ESPE Abstracts

Background: To delineate testicular responses to gonadotropin replacement in young males with genetically proven CHH.

Patients and Methods: In n=72 young males with CHH and at least one variant detected within twenty-four investigated known CHH genes, gonadotropin replacement with hCG and rFSH s.c. was performed over a mean of 2±1 years. Bi-testicular volumes and serum Inhibin B served as baseline parameters, maximal bi-testicular volumes and maximal sperm concentrations in semen achieved on treatment were used as outcome parameters.

Setting and study design: single centre retrospective cohort study

Results: 74 genetic variants were detected within 22/24 investigated CHH genes. The most commonly affected genes were FGFR1 (17%), ANOS1 (9%) GnRHR (8%), PROKR2 (8%), TACR3 (6%), SPRY (5%), CHD7 (4%) and NSMF (4%). Mean bi-testicular volumes at baseline in males with PROKR2 variants were 11±12 ml, vs. 10±9 ml in those with GnRHR variants, 9±9 ml in FGFR1, 4±2 ml in ANOS1, and 4±1 ml in those with TAC3R variants. Inhibin B at baseline was 69±48 pg/ml in males with GnRHR variants; 61±54 pg/ml in those with PROKR2, 53±52 pg/ml in FGFR1, 27±9 pg/ml inTAC3R, and 20±12 pg/ml in those with ANOS1 variants. Mean maximal bi-testicular volumes (by ultrasound) achieved on treatment were 26±6 ml (GnRHR), 22±10 ml (TAC3R); 20±6 ml (PROKR2), 18±9 ml (FGFR1) and 14±8 ml (ANOS1). Median sperm concentrations in semen were 16.4 mill/ml (0-247) in males with GnRHR variants, 15.5 mill/ml (4.7-184) in those with PROKR2 variants, vs. 4.0 (0-66) in FGFR1, 1.2 (0-21) in ANOS1 and 1.1(0-50) in those with TACR3 variants, respectively. Two males with GnRHR mutations had full reversal of their central HPG axis function: One had persisting spermatogenesis on hCG alone and one persisting spermatogenesis on subsequent testosterone gel replacement.

Conclusion: Testicular baseline parameters and responses to gonadotropin replacement are most favourable in males with variants in GnRHR and PROKR2; they are worst in those with variants in ANOS1 and TAC3R. Males with GnRHR variants have a chance for reversal of their central HPG axis dysfunction after therapeutic induction of testicular maturation by gonadotropin replacement.