Endocrine Abstracts

Background and aims: Hypogonadotropic hypogonadism is characterised by inadequate secretion of gonadotropins (luteinising hormone (LH) and follicle-stimulating hormone (FSH)) leading to absent, partial or arrested puberty. In males, classical treatment with testosterone promotes virilisation but does not facilitate testicular growth or spermatogenesis. Conversely, treatment with gonadotropins or gonadotropin-releasing hormone (GnRH) stimulates Sertoli and Leydig cells directly, leading to increased testicular volumes, appropriate serum testosterone concentrations and spermatogenesis. To quantify treatment practices and efficacy, we aimed to systematically review all studies investigating gonadotropin and GnRH therapies for the induction or completion of puberty in males with hypogonadotropic hypogonadism.

Methods: A systematic review of Medline, EMBASE, Global Health, and PsychInfo databases was conducted in December 2022, with RoB 2.0/ROBINS-I/NHLBI scoring for quality appraisal. Protocol registered on PROSPERO (CRD42022381713). Eligibility criteria: studies since 1990 of patients with hypogonadotropic hypogonadism treated with gonadotropins/GnRH for 6+ months assessing pubertal outcomes, including testicular volumes, penile length, LH/FSH, testosterone, inhibin B, anti-Müllerian hormone (AMH), spermatogenesis and fertility.

Results: After screening 3,917 abstracts, 102 studies met inclusion criteria (78 pre-post observational studies, 18 comparative non-randomised studies, 6 randomised controlled trials), including 4,945 patients from 24 countries. Median NIHLBI score for observational studies was 9/12 (interquartile range (IQR) 8-10) and 41.6% of comparative studies had serious risk of bias in at least one domain. The average age of participants was <25 years in 47.1% (n=48) of studies. The most frequently described gonadotropin was hCG (n=96, 94.2% of studies), followed by FSH (n=36, 35.3%) and hMG (n=36, 35.3%). 22.5% (n=23) of studies described use of GnRH. Median reported duration of treatment/follow-up was 17 months (IQR 10-24 months). 73 studies described change in testicular volume, and 51 of 55 statistical analyses (92.7%) reported a significant increase in size post-treatment. Among other outcomes, 12 studies (11.8%) assessed penile length, 27 (26.4%) LH, 35 (34.3%) FSH, 73 (71.6%) testosterone, 14 (13.7%) inhibin B, 7 (6.9%) AMH, 67 (65.7%) spermatogenesis and 31 (30.4%) fertility. 37 (36.2%) of studies characterised adverse effects, most frequently local reactions, changes to biochemical parameters, acne and gynaecomastia.

Conclusions: There is a growing body of evidence regarding the use of gonadotropins or GnRH for attainment of pubertal outcomes in patients with hypogonadotropic hypogonadism and outcomes are promising. However, there remains substantial heterogeneity in terms of treatment choice, dose, duration, and outcomes assessed, and in particular, randomised studies are needed to increase the quality of evidence for this important patient group.