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.

Necrozoospermia: The tree that hides the forest.

BACKGROUND: Necrozoospermia is a condition found in 0.2%-0.4% of male infertility cases. The causes of necrozoospermia are multiple: they can be related to testicular and/or post-testicular damage. Additionally, these causes most often involve the production of reactive oxygen species (ROS) and/or sperm DNA fragmentation (SDF) which can reduce the chances of spontaneous pregnancy or affect the outcome of assisted reproductive technologies. OBJECTIVE: To focus on potential etiologies of necrozoospermia, its diagnosis and its therapeutic management especially before the employment of ICSI. METHODS: Authors searched PubMed/Medline, Web of Science, Cochrane Library, Google and Institutional websites for medical subheading terms and free text words referred to "necrozoospermia", "sperm vitality", "sperm viability", SDF and "ICSI". RESULTS: We identified 12 main etiologies of necrozoospermia responsible for either a decrease of sperm vitality, a mild, a moderate or a severe necrozoospermia. In case of a confirmed decreased vitality, a thorough check-up should be conducted and if available, etiological treatment should be proposed. Therapeutic management could also include repeated ejaculations, drug treatments, the use of ICSI with ejaculated or surgically extracted spermatozoa in case of a non-treatable necrozoospermia. DISCUSSION AND CONCLUSION: The potential causes of necrozoospermia should be investigated because many of them could be corrected, thus avoiding the use of ICSI. Moreover, if ICSI procedure remains necessary, the therapeutic management of necrozoospermia could also improve the chances of success by reducing oxidative stress and/or SDF.

Landscape composition drives the impacts of artificial light at night on insectivorous bats.

Among the most prevalent sources of biodiversity declines, Artificial Light At Night (ALAN) is an emerging threat to global biodiversity. Much knowledge has already been gained to reduce impacts. However, the spatial variation of ALAN effects on biodiversity in interaction with landscape composition remains little studied, though it is of the utmost importance to identify lightscapes most in need of action. Several studies have shown that, at local scale, tree cover can intensify positive or negative effects of ALAN on biodiversity, but none have - at landscape scale - studied a wider range of landscape compositions around lit sites. We hypothesized that the magnitude of ALAN effects will depend on landscape composition and species' tolerance to light. Taking the case of insectivorous bats because of their varying sensitivity to ALAN, we investigated the species-specific activity response to ALAN. Bat activity was recorded along a gradient of light radiance. We ensured a large variability in landscape composition around 253 sampling sites. Among the 13 bat taxa studied, radiance decreased the activity of two groups of the slow-flying gleaner guild (Myotis and Plecotus spp.) and one species of the aerial-hawking guild (Pipistrellus pipistrellus), and increased the activity of two species of the aerial-hawking guild (Pipistrellus kuhlii and Pipistrellus pygmaeus). Among these five effects, the magnitude of four of them was driven by landscape composition. For five other species, ALAN effects were only detectable in particular landscape compositions, making the main effect of radiance undetectable without account for interactions with landscape. Specifically, effects were strongest in non-urban habitats, for both guilds. Results highlight the importance to prioritize ALAN reduction efforts in non-urban habitats, and how important is to account for landscape composition when studying ALAN effects on bats to avoid missing effects.

Role of Anti-Müllerian Hormone in the Pathogenesis of Polycystic Ovary Syndrome.

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.

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.

Serum FSH level is lower in dysovulating than in ovulating non-PCOS obese women, independently of body mass index.

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

Bilateral versus unilateral cryptorchidism in nonobstructive azoospermia: Testicular sperm extraction outcomes.

Cryptorchidism is one of the most frequent causes of nonobstructive azoospermia (NOA) in adulthood. Although it is well known that spermatogenesis is more impaired in bilateral than in unilateral cryptorchidism, previous studies have only described small cohorts or inhomogeneous population. Consequently, we analyzed a cohort of 225 men with only a history of cryptorchidism as sole etiopathogenetic factor for NOA, and compared testicular sperm extraction (TESE) outcomes between men with bilateral versus unilateral cryptorchidism. Our results show no difference in follicle-stimulating hormone (FSH) levels and testicular volumes between men with a history of bilateral cryptorchidism compared to unilateral cryptorchidism (median: 21.3 IU l-1 vs 19.3 IU l-1, P = 0.306; and 7.2 ml vs 7.9 ml, P = 0.543, respectively). In addition, sperm retrieval rates were similar (66.2% vs 60.0%, P = 0.353). Using multivariate analysis, we have found that only a low inhibin B level (above the assay's detection limit) was positively associated with successful sperm retrieval (P < 0.05). Regarding intracytoplasmic sperm injection outcomes, we found that cumulative pregnancy rate and live birth rate per cycle were not statistically different between the two groups (17.4% vs 27.8%, P = 0.070; and 16.1% vs 26.4%, P = 0.067, respectively). Unexpectedly, there was no significant difference in hormonal profiles (FSH, luteinizing hormone [LH], testosterone, and inhibin B levels) and TESE outcomes between unilateral versus bilateral cryptorchidism. This suggests that a history of unilateral cryptorchidism could reflect a bilateral testicular impairment. Interestingly, inhibin B level might be a predictor of successful TESE.

Anti-müllerian hormone in the pathophysiology and diagnosis of polycystic ovarian syndrome.

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

Effect of obesity and its related metabolic factors on serum anti-Müllerian hormone concentrations in women with and without polycystic ovaries.

The relationship between serum anti-Müllerian hormone (AMH) levels, body mass index (BMI) and related metabolic factors were investigated in women with polycystic ovary syndrome (PCOS). A total of 691 women aged between 18 and 35 years, referred to the Department of Gynaecological Endocrinology at the University Hospital of Lille between 2009 and 2014 were included: 137 controls and 554 women with PCOS. Mean serum AMH levels were slightly but significantly lower in women with PCOS who were overweight or obese (BMI ≥25) compared with women of normal weight (BMI <25) (P < 0.05). No such difference was found in the control group. After bivariate analysis, no significant correlation was found between BMI and AMH in controls. In the PCOS group, this relationship was significant (P = 0.0001) but weak (r = -0.177). Stepwise multiple regression analysis yielded a significant model, including five variables (follicle count, serum androstenedione, BMI, serum LH and FSH) explaining 38.6%, 3.4%, 1.4%, 0.7% and 1.4% of the total serum AMH variance, respectively. No effect of metabolic status was found on serum AMH levels in controls, but a significant, albeit weak, negative independent correlation was found between AMH and BMI in women with PCOS.

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.

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.

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.

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.

Pregnancy outcomes among women with Marfan syndrome.

OBJECTIVE: To determine cardiac and obstetric outcomes among women with Marfan syndrome (MS) whose pregnancies were managed in accordance with the French national guidelines. METHODS: A descriptive analysis was conducted for a prospective cohort of 18 women with MS who gave birth in the maternity unit of Bichat-Claude Bernard Hospital, Paris, France, between January 1, 1998, and May 31, 2011. The study hospital was the national referral center for MS and related diseases. RESULTS: A total of 22 pregnancies were recorded among the study cohort. Of these, 21 were managed according to the national guidelines. One woman who was referred to the study hospital during late pregnancy was not managed according to the national guidelines; this patient experienced aortic dissection at 37 weeks. In the cohort, aortic diameter did not increase significantly during pregnancy. Vascular fetal growth restriction was observed in 7 (31.8 %) of the pregnancies. Cesarean delivery was planned for 17 (77.3%) of the pregnancies. CONCLUSION: Risk of aortic dissection was low among a cohort of pregnant women with MS who were managed according to the French national guidelines.