Comparing the response of triple therapy and conventional treatment in male congenital hypogonadotropic hypogonadism: a randomized controlled trial

Background: This study investigated whether triple therapy with human chorionic gonadotropin (hCG), follicle-stimulating hormone(FSH) and testosterone(T) in congenital hypogonadotropic hypogonadism(CHH) promoted more timely virilization, aiding psychosocial development while reducing hCG requirements, offering a balanced approach to long-term management. Methods: An open-label randomized controlled trial (1:1:1) was conducted in adult males with CHH. Group A received triple therapy, Group B received combined hCG and FSH from the outset, and Group C received hCG monotherapy followed by combined FSH and hCG. Initial doses comprised hCG 2,000 IU twice weekly, FSH 75 IU thrice weekly and intramuscular testosterone(T) 100 mg every two weeks. Group A titrated hCG to achieve AMH of 7.4ng/ml; Groups B and C aimed for T normalization. Primary outcomes were hCG/FSH doses required for spermatogenesis induction and the time to spermatogenesis. Results: Forty-five CHH males (mean age 25.8 ± 6.1years) were randomized. Spermatogenesis was achieved in 84.6% of group A participants compared with 69.2% and 75% in groups B and C, respectively(p=0.648). Median hCG dose at spermatogenesis was 7500IU/week in group A and 9000IU/week in groups B and C(p=0.016). The time to spermatogenesis was comparable (Groups A/B:12 months; Group C:15 months;p=0.345). Group A participants achieved an AMH of 3.5(2.31-5.38)ng/ml, comparable to the other groups(p=0.962). Predictors of spermatogenesis included USGmTV cut-off of 1.97ml (sensitivity-86.2%,specificity-62.5%), hCG dose of 9,000 IU/week (sensitivity-79.3%,specificity-87.5%) and an Inh B cut-off of 66.8 pg/ml(sensitivity-92.6%,specificity-100%). Conclusions: Triple therapy provided a better quality of life without compromising spermatogenesis. The AMH and Inh B provided an effective means of monitoring. Clinical trial registration: www.ctri.nic.in, identifier CTRI/2022/05/042795.