Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.

BACKGROUND: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. METHODS: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. FINDINGS: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. INTERPRETATION: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. FUNDING: Université Paris Saclay, Agence Nationale de Biomédecine.

Pulsatile gonadotropin-releasing hormone therapy in persistent amenorrheic weight-recovered anorexia nervosa patients.

OBJECTIVE: To compare hormonal and clinical responses to GnRH pulsatile treatment in weight-recovered anorexia nervosa patients (Rec-AN) with persistent functional hypothalamic amenorrhea (HA) vs. in patients with secondary and primary HA. DESIGN: Retrospective, observational, ambulatory study. SETTING: University hospital. PATIENT(S): Forty-one women: 19 Rec-AN (body mass index >18.5 kg/m2 without menses recovery), 15 secondary HA without any eating disorders patients (SHA), and 7 primary HA patients (PHA). INTERVENTION(S): Gonadotropin-releasing hormone pulsatile therapy. MAIN OUTCOME MEASURE(S): Baseline E2, LH, and P plasma levels and their changes during induction cycles; ovulation, follicular recruitment, and pregnancies. RESULTS: The Rec-AN group displayed higher basal E2 and LH plasma levels after GnRH injection compared with SHA and PHA. Higher E2 and LH levels were observed during induction cycles in Rec-AN compared with SHA and PHA. Follicular recruitment was higher in Rec-AN. The ovulation rate was higher in Rec-AN compared with PHA but similar to SHA. CONCLUSION(S): This study showed increased gonadal status and higher E2 response to pulsatile GnRH therapy in persistent amenorrheic weight-recovered AN compared with HA from other causes. It suggests that their individual set-point of body weight allowing a fully functional gonadal axis is not reached yet. Specific factors of gonadal inertia in Rec-AN still remain unclear.