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An 18-year-old woman was referred by her GP to the endocrinology department of the University Hospital of Bordeaux on suspicion of premature ovarian failure because of a disorder of the menstrual cycle and pathological results of biological exploration of the gonadotropic axis. Repeatedly-found elevated concentrations of FSH contrasted with a normal concentration of LH leading to a hypothesis of ovarian failure. However, different investigations favoured an analytical interference. The presence of heterophilic antibodies or anti-mouse antibodies (HAMA) was unlikely but, finally, a complex combining FSH and autoantibody (called macro-FSH) was evidenced.

International audience; 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. ((C) 2021 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.

Combined oral contraceptives (COC) and spironolactone are the first and second-line treatments of mild hirsutism, since the use of cyproterone acetate was restricted to the treatment of severe hirsutism by the French guidelines for hyperandrogenism published in May 2020. Because spironolactone was until now barely used in France, the aim of this study was to evaluate the indication, efficacy and impact on quality of life of COC and spironolactone treatments on mild hirsutism in non-menopausal women.This retrospective monocentric study was conducted between June 2020 and October 2021. It included patients with mild hirsutism who received a prescription of COC or/and spironolactone. Modified Ferriman and Gallwey score (FGm) was performed by clinicians and self-rated by patients during the follow-up. Hirsutism-related quality of life was assessed using the Dermatology Life Quality Index (DLQI) and a visual analog scale.A total of 44 patients were included, but only 30 patients received the treatment for 6 months. 70% of patients were free of side effects. Clinically we observed a decrease of 26% in the FGm score rated by clinicians and patients after 6 months of treatment (P0,01). This was not correlated with an improvement in quality of life.The data collected showed the clinical efficacy of both COC and spironolactone in the treatment of mild hirsutism. These two treatments were well-tolerated. However, the quality of life scores did not improve after 6 months. These treatments should be evaluated after a longer period.

International audience; Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and development of ventricular arrhythmias. The QT interval, which represents the duration of ventricular repolarization of the heart, can be affected by androgen levels, resulting in a sex-specific predilection for acquired and inherited channelopathies such as acquired long QT syndrome in women and Brugada syndrome and early repolarization syndrome in men. Manipulation of the homeostasis of these sex hormones as either hormonal therapy for certain cancers, recreational therapy or family planning and in transgender treatment has also been shown to affect QT interval duration and increase the risk for ventricular arrhythmias. In this review, we highlight the effects of endogenous and exogenous sex hormones in the physiological and pathological states on QTc variation and predisposition to gender-specific pro-arrhythmias.

Background Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune-related adverse events (irAEs). Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI-irAE. Materials and Methods Suspected PAI-irAE cases were identified using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports. Results From September 2, 2008, through October 5, 2018, a total of 50,108 ICI-associated ADRs were reported. Since 2008, there were 451 cases of PAI-irAE identified of which 45 were “definite PAI” and 406 “possible PAI.” Patients were mainly male (58.1%) with a median age of 66 years (range, 30–95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6–576). ICI-associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between “definite” versus “possible” PAI group. Conclusion Our study represents the largest clinical description and characterization of PAI-irAE. Although ICI-associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242 Implications for Practice Immune checkpoint inhibitor (ICI)-associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life-threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI-related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI-PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.

Objective Multiple fibroadenomas (MFA) of the breast is a rare benign disease, thus its natural history is poorly understood. The aim of our study was to describe the radiological evolution of MFA and to evaluate the influence of different factors on this evolution. Methods This was a longitudinal cohort study. All patients included had two clinical and radiological assessments (breast ultrasound (US) and/or MRI) at least 5 years apart. Results Seventy-two women were followed for 7.6 ± 2.1 years. The radiological evolution showed a decrease or stability in the number of fibroadenomas (FA) in 26/44 cases on the MRI and in 38/64 cases on the US. There was a decrease of size in 35/44 cases on the MRI and in 53/64 cases on the US. An increase in the number of FAs was found in 18/44 cases in the MRI and 26/64 cases in the US with, for the majority, a decrease of size (19/26 by MRI and 16/18 by MRI). Older age at the first FA (P < 0.0001) and at the diagnosis of MFA (P < 0.0001), pregnancy (P = 0.003) and progestin use (P < 0.001), particularly lynestrenol (P < 0.0001), had a beneficial effect on the evolution of MFA. Conclusion This is the first longitudinal study describing women with MFA. The radiological evolution of MFA seamed favorable and similar to that expected for a single FA. We identified factors influencing the evolution of the disease, including progestin treatments such as lynestrenol, which could have a beneficial effect. Our cohort should be followed further in order to expand our knowledge of MFA, especially concerning the risk of breast cancer.

We were interested in the comment from Cosson et al. (1) on our recent report about high skin autofluorescence (sAF) in hyperglycemic mothers of large-for-gestational-age (LGA) newborns (2). Several reasons can explain why Cosson et al., and previously de Ranitz-Greven et al. (3), failed to detect a relationship between sAF and macrosomia. The first explanation is the low number of participants, 100 in de Ranitz-Greven et al. (3) and 148 in Cosson et al. (1), which can lead to an underpowered study and a lack of statistical power, versus 343 …

OBJECTIVE Osteoporotic fractures associated with Cushing's syndrome (CS) may occur despite normal bone mineral density (BMD). Few studies have described alterations in vertebral microarchitecture in glucocorticoid-treated patients and during CS. Trabecular bone score (TBS) estimates trabecular microarchitecture from dual-energy X-ray absorptiometry acquisitions. Our aim was to compare vertebral BMD and TBS in patients with overt CS and mild autonomous cortisol secretion (MACE), and following cure of overt CS. SETTING University Hospital. DESIGN Monocentric retrospective cross-sectional and longitudinal studies of consecutive patients. PATIENTS A total of 110 patients were studied: 53 patients had CS (35, 11 and 7 patients with Cushing's disease, bilateral macronodular adrenal hyperplasia and ectopic ACTH secretion respectively); 39 patients had MACE (10 patients with a late post-operative recurrence of Cushing's disease and 29 patients with adrenal incidentalomas); 18 patients with non-secreting adrenal incidentalomas. 14 patients with overt CS were followed for up to 2 years after cure. RESULTS Vertebral osteoporosis at BMD and degraded microarchitecture at TBS were found in 24% and 43% of patients with CS, respectively (P

ObjectiveA prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.MethodsWe performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.ResultsSERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11–8.55), pConclusionsSERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.Trial registration numberNCT03259711.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.

In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRThis study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis.This was an observational study and transgenic mouse model analysis.The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris.We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRWe aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer.This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRPRLR

21-Hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia. 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 gets better over the years. Subfertility seems contrariwise to be relative in nonclassic CAH women. Before pregnancy, genotyping the partner and genetic counseling is mandatory. The use of dexamethasone during pregnancy in order to prevent the virilization of the young affected CAH girl remains a matter of debate.

Aim To determine whether skin autofluorescence can help to detect those who have previously had abnormal glucose levels among women referred for diabetes during pregnancy. Methods Using an advanced glycation end product reader (AGE Readertm; DiagnOptics BV, Groningen, the Netherlands), we measured forearm skin autofluorescence at 24–30 weeks of gestation in all women who were referred to our Nutrition Diabetology unit for diabetes during pregnancy. Results The study included 230 women (200 with gestational diabetes and 30 with pre-gestational diabetes, of whom 21 had Type 1 and nine had Type 2 diabetes) and a reference group of 22 normoglycaemic non-pregnant women. Skin autofluorescence was significantly higher in women with pre-gestational diabetes (1.97 ± 0.44 arbitary units) compared with gestational diabetes (1.77 ± 0.32 arbitary units; P = 0.003) and lower in the reference group (1.60 ± 0.32 arbitary units; P = 0.009 vs all pregnant women). Among women with gestational diabetes, 71 had a history of hyperglycaemia (i.e. gestational diabetes or macrosomia in a previous pregnancy or discovery of diabetes before 24th gestational week in the present pregnancy). These women had higher levels of skin autofluorescence (1.83 ± 0.35 arbitary units) than women with gestational diabetes without previous history of hyperglycaemia (1.73 ± 0.30 arbitary units; P = 0.04, non-significant, adjusted for age). Skin autofluorescence increased with the number of criteria present for previous hyperglycaemia (P for trend = 0.008) and was significantly associated with having two or three criteria for hyperglycaemia after adjusting for age (P = 0.02). Conclusions Skin autofluorescence could reflect previous long-term hyperglycaemia in pregnant women, and could therefore be a marker of metabolic memory.

We were interested in the article by Law et al. (1), who reported that high nocturnal glucose, as recorded by continuous glucose monitoring (CGM), was associated with large for gestational age (LGA) newborns in women with gestational diabetes mellitus (GDM). The nocturnal hyperglycemia was not detected by fasting self-monitored blood glucose (SMBG), which argues for performing CGM in GDM. The figure in the article nicely depicts how nocturnal hyperglycemia was missed by conventional SMBG: as underlined by the authors, the difference in nocturnal CGM glucose between mothers of LGA infants and those of normal-weight newborns was a peak displayed at 0200–0300 h, which then progressively declined to become nonsignificant when the women …

Objet Une cause genetique de l’insuffisance ovarienne prematuree (IOP) est retrouvee dans 20 a 25 % des IOP [1] . Les anomalies cytogenetiques (10 a 13 %) concernent le plus souvent le chromosome X mais des remaniements des autosomes sont egalement possibles. Methodes Etude en cytogenetique classique et moleculaire d’une patiente adressee pour IOP a l’âge de 38 ans et qui presente egalement une maladie inflammatoire chronique de l’intestin (MICI) de type rectocolite hemorragique (RCH) et un asthme. Le pere et la grand-mere paternelle presentent egalement une MICI de type maladie de Crohn (MC). Resultats Presence d’une inversion pericentrique du chromosome 7 : 46,XX, inv(7)(p14q21.1).ish inv(7)(p14q21.1)(wcp7 + ,LSI ELN + ,D7Z1 + ,RP5-998H4 + ,TelVysion 7q + ). Discussion Le point de cassure sur le bras court est situe dans la bande p14 qui contient le gene PTHB1. Kang et al. en 2008 ont montre dans une etude d’association de genome (GWAS), l’implication de PTHB1 comme facteur de susceptibilite dans les IOP [2] . Par ailleurs, le point de cassure sur le bras long est contenu dans un intervalle de 15Mb qui contient le gene ABCB1 qui a ete propose comme gene candidat dans les MICI [3] et dont l’expression est diminuee dans les cas de MICI [4] . Une interruption de ces genes ou de leurs regions regulatrices pourrait expliquer le phenotype presente par la patiente. Afin de completer cette etude, un clonage des points de cassure et une etude en ACPA (analyse chromosomique sur puce a ADN) pour confirmer le caractere equilibre du remaniement sont prevus. Par ailleurs, le caryotype des parents va egalement etre realise pour rechercher une origine familiale de ce remaniement en particulier chez le pere qui presente egalement une MICI. Conclusion Nous rapportons le cas d’une patiente presentant une IOP et une MICI avec une inversion pericentrique d’un chromosome 7 qui pourrait expliquer l’ensemble des symptomes presentes par la patiente.