Boosting Male Fertility: The Impact of Gonadotropin Therapy on Hypogonadotropic Hypogonadism-A Systematic Review and...

Male hypogonadotropic hypogonadism typically presents with azoospermia and is one of the few causes of infertility amenable to a medical intervention. Gonadotropin therapy offers a chance to restore spermatogenesis and fertility in these individuals. Therefore, this study aims to determine the efficacy of gonadotropins in inducing spermatogenesis and achieving pregnancies in males with hypogonadotropic hypogonadism and azoospermia. Additionally, the time needed to induce spermatogenesis and pregnancy, and potential predictors associated with better outcomes, were evaluated.

A systematic literature search was conducted in the Medline, Embase, and Cochrane databases till May 16, 2025. Clinical studies, including randomized control trials, cohort studies, and case-control studies, using gonadotropins as a treatment for hypogonadotropic hypogonadism and assessing sperm induction or pregnancy outcomes, were eligible for inclusion. Primary outcomes included sperm parameters (appearance, concentration, motility, morphology, time needed to induce spermatogenesis) and pregnancy outcomes (pregnancy rate, proportion of naturally achieved pregnancies, proportion of live births, and time to conception). The methodological quality and risk of bias were assessed using the Effective Public Health Practice Project quality assessment tool for quantitative studies, and showed that most included studies were of poor methodological quality.

A total of 50 studies were included from 2351 identified articles, treating 1583 male patients with hypogonadotropic hypogonadism and azoospermia. The pooled success rate of spermatogenesis induction was 74% (95% confidence interval: 66%-82%), with a mean time to spermatogenesis of 11.8 months. The overall pregnancy rate among couples with a child wish was 52% (95% confidence interval: 42%-62%), with a mean time to pregnancy from the start of treatment of 19 months. Mean post-treatment sperm concentration was 9.8 million/mL (95% confidence interval 8.6-11.0), and spontaneous pregnancies also occurred with suboptimal sperm parameters. Gonadotropin dual therapy was more effective than human chorionic gonadotropin monotherapy.

Gonadotropin therapy, particularly combined gonadotropin treatment, is effective in restoring spermatogenesis and achieving pregnancy in men with hypogonadotropic hypogonadism. While sperm quality often remains below normal thresholds, natural conception is frequently achieved. These findings support the use of combined gonadotropin therapy as the first-line approach for fertility induction in this population.

This review was registered on PROSPERO under the registration number CRD4202232149. A review protocol was not previously published.