Endocrine 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 or spermatogenesis. Conversely, treatment with gonadotropins stimulates Sertoli and Leydig cells directly, leading to increased testicular volumes, testosterone concentrations, and spermatogenesis. We sought to systematically review studies of gonadotropins for the induction of spermatogenesis in males with hypogonadotropic hypogonadism.

Methods: Systematic review of studies since 1990 of patients with hypogonadotropic hypogonadism treated with gonadotropins for 6+ months, across Medline, EMBASE, Global Health, and PsychInfo databases, in December 2022. RoB 2.0/ROBINS-I/NHLBI scoring for quality appraisal. Protocol registered on PROSPERO (CRD42022381713).

Results: After screening 3925 abstracts, 106 studies were identified (81 observational studies, 19 comparative non-randomised studies, six randomised controlled trials), including 5377 patients from 21 countries. Of these, 98 evaluated spermatogenesis. Median NIHLBI score for observational studies was 9/12 (interquartile range (IQR) 8–10) and 44.0% of comparative studies had serious risk of bias in at least one domain. The average age of participants was <25 years in 45.3% (n=48) 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 38.9% for hCG (95% CI 24.5–54.1%), 85.7% for hCG + FSH (95% CI 81.1%–89.8%), 73.7% for hCG + hMG (95% CI 65.3–81.4%) and 72.1% for GnRH (95% CI 58.9–83.9%). There was substantial heterogeneity for all treatment modalities except hCG + FSH, where there was moderate heterogeneity. The most frequent adverse effects were gynaecomastia, acne and injection site pain/reaction.

Conclusions: There is increasingly promising evidence regarding the use of gonadotropins to induce spermatogenesis in males with hypogonadotropic hypogonadism. We found that hCG + FSH was superior to hCG alone for induction of spermatogenesis. However, there remains substantial heterogeneity in study design and therapeutic regimens, and randomised studies are needed to inform guideline development for this important cohort.