Ovarian reserve in patients with FMR1 gene premutation and the role of fertility preservation.

INTRODUCTION: Women with premutation (PM) of the FMR1 gene may suffer from reduced ovarian reserve or even premature ovarian insufficiency (POI). We studied hormonal and ultrasound ovarian reserve, fertility and fertility preservation outcomes in these patients. PATIENTS AND METHOD: Retrospective cohort study of 63 female FMR1 premutation carriers. RESULTS: Sixty-three female patients bearing an FMR1 premutation were included. Median age was 30 years [26.5-35]. Median number of CGG triplets was 83 [77.2-92]. Before diagnosis of PM, 19 women (30%) had had in all 35 pregnancies, resulting in 20 births, including 7 affected children. After diagnosis of PM, 17 women (26.1%) had in all 23 pregnancies, at a median age of 34.5 years [32.2-36.0]: 2 after preimplantation genetic diagnosis, 3 after oocyte donation, 18 spontaneously, and 5 ending in medical termination for Fragile X syndrome. Thirty-three patients (52.4%) had POI diagnosis (median age, 30 years [27-34]) with median FSH level 84 IU/L [50.5-110] and median AMH level 0.08 ng/ml [0.01-0.19]. After POI diagnosis, 8 women had in all 9 pregnancies: 3 following oocyte donation, and 6 spontaneous in 5 women (15.1%). Eight of the 9 pregnancies resulted in a live birth (including 2 affected children) and 1 in medical termination for trisomy 13. The median age of the 30 patients without POI was 31 years [25.2-35.0]. Thirteen women (20.6%) underwent fertility preservation, at a median age of 29 years [24-33]: FSH 7.7 IU/L [6.8-9.9], AMH 1.1 ng/mL [0.95-2.1], antral follicle count 9.5 [7.7-14.7]. A median 15 oocytes [10-26] were cryopreserved in a median 2 cycles [1-3]. At the time of writing, no oocytes had yet been thawed for in vitro fertilization. CONCLUSIONS: This study shows the importance of early fertility preservation after diagnosis of FMR1 premutation in women, due to early deterioration of ovarian reserve. Genetic counseling is essential in these patients, as spontaneous pregnancies are not uncommon, even in cases of impaired ovarian reserve, and can lead to birth of affected children.

Long-term outcomes in non-CAH 46,XX DSD.

Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.

Shifting the landscape: Dominant C-terminal rare missense FOXL2 variants in non-syndromic primary ovarian failure etiology.

Pathogenic germline variants in the FOXL2 gene are associated with Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) in humans, an autosomal dominant condition. Two forms of BPES have emerged: (i) type I (BPES-I), characterized by ocular signs and primary ovarian failure (POI), and (ii) type II (BPES-II) with no systemic associations. This study aimed to compare the distribution of FOXL2 variants in idiopathic POI/DOR (diminished ovarian reserve) and both types of BPES, and to determine the involvement of FOXL2 in non-syndromic forms of POI/DOR. We studied the whole coding region of the FOXL2 gene using next-generation sequencing in 1282 patients with non-syndromic POI/DOR. Each identified FOXL2 variant was compared to its frequency in the general population, considering ethnicity. Screening of the entire coding region of the FOXL2 gene allowed us to identify 10 different variants, including nine missense variants. Of the patients with POI/DOR, 14 (1%) carried a FOXL2 variant. Significantly, six out of nine missense variants (67%) were overrepresented in our POI/DOR cohort compared to the general or specific ethnic subgroups. Our findings strongly suggest that five rare missense variants, mainly located in the C-terminal region of FOXL2 are high-risk factors for non-syndromic POI/DOR, though FOXL2 gene implication accounts for approximately 0.54% of non-syndromic POI/DOR cases. These results support the implementation of routine genetic screening for patients with POI/DOR in clinical settings.

Position statement on the diagnosis and management of congenital pituitary deficiency in adults: The French National Diagnosis and Treatment Protocol (NDTP).

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

Prognostic impact of hypothalamic perforation in adult patients with craniopharyngioma: a cohort study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension and hypothalamic involvement are essential for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in three groups, depending on the type of hypothalamus involvement assessed by preoperative MRI: infra-hypothalamic (type A, n=33); perforating the hypothalamus (type B, n=40); supra-hypothalamic (type C, n=6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%) and 5/6 (83%) patients in type A, B and C respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable or worsened in 6/40 (15%), 32/40 (80%) and 2/40 (5%) patients respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%) and 3/6 (50%) patients in types A, B and C respectively. In four patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF-mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

Pituitary surgery outcome in patients 75 years and older: a retrospective study.

BACKGROUND: As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. METHODS: A retrospective cohort study of patients with pituitary adenomas and Rathke's cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. RESULTS: Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3-96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing's disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. CONCLUSIONS: Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Changes in the clinical management of 5α-reductase type 2 and 17ß-hydroxysteroid dehydrogenase type 3 deficiencies in France.

Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17ß-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods: Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994-2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results: Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients' age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0-53.2) years for patients born before 2007 and 0.4 (0-9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion: This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

Combining metabolomics and machine learning models as a tool to distinguish non-classic 21-hydroxylase deficiency from polycystic ovary syndrome without adrenocorticotropic hormone testing.

STUDY QUESTION: Can a combination of metabolomic signature and machine learning (ML) models distinguish nonclassic 21-hydroxylase deficiency (NC21OHD) from polycystic ovary syndrome (PCOS) without adrenocorticotrophic hormone (ACTH) testing? SUMMARY ANSWER: A single sampling methodology may be an alternative to the dynamic ACTH test in order to exclude the diagnosis of NC21OHD in the presence of a clinical hyperandrogenic presentation at any time of the menstrual cycle. WHAT IS KNOWN ALREADY: The clinical presentation of patients with NC21OHD is similar with that for other disorders of androgen excess. Currently, cosyntropin stimulation remains the gold standard diagnosis of NC21OHD. STUDY DESIGN, SIZE, DURATION: The study was designed using a bicentric recruitment: an internal training set included 19 women with NC21OHD and 19 controls used for developing the model; a test set included 17 NC21OHD, 72 controls and 266 PCOS patients used to evaluate the performance of the diagnostic strategy thanks to an ML approach. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fifteen steroid species were measured in serum by liquid chromatography-mass spectrometry (LC-MS/MS). This set of 15 steroids (defined as 'steroidome') used to map the steroid biosynthesis pathway was the input for our models. MAIN RESULTS AND THE ROLE OF CHANCE: From a single sample, modeling involving metabolic pathway mapping by profiling 15 circulating steroids allowed us to identify perfectly NC21OHD from a confounding PCOS population. The constructed model using baseline LC-MS/MS-acquired steroid fingerprinting successfully excluded all 17 NC21OHDs (sensitivity and specificity of 100%) from 266 PCOS from an external testing cohort of originally 549 women, without the use of ACTH testing. Blood sampling timing during the menstrual cycle phase did not impact the efficiency of our model. LIMITATIONS, REASONS FOR CAUTION: The main limitations were the use of a restricted and fully prospective cohort as well as an analytical issue, as not all laboratories are equipped with mass spectrometers able to routinely measure this panel of 15 steroids. Moreover, the robustness of our model needs to be established with a larger prospective study for definitive validation in clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: This tool makes it possible to propose a new semiology for the management of hyperandrogenism. The model presents better diagnostic performances compared to the current reference strategy. The management of patients may be facilitated by limiting the use of ACTH tests. Finally, the modeling process allows a classification of steroid contributions to rationalize the biomarker approach and highlight some underlying pathophysiological mechanisms. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by 'Agence Française de Lutte contre le dopage' and DIM Région Ile de France. This study was supported by the French institutional PHRC 2010-AOR10032 funding source and APHP. All authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Fertility and pregnancy outcomes in women with nonclassic 21-hydroxylase deficiency.

INTRODUCTION: Overall fertility and pregnancy outcomes in patients with nonclassic congenital adrenal hyperplasia (NCCAH) have been poorly studied. It has been suggested that hydrocortisone (HC) may decrease the time to conceive (TTC) and the rate of miscarriage in these patients. OBJECTIVES: To describe fertility and pregnancy outcomes in a large cohort of NCCAH women. The secondary objective was to identify factors that could impact reproductive outcomes, with a particular focus on HC dose and genetic status. DESIGN: Retrospective study in a referral center for congenital adrenal hyperplasia. PATIENTS AND MEASUREMENTS: One hundred seventy-three female patients with NCCAH confirmed by genetic testing, followed in our center between 2010 and 2019. RESULTS: Among the 173 patients, 95 women had a parental project, 86 of whom presented 176 pregnancies, 56% under glucocorticoid (GC) treatment and 44% without, and 76 women obtained 128 live births. Two-thirds of the patients regularized their cycle under GC treatment, with significant decrease of androgens and progesterone levels. This treatment was associated with a shortening of TTC (coef ß = -.196, information coefficient [IC] = [-10.7; -0.91], p = .021). Androgen levels and TTC were positively correlated to the rate of miscarriage (OR = 4.8, IC = [1.15; 20.34], p = .021 for testosterone, OR = 1.4, IC = [1.05; 1.81], p = .02 for androstenedione, and OR = 1.03, IC = [1.01; 1.06], p = .015 for TTC). There was no difference in terms of obstetric outcomes between patients with or without GC treatment. CYP21A2 genotype had no impact on pregnancy outcome or TTC. CONCLUSIONS: Infertility is relative in patients with NCCAH. HC seems beneficial for fertility and pregnancy outcomes, especially for patients with menstrual disorders and high preconceptional androgen levels.

Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype.

Introduction: A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective: This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods: Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results: A total of 70 patients were recruited, with a median age of 29.5 years (21.0-36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions: In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement: About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.

Turner syndrome: French National Diagnosis and Care Protocol (NDCP; National Diagnosis and Care Protocol).

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.

Classical and non-classical congenital adrenal hyperplasia: What is the difference in subsequent fertility?

21-Hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia. Increased production of adrenal-derived androgens and progesterone in 21OHD women interfere with their reproductive function and their fertility in many different ways, depending on the severity of the disease. Sexuality and fertility in women with classic 21OHD is impaired, due to several issues such as disrupted gonadotropic axis due to androgen and progesterone overproduction, and mechanical, psychological factors related to genital surgery. Fertility and fecundity in these women get better over the years. Subfertility seems contrariwise to be relative in non-classic 21OHD women. Before pregnancy, genotyping the partner and genetic counselling is mandatory.

Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families.

OBJECTIVE: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). DESIGN: Cross-sectional study. SETTING: Endocrinology and reproductive medicine teaching hospital departments. PATIENTS: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. RESULTS: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). CONCLUSIONS: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01177891.

Androgens, QT, sex and ventricular repolarization-a double-edged sword: A case series.

The prevalence and incidence of cardiac pro-arrhythmic disorders are often influenced by sex due to specific effects on the QT interval. Androgens shorten QT, which may be protective against acquired long QT syndromes and their related arrhythmias in men such as torsade de pointes (TdP). On the other hand, androgens can potentiate Brugada and early repolarization syndromes, which are most prevalent in men. In this case series, we highlight four male patients with aborted SCD in the setting of abnormal testosterone status; two patients with TdP in a setting of testosterone deprivation (of which one drug-induced) and 2 patients with ventricular fibrillation associated with exogenous androgenic booster (Tribulus terrestris) intake. From this case series, we review the current available literature of the effects of androgen as a double-edged sword on the QTc interval and emphasize the importance of QTc monitoring in this subset of patients.

Proof of concept and development of a couple-based machine learning model to stratify infertile patients with idiopathic infertility.

We aimed to develop and evaluate a machine learning model that can stratify infertile/fertile couples on the basis of their bioclinical signature helping the management of couples with unexplained infertility. Fertile and infertile couples were recruited in the ALIFERT cross-sectional case-control multicentric study between September 2009 and December 2013 (NCT01093378). The study group consisted of 97 infertile couples presenting a primary idiopathic infertility (> 12 months) from 4 French infertility centers compared with 100 fertile couples (with a spontaneously conceived child (< 2 years of age) and with time to pregnancy < 12 months) recruited from the healthy population of the areas around the infertility centers. The study group is comprised of 2 independent sets: a development set (n = 136 from 3 centers) serving to train the model and a test set (n = 61 from 1 center) used to provide an unbiased validation of the model. Our results have shown that: (i) a couple-modeling approach was more discriminant than models in which men's and women's parameters are considered separately; (ii) the most discriminating variables were anthropometric, or related to the metabolic and oxidative status; (iii) a refined model capable to stratify fertile vs. infertile couples with accuracy 73.8% was proposed after the variables selection (from 80 to 13). These influential factors (anthropometric, antioxidative, and metabolic signatures) are all modifiable by the couple lifestyle. The model proposed takes place in the management of couples with idiopathic infertility, for whom the decision-making tools are scarce. Prospective interventional studies are now needed to validate the model clinical use.Trial registration: NCT01093378 ALIFERT https://clinicaltrials.gov/ct2/show/NCT01093378?term=ALIFERT&rank=1 . Registered: March 25, 2010.

[Contraception in women with obesity]. / Contraception dans le contexte de l'obésité.

Obese women are at high risk of unintended pregnancy. In addition, obesity is an important risk factor for venous thromboembolism events and arterial thrombosis. All of these data are to be considered in choosing a contraceptive method for obese women. The metabolic changes and the increased body mass of these women may be the cause of a reduction in the effectiveness of hormonal contraception. The progestin-only contraceptives (progestin only pills and etonogestrel subdermal implant) and the intra-uterine devices are the preferred contraceptive methods in women with obesity. The combined estrogen-progestin contraceptives may be proposed in young obese women without other cardiovascular risk factor. Obesity per se does not seem to increase the risk of failure of most contraceptive methods. Bariatric surgery is a complex situation. Contraception is needed for at least 12 months after surgery. Some bariatric surgery such as bypass can induce gastrointestinal malabsorption. In this situation, all oral contraceptives are not recommended because of a higher risk of failure.

TITLE: Contraception dans le contexte de l'obésité. ABSTRACT: La question de l'influence de l'obésité sur la contraception peut être envisagée sous plusieurs angles : comme facteur de risque d'échec d'une contraception hormonale ; comme facteur de risque cardio-vasculaire, pouvant majorer ce risque lors de l'association à une contraception hormonale. Les modifications métaboliques observées au cours de l'obésité et la masse corporelle plus importante des femmes présentant une obésité peuvent en effet être à l'origine d'une réduction de l'efficacité de la contraception hormonale. Néanmoins, les données, mêmes peu nombreuses, laissent penser que l'efficacité de la plupart des méthodes de contraception n'est a priori pas diminuée chez ces femmes. La chirurgie bariatrique, utilisée pour remédier à l'obésité, constitue une situation complexe, qui impose une contraception dans la première année post-opératoire afin d'éviter toute grossesse. Si la technique chirurgicale induit une malabsorption (comme le bypass), toute contraception administrée par voie orale verra son efficacité fortement diminuée et sera donc déconseillée en raison d'un haut risque d'échec.