Gonadotropin therapy for mini-puberty induction in male infants with hypogonadotropic hypogonadism: a systematic review

Abstract Context Congenital hypogonadotropic hypogonadism (CHH) is defined as an isolated deficiency of gonadotropin hormones. Mini-puberty, a transient postnatal activation of the hypothalamic-pituitary-gonadal axis in healthy infants, provides a window of opportunity to diagnose and treat CHH. Currently, in male infants with CHH, testosterone is used to increase phallus size. However, gonadotropin replacement could additionally promote testicular descent and development, particularly relating to Sertoli cells. We conducted a systematic review of the effectiveness of gonadotropin therapy in stimulating mini-puberty related outcomes in male infants with CHH. Evidence Acquisition In line with PRISMA guidelines, a systematic review of eleven databases was carried out (August 2023). Evidence quality was assessed using the Cochrane Risk of Bias for Non-Randomised Studies of Interventions tool. Protocol registered on PROSPERO (CRD42023453080). Evidence Synthesis After a double-consensus screen of 767 abstracts and 66 full texts, 11 studies were included from seven countries. 71 male infants were enrolled, 12 with Kallmann syndrome. Median age at treatment initiation was 4.2 months (0.25-57) and follow-up ranged from 3 to 10 years. Gonadotropin therapy was administered using continuous subcutaneous infusion (n=35) or subcutaneous injection (n=36). Due to treatment variability, modalities were combined for data synthesis. Gonadotropins induced a significant increase in penile length and inhibin B concentration (P=0.0007) and led to partial or full testicular descent in 73% (n=62) of patients. Conclusions This systematic review provides unique evidence supporting the efficacy of gonadotropins for induction of mini-puberty. However, the reliability and generalisability are limited due to disparate data and treatment modality variation.