The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways-Insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement

Objective To delineate the role of gonadotropins in male androgen biosynthesis pathways. Design Case-control study. Patients and measurements Twenty five males with congenital hypogonadotropic hypogonadism (CHH) underwent hCG/rFSH and testosterone treatment sequentially. Serum steroid hormone profiles (testosterone precursors and metabolites) on both replacement regimens were analysed, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared to those of healthy controls, matched by age, BMI and serum testosterone. Results On testosterone replacement, serum concentrations of the classic Delta 4 pathway hormones progesterone and 17-hydroxy-progesterone (17-OHP), and the marker steroid of an alternative pathway of testosterone synthesis (androstenediol) were decreased, compared to controls. Androstanediol, a marker of the backdoor pathway of dihydrotestosterone (DHT) synthesis, was increased. 17-OH-pregnenolone, androstenedione and DHEAS (Delta 5 pathway), three 11-oxygenated C19 androgens (11-keto-A4, 11-keto-T and 11-keto-DHT) and the testosterone (T) metabolites DHT and 17ss-oestradiol (E2) were similar to controls. On gonadotropin replacement, 17-OHP, 17-OH-pregnenolone, DHEAS and androstenedione, as well as DHT, androstenediol, and all 11-oxygenated C19 androgens were normal. Progesterone (Delta 4 pathway) was slightly decreased, and androstanediol (backdoor DHT pathway) and E2 (T metabolite) were increased. Conclusions In males with CHH, serum steroid hormone profiles resemble those of healthy men, if hCG/rFSH is used for substitution. Gonadotropins contribute to steroid hormone production along the classic Delta 4 pathway and co-activate an alternative pathway of testosterone biosynthesis via androstenediol. Backdoor DHT biosynthesis, Delta 5 17-OH-pregnenolone, DHEA(S) and androstenedione synthesis and 11-oxygenated C19 androgen production are activatedindependently of gonadotropins. The androgen replacement modality used for treatment of hypogonadal males with absent or reduced endogenous LH/FSH secretion may impact on long-term health and quality of life.

Automated summary

In males with CHH, treatment with hCG/rFSH leads to similar serum steroid hormone profiles as healthy men. Gonadotropins play a role in steroid hormone production along the classic Delta 4 pathway and activate an alternative pathway of testosterone biosynthesis via androstenediol.