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Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-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.

Résumé Contexte Les androgènes sont bien connus pour être nécessaires à la spermatogenèse. Le but de l’étude était de déterminer l’évolution de la réactivité des cellules de Sertoli aux androgènes en fonction de l’âge depuis la période néonatale jusqu’à la puberté. Résultats Des échantillons de tissu testiculaire ont été étudiés dans une population de 84 garçons témoins classés en 7 groupes selon l’âge: groupe 1 (1–30 jours), groupe 2 (1–3 mois), groupe 3 (3–6 mois), groupe 4 (0,5–3 ans), groupe 5 (3–6 ans), groupe 6 (6–12 ans), groupe 7 (12–16 ans). Nous avons comparé ces données avec celles de deux situations de pathologies liées aux androgènes: 1/ une sécrétion prématurée de testostérone: 4 cas de tumeur à cellules de Leydig (LCT) dans l’enfance; 2/ une résistance aux androgènes par mutation du récepteur aux androgènes (AR): 4 cas de forme complète de syndrome insensibilité aux androgènes (CAIS). Chez les garçons témoins, l’immunoreactivité (ir) au AR dans les cellules de Sertoli est. apparue entre 4,6 et 10,8 ans, l’ir de l’hormone anti-mullerienne (AMH) dans les cellules de Sertoli a disparu entre 9,2 et 10,2 ans. L’ir de la connexine 43 (Cx 43) dans les cellules de Sertoli et les caractéristiques histologiques du début de la spermatogenèse sont apparues plus tard entre 10,8 et 13,8 ans. L’intensité de Cx 43 ir était significativement plus élevée chez les 12–16 ans que chez les garçons plus jeunes. Dans les cas de CAIS, aucune spermatogenèse n’a été observée, AR ir et Cx 43 ir étaient indétectables et AMH ir restait élevée dans les cellules de Sertoli à l’âge de la puberté. En outre à proximité des LCT, il est. observé une initiation de la spermatogenèse; AR ir et Cx43 ir étaient franchement augmentées et AMH ir dans les cellules de Sertoli était faible pour l’âge. Conclusions L’action des androgènes au niveau des cellules de Sertoli est. nécessaire pour initier la spermatogenèse. De plus, une sécrétion prématurée d’androgènes, comme dans la situation de cas de LCT, est. capable induire une spermatogenèse à proximité de la tumeur. AR ir apparait un peu avant le démarrage de la spermatogenèse, il existe cependant avec une grande variabilité interindividuelle. L’apparition d’une réponse aux androgènes apparait comme un paramètre important à évaluer pour améliorer la compréhension de l’induction de la spermatogenèse.

BackgroundNR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging.ObjectiveThe aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation.PatientsWe included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed.ResultsBilateral testicular volume increased from 8 ml (interquartile range, 6–9) to 12 ml (10–16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46–139) before and 91 ng/L (20–120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any.ConclusionWe characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.