ESPE Abstracts

Background: Steroidogenic factor 1 (encoded by the NR5A1 gene) is a transcriptional regulator of genes involved in gonadal development and steroidogenesis. Mutations in NR5A1 are associated with a wide phenotypic spectrum in 46,XY individuals ranging from partial/complete gonadal dysgenesis or anorchia, ambiguous genitalia, hypospadias, to infertility. However, little is known about the longitudinal course of endocrine markers for Sertoli and Leydig cell function from infancy to adolescence in these patients.

Objective: To investigate the Sertoli and Leydig cell function in 46,XY patients with an NR5A1 variant reared as males by longitudinal analyses of the Sertoli cell markers inhibin B and anti-Müllerian hormone, the gonadotropins FSH and LH as well as testosterone.

Results: We retrospectively analyzed the laboratory results of six male 46,XY patients with NR5A1 variants. During mini-puberty, inhibin B levels were in the low or low normal range, but variable (median 91 pg/ml, range 55–172 pg/ml). From the age of 10–18 years, inhibin B levels strongly decreased in all patients (median 13 pg/ml, range 3–21 pg/ml). During adolescence, anti-Müllerian hormone levels were very low as well (median 0.46 ng/ml, range 0.14–1.2 ng/ml). 3 of 4 patients who were followed during adolescence had a strong rise of FSH from a median of 9.02 IU/l (range 8.8–49.9 IU/l) to 56.1 IU/l (range 27.1–77.2 IU/l). LH increased from a median of 2.41 IU/l (range 1.03–8.8 IU/l) to 14.9 IU/l (range 7.6–48.0 IU/l). During infancy, testosterone levels ranged from 0.03 μg/l to 1.87 μg/l (median 0.48 μg/l). Interestingly, despite elevated gonadotropin levels indicating gonadal dysfunction, testosterone levels spontaneously rose into adequate levels (median of maximal testosterone 4.75 μg/l, range 2.27–7.1 μg/l) during the course of puberty.

Conclusion: Follow-up laboratory investigations may provide useful information on Sertoli and Leydig cell function in 46,XY individuals with NR5A1 variants. Primary gonadal dysgenesis in these patients is associated with hypergonadotropic hypogonadism and low Sertoli-cell markers, but spontaneous testosterone production during adolescence. Thus, Sertoli cell function seems to be more affected than Leydig cell function. More clinical studies are needed to better predict the future gonadal function including spermatogenesis and testosterone production, and to derive therapeutic implications for clinical practice.