Stratification of the risk of ovarian dysfunction by studying the complexity of intermediate and premutation alleles of the FMR1 gene.

FMR1 premutation female carriers are at risk of developing premature/primary ovarian insufficiency (POI) with an incomplete penetrance. In this study, we determined the CGG repeat size among 1095 women with diminished ovarian reserve (DOR) / POI and characterized the CGG/AGG substructure in 44 women carrying an abnormal FMR1 repeat expansion number, compared to a group of 25 pregnant women carrying an abnormal FMR1 CGG repeat size. Allelic complexity scores of the FMR1 gene were calculated and compared between the two groups. In the DOR/POI cohort, 2.1% of women presented with an intermediate repeat size and 1.9% with a premutation. Our results suggest that the risk of POI is highest in the mid-range of CGG repeats. We observed that the allelic score is significantly higher in POI women compared to the pregnant women group (p-value = 0.02). We suggest that a high allelic score due to more than 2 AGG interspersions in the context of an intermediate number of repetitions could favor POI. Larger studies are still needed to evaluate the relevance of this new tool for the determination of the individual risk of developing POI in women with abnormal number of CGG repeats.

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.

Revisiting the serum level of anti-Müllerian hormone in patients with functional hypothalamic anovulation.

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 < 0.0001, <0.002 and <0.05, respectively). The positive correlation between AMH and LH was significant in the controls but not in the FHA group. However, in the FHA PCOM+, there was a strong positive correlation between BMI and LH. 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.

Anti-Müllerian hormone as a driving force of polycystic ovary syndrome, independently from insulin resistance.

RESEARCH QUESTION: Which clinical features, along with biological features, ultrasound features, or both, are the most strongly associated with either high or low anti-Müllerian 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 < 0.0001), whereas body mass index had less, although significant, effect (R2 = 0.075, P < 0.0001). In control women, discriminant analysis yielded a significant discriminant model, including only FNPO and age (R2 at 0.62 and 0.27, both P < 0.0001). 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.

Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.

STUDY QUESTION: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER: PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility. WHAT IS KNOWN ALREADY: PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD. STUDY DESIGN, SIZE, DURATION: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients. MAIN RESULTS AND THE ROLE OF CHANCE: All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies. LIMITATIONS, REASONS FOR CAUTION: The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD. WIDER IMPLICATIONS OF THE FINDINGS: The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Views of French oocyte donors at least 3 years after donation.

RESEARCH QUESTION: The study aimed to evaluate the percentage of oocyte donors who regretted their donation at least 3 years later. DESIGN: Between December 2018 and January 2019, this single-centre study sought to contact by telephone all women who had donated oocytes during the 6-year period from 2010 to 2015 at the Lille Centre for the study and storage of eggs and spermatozoa (CECOS). RESULTS: Among 118 women, 72 responded to the questionnaire by telephone and were included in the study. The response rate was 61%. No woman regretted having donated an oocyte, and 89% said that they would do it again in the same situation. The survey distinguished two types of donors: 'relational' (58%) and 'altruistic' (42%); some of their responses differed. Ninety per cent of the women had talked about the donation to family and friends. Among them, 74% felt supported by their family and friends, and 72% by their partner. The donation was something that 76% of the women sometimes thought about; 83% felt that this donation was something useful that they had accomplished. Finally, most donors felt that oocyte donation should remain unremunerated and anonymous. CONCLUSIONS: None of the donors we interviewed regretted their donation. In France, the current principles governing this donation appear satisfactory to oocyte donors.

The proportion of cleaved anti-Müllerian hormone is higher in serum but not follicular fluid of obese women independently of polycystic ovary syndrome.

RESEARCH QUESTION: Does the relative distribution of anti-Müllerian hormone (AMH) isoforms differ between patients depending on their body mass index (BMI) and polycystic ovary syndrome (PCOS) status in serum and follicular fluid? DESIGN: Obese and normal weight patients (PCOS [n = 70]; non-PCOS [n = 37]) were selected for this case-control study in the serum. Between 2018 and 2019, obese (n = 19) and normal weight (n = 20) women with or without PCOS who were receiving IVF treatment were included in the follicular fluid study. The bio-banked serums and follicular fluid were tested for total AMH (proAMH and AMHN,C combined) and proAMH using an automatic analyzer. The AMH prohormone index (API = [proAMH]/[total AMH]x 100) was calculated as an inverse marker of conversion of proAMH to AMHN,C, with only the latter isoform that could bind to the AMH receptor complex. RESULTS: The API was not significantly different between controls and women with PCOS, whereas obese women had a lower API compared with their normal weight counterparts. Grouping PCOS and controls, a lower API was found in obese versus normal weight women, suggesting a greater conversion of proAMH to AMHN,C. The API in the serum was significantly correlated with metabolic parameters. In the follicular fluid, API is not different between obese and normal weight women independently of PCOS and is higher than in the concomitant serum. CONCLUSIONS: The proportion of inactive form of AMH in the serum is higher in normal weight versus obese women but not in the follicular fluid, independently of PCOS. The conversion of proAMH into the cleaved isoform is likely to occur in extra-ovarian tissues and to exacerbate in obese individuals.

In cases of familial primary ovarian insufficiency and disorders of gonadal development, consider NR5A1/SF-1 sequence variants.

RESEARCH QUESTION: Primary ovarian insufficiency (POI) is defined as the early exhaustion of ovarian function, before the age of 40 years. Its origin is genetic in 20-25% of cases. In rare cases, sequence variants of the NR5A1/SF-1 gene may result in POI, or in various disorders of gonadal development (DGD) or adrenal insufficiency. DESIGN: This study describes the cases of two families in which the association of DGD and POI enabled a diagnosis of NR5A1 deleterious variations. Their clinical, hormonal, ultrasound and genetic characteristics are reported. RESULTS: The mothers of the affected children were 21 and 29 years when POI was diagnosed. Each nonetheless had two spontaneous pregnancies. The children have different phenotypes and different forms of DGD. None of the affected family members had adrenal insufficiency. A new sequence variant of the NR5A1 gene was identified in one family: p.Cys283Phe (c.848G>T), and the NR5A1 sequence variant c.86G>C was found in the other family. CONCLUSION: Sequence variation of the NR5A1 gene is a possibility that must be considered when a woman with POI or a diminished ovarian reserve has a family member or child with DGD. If a variant is identified, genetic counselling is essential for the patient and his/her family.

Weekly intramuscular progesterone for luteal phase support in women receiving oocyte donation is associated with a decreased miscarriage rate.

RESEARCH QUESTION: To determine whether adding intramuscular to vaginal administration of progesterone reduces miscarriage rates compared with those of vaginal administration alone for luteal phase support in women receiving oocyte donation and to determine the best time to introduce intramuscular progesterone. DESIGN: Retrospective analysis of miscarriage rates in women receiving oocyte donation. Recipients underwent endometrial preparation by hormone replacement treatment. Vaginal progesterone alone or associated with intramuscular progesterone was used for luteal support. RESULTS: This study analysed 186 oocyte donation cycles from January 2016 to May 2018 with embryo transfer on Day 2 or 3 and vaginal progesterone administration: 106 embryo transfer cycles with vaginal progesterone alone, 29 with weekly intramuscular progesterone added once the human chorionic gonadotrophin (HCG) assay was positive, and 51 with weekly intramuscular progesterone added the evening of embryo transfer. The rates of positive HCG assays, biochemical pregnancies and clinical pregnancies did not differ between the treatment groups. The miscarriage rate was significantly lower when intramuscular progesterone began the evening of embryo transfer than with vaginal administration alone (16.7% versus 47.0%, respectively; P = 0.049 after Bonferroni correction). The live birth rate was higher when intramuscular progesterone began the evening of embryo transfer than with vaginal administration alone (37.3% versus 16.0%, respectively; P = 0.009 after Bonferroni correction). CONCLUSIONS: Adding intramuscular to vaginal progesterone administration appears to decrease the miscarriage rate and increase the live birth rate in oocyte donations. The initiation of intramuscular progesterone is most beneficial when it is introduced the evening of embryo transfer.

Use of the serum anti-Müllerian hormone assay as a surrogate for polycystic ovarian morphology: impact on diagnosis and phenotypic classification of polycystic ovary syndrome.

STUDY QUESTION: Does the use of the serum anti-Müllerian 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.

Anti-Müllerian hormone concentrations and parity in fertile women: the model of oocyte donors.

In France until the end of 2015, oocyte donors must have had at least one child and be aged 18-37 years. This population of fertile women was selected to examine whether serum anti-Müllerian hormone (AMH) concentration could be a reliable correlate of spontaneous pregnancy in women who had proven their fertility before. A cohort of 217 women followed between 2009 and 2015 for oocyte donation at the University Hospital of Lille comprised this retrospective study. In these egg donors, aged 20-37 (median: 32 years), the median serum AMH level was 22 pmol/l (5-95th percentiles: 4.9-61.8). No significant correlation was found between serum AMH level and the number of children or the youngest child's age. Among the 32 women with AMH <10 pmol/l, 9 and 3 were less than 30 and 25 years old, respectively. Six women (2.8%) had undetectable serum AMH, i.e. <3 pmol/l. In conclusion, serum AMH level measured in this fertile female cohort showed too much variability to be a good fertility index. Assessment of serum AMH should only be discussed for patients at risk of ovarian failure.

Obstetrical and perinatal complications of twin pregnancies: is there a link with the type of infertility treatment?

INTRODUCTION: The aim of this study was to compare the maternal and perinatal data from spontaneous twin pregnancies with twin pregnancies conceived via assisted reproductive technology, and to evaluate the outcomes depending on the type of treatment. MATERIAL AND METHODS: A historical cohort of all twin live births between 1997 and 2014 was used to create two groups: spontaneous pregnancies and pregnancies after infertility treatment (ovulation induction, intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection). The population characteristics and pregnancy, childbirth, and neonatal complications were compared, and the data were adjusted for age, parity, chorionicity, and the mother's body mass index to assess only the impact of the infertility treatments. RESULTS: In total, 1580 twin pregnancies were included, with 575 requiring assisted conception. We did not observe any differences between the assisted conception pregnancies and the spontaneous twin pregnancies with regard to the obstetric and childbirth complications and neonatal outcomes. In addition, there were no statistically significant differences between the types of infertility treatment. CONCLUSION: After adjusting for the maternal parameters and chorionicity, the twin pregnancies conceived via assisted reproductive technology were not at an increased risk of obstetric and neonatal complications. Moreover, the type of treatment did not alter the obstetric and neonatal complications. Therefore, the higher complication rate was related to the patient's medical specifics, rather than to the infertility treatment.

Anti-Müllerian hormone serum level and other markers associated with pregnancy outcome in oocyte donation.

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.

Does polycystic ovarian morphology influence the response to treatment with pulsatile GnRH in functional hypothalamic amenorrhea?

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.

Comparison between pulsatile GnRH therapy and gonadotropins for ovulation induction in women with both functional hypothalamic amenorrhea and polycystic ovarian morphology.

CONTEXT: 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. OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Is the suppressive effect of cyproterone acetate on serum anti-Müllerian-hormone levels in women with polycystic ovary syndrome stronger than under oral contraceptive pill?

OBJECTIVE: 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. METHODS: 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. RESULT(S): 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). CONCLUSION(S): 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.

Role of Anti-Müllerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review.

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.

[Impact of donor parity on oocyte donation outcomes]. / Impact de la parité des donneuses sur les résultats du don d'ovocytes.

OBJECTIVES: Since 2015, in France, men and women who have never procreated are allowed to donate their gametes. This has led to an increase in the number of female oocyte donors, whereas there are many couples waiting for gametes that have a long waiting time. The aim of this study is to compare the results of donation with oocytes from nulliparous and non-nulliparous donors. METHODS: Monocentric retrospective observational study (Lille University Hospital) between January 1st, 2016 and December 31st, 2019. Phenotypic characteristics and clinical and biological outcomes of oocytes donations were compared according to donor parity (nulliparous versus primiparous or multiparous). RESULTS: One hundred and eighty-five donors (66 nulliparous and 119 non-nulliparous) were included in the study, allowing 284 ICSI cycles to be performed in recipient couples. On average, 11.5 oocytes were obtained per donation cycle, of which 7.8 were mature. In total, 4.6 mature oocytes were obtained per attempt and per recipient couple. Nulliparous donors are younger than non-nulliparous ones. An early pregnancy was obtained in 55.6% of the nulliparous donors and in 50.8% of the non-nulliparous donors (P=0.55). A progressive pregnancy was obtained in 49.2% of the nulliparous women and in 42.1% of the non-nulliparous women (P=0.36). There was therefore no difference in terms of early pregnancy and ongoing pregnancy whether the donation came from a nulliparous or non-nulliparous woman. CONCLUSION: Donor parity does not seem to have an impact on the success of oocyte donation attempts.

Is it useful to measure DHEAS levels in PCOS?

INTRODUCTION: A high prevalence of increased DHEAS (dehydroepiandrosterone sulfate) levels (about a third of cases) has been reported in women with polycystic ovary syndrome (PCOS). This excess of adrenal androgens remains a mystery in this ovarian pathology. It is well known that DHEAS production correlates negatively with age, and study populations of women with PCOS are generally young. To avoid this bias, a study was carried out on a large population of women with PCOS and control women, using normal DHEAS values for each age group, to better assess prevalence and better understand the link between PCOS and DHEAS. METHODS: A retrospective cross-sectional study was conducted at the Lille University Hospital. A total of 1223 patients with PCOS according to the Rotterdam criteria and 517 control women were included. DHEAS elevation was diagnosed according to the standards of the Lille University Hospital Institute of Biochemistry and Molecular Biology, based on patient age. The prevalence of increased serum DHEAS levels was calculated in each population and according to PCOS phenotype. Correlations were assessed between serum DHEAS levels and clinical, hormonal, and metabolic markers, with adjustment for age. RESULTS: Prevalence of increased DHEAS was significantly higher in the PCOS group than in the control group (8.1 vs. 4.3%; OR=1.98 (95%CI: 1.23-3.19), P=0.005, and OR=1.07 (95%CI: 1.05-1.09), P=0.014 without and with adjustment for BMI respectively), and in phenotypes A and C than in controls (OR=2.88 (95%CI: 1.76 to 4.72), P<0.001 and OR=2.81 (95%CI: 1.39 to 5.67), P=0.004 respectively), but not in phenotype D. A correlation was found between DHEAS level and total testosteronemia (r=0.34, P<0.001), androstenedione (r=0.24, P<0.001), 17 hydroxyprogesteronemia (r=0.22, P<0.001) and age (r=0.25, P<0.001). No correlations were found with AMH, LH or FSH, and a very weak positive correlation was found with BMI (r=0.15; P<0.001). CONCLUSION: Using age-dependent norms, DHEAS elevation was found in only 8.1% of women with PCOS (11% in the case of phenotypes A and C) versus 4.3% in controls and women with phenotype D. DHEAS levels correlated only with other androgens, and not (or only minimally) with other ovarian, pituitary or metabolic markers. DHEAS assay therefore appears to be of no interest for positive diagnosis or understanding of the pathophysiology of PCOS, except in case of very high testosterone levels.

Loss of LH-induced down-regulation of anti-Müllerian hormone receptor expression may contribute to anovulation in women with polycystic ovary syndrome.

STUDY QUESTION: Are anti-Müllerian hormone (AMH) and AMH type II receptor (AMHR-II) mRNAs similarly regulated by gonadotrophins in lutein granulosa cells (GCs) from control, normo-ovulatory and oligo/anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: AMH mRNA expression was induced by LH only in lutein GC of oligo/anovulatory PCOS women; down-regulation of AMHR-II, induced by LH in control and normo-ovulatory PCOS women, was absent in oligo/anovulatory women. WHAT IS KNOWN ALREADY: It was suggested that AMH could be responsible for the blockade of follicles at the small antral stage in PCOS women. In keeping with this hypothesis, both AMH and AMHR-II are overexpressed in lutein GCs from oligo/anovulatory PCOS women. STUDY DESIGN, SIZE, DURATION: Women undergoing IVF were included in this prospective study, either in the control group (30 women) or in the PCOS group (21 normo-ovulatory and 19 oligo/anovulatory patients) between January 2010 and July 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human lutein GCs were isolated from follicular fluid during IVF protocols. Twenty-four hours after seeding, lutein GCs from each woman were serum starved and cultured for 48 h ± FSH, LH or cAMP. Then AMH and AMHR-II mRNAs were quantified by quantitative RT-PCR and AMH protein concentration was measured in the culture medium by ELISA. Experimental results were analyzed, within each group of women, by the non-parametric Wilcoxon test for paired comparisons between cells cultured in control medium and FSH, LH or cAMP treated cells. Clinical comparisons between the three groups of women were performed on log values using the ANOVA test with Bonferroni correction. MAIN RESULTS AND THE ROLE OF CHANCE: FSH up-regulated both AMH expression and secretion by lutein GCs from the three groups of women (P < 0.05). LH had no effect on AMH mRNAs levels in lutein GCs from controls and normo-ovulatory PCOS women, but increased AMH expression in oligo/anovulatory PCOS women (P < 0.05). Interestingly, LH and cAMP treatments reduced AMHR-II expression by lutein GCs from controls and normo-ovulatory PCOS women (P < 0.05), but had no effect on AMHR-II mRNA levels in oligo/anovulatory PCOS women. LIMITATIONS, REASONS FOR CAUTION: The lutein GCs are not the best model to study AMH and AMHR-II regulation by gonadotrophins. Indeed, AMH and AMHR-II are down-regulated in luteinized cells. Furthermore, these cells have been exposed to non-physiological levels of gonadotrophins and hCG. However, AMH and AMHR-II mRNAs are quantifiable by real-time RT-PCR, and the cells are still responsive to FSH and LH. The age of patients is significantly different between control and oligo/anovulatory PCOS women: this may be a bias in the interpretation of results but older women in the control group had a good ovarian reserve. WIDER IMPLICATIONS OF THE FINDINGS: The overexpression of AMH and AMHR-II in oligo/anovulatory PCOS women could be due to increased LH levels and/or inhibition of its repressive action. The fact that this dysregulation is observed in oligo/anovulatory, but not in normo-ovulatory, PCOS women emphasizes the role of LH in the follicular arrest of PCOS women and suggests that this involves the AMH/AMHR-II system. STUDY FUNDING/COMPETING INTEREST(S): The Assistance-Publique Hôpitaux de Paris provided a Contrat d'Interface and the Agence de Biomédecine provided a grant to Nathalie di Clemente. Schering-Plough provided an FARO grant to Alice Pierre. The authors have nothing to disclose.