ESPE Abstracts

Background: 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 and 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 of spermatogenesis 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 spermatogenesis.

Results: After screening 3,925 abstracts, 106 studies were identified assessing pubertal outcomes (81 observational studies, 19 comparative non-randomised studies, six randomised controlled trials), including 5,283 patients from 21 countries. Of these, 98 evaluated spermatogenesis. Median NIHLBI score for observational studies was 9/12 (interquartile range (IQR) 8-10) and 41.4% of comparative studies had serious risk of bias in at least one domain. The average age of participants was <25 years in 49.1% (n=52) of studies. Studies utilised hCG (n=96, 90.6% of studies), hMG (n=44, 41.5%), FSH (n=38, 35.8%), and 28.3% (n=30) used GnRH. Median reported duration of treatment/follow-up was 18 months (IQR 11.5-24 months). Meta-analysis of proportions found a pooled proportion of patients achieving spermatogenesis with a random effects model was 40.1% for hCG (95% CI 25.0-56.1%), 84.5% for hCG + FSH (recombinant or urinary) (95% CI 80.2%-88.4%), 75.2% for hCG + hMG (95% CI 66.7-83.0%) and 72.4% for GnRH (95% CI 59.3-84.0%). There was a significant degree of heterogeneity for all treatment modalities except hCG + FSH. The most frequent adverse effects were gynaecomastia, acne and injection site pain/reaction.

Conclusion: There is a growing body of evidence regarding the use of gonadotropins or GnRH for attainment of spermatogenesis in patients with hypogonadotropic hypogonadism and outcomes are promising. We found that hCG + FSH was superior to hCG alone for induction of spermatogenesis. However, there remains substantial heterogeneity across studies in terms of treatment choice, dose, duration, and outcomes assessed, and in particular, randomised studies are needed to inform the development of guidelines for this important patient group.