including natural progesterone 600 mg/day) and artificial cycle (6 mg oral estradiol valerate and 800 mg micronized vaginal progesterone daily). RESULTS: 137 FET were performed under stimulated cycle and 118 FET under artificial cycle. Early pregnancy rates (30% versus 37.3%, p = NS), miscarriage rates (22% versus 25%, p = NS) and live birth rates (23.4% versus 26.3%, p = NS) were similar. CONCLUSIONS: In anovulatory PCOS women, the type of endometrial preparation does not influence FET outcomes, specifically regarding the miscarriage rate.

Polycystic ovary syndrome phenotype does not have impact on oocyte morphology.

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.

Inositols: From Established Knowledge to Novel Approaches.

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.