ESPE Abstracts (2019) 92 LB-3

Insights into the Regulation of Androgen Biosynthesis from Males with Congenital Hypogonadotropic Hypogonadism: Quantification of Bioactive Steroid Hormones Reveals Differences Between Gonadotropin Replacement and Testosterone Replacement

Julia Rohayem1, Paul-Martin Holterhus2, Sabine Kliesch1, Eberhard Nieschlag1, Michael Zitzmann1, Alexandra Kulle2


1Centre for Reproductive Medicine and Andrology, Department of Clinical and Operative Andrology, University of Münster, Münster, Germany. 2Children's Hospital Kiel, Department of Pediatric Endocrinology and Diabetes, University of Schleswig-Holstein, Kiel, Germany


Background: In males with congenital hypogonadotropic hypogonadism (CHH), LH/FSH stimulation of gonads is deficient. In clinical practice, two hormone replacement strategies are employed to induce and maintain virilisation: Treatment with testosterone and gonadotropin replacement with hCG/rFSH.

Objective: To delineate the role of gonadotropins in pathways of male androgen biosynthesis and to thereby better define the gonadal and adrenal contribution to the circulating steroid hormone pool.

Patients and Methods: In 25 males with CHH, serum steroid hormone profiles (specifically precursors of testosterone and its metabolites) were analyzed, using liquid chromatography-tandem mass spectrometry (LC-MS/MS), once, while patients were undergoing hCG/rFSH treatment and again, while on testosterone replacement. Data were compared to those of healthy controls (matched for age, BMI and serum testosterone).

Results: On replacement with testosterone, decreased levels of progesterone, 17-hydroxy-progesterone (17-OHP) (Δ4 classic pathway of androgen biosynthesis) and androstenediol (alternative pathway of testosterone synthesis), and mildly decreased levels of androstenedione and were observed, as compared to controls. The backdoor steroid pathway for DHT synthesis, represented by androstanediol, was increased. Serum levels of DHEAS, DHT, E2 and 11-oxygenated C19 androgens (11-keto-A4 11-keto-T, 11-keto-DHT) were comparable to those of controls.

On hCG/rFSH replacement, classic Δ4 pathway hormones were normal, including 17-OHP, androstenedione, DHT, and progesterone (near-normal), as well as the Δ5 hormone DHEAS, the alternative T pathway steroid androstenediol and all above-mentioned 11-oxygenated C19 androgens. Androstanediol (backdoor DHT pathway) and E2 were increased.

Conclusions: In males with CHH, a replacement with hCG/rFSH mimics physiologic steroid hormone profiles better than a substitution with testosterone. Gonadotropins induce Δ4 classic pathway steroid production via 17-OHP and androstenedione and co-activate the alternative pathway of T biosynthesis via androstenediol. The backdoor pathway of DHT and synthesis of 11-oxygenated C19 steroids and DHEAS are activated independently of gonadotropins. The documented differences in steroid profiles may cause differential steroid hormone-mediated gene expression patterns in target tissues and may thus have consequences for long term male health.