Spermatogenesis of Male Patients with Congenital Hypogonadotropic Hypogonadism Receiving Pulsatile Gonadotropin-Releasing Hormone Therapy Versus Gonadotropin Therapy: A Systematic Review and Meta-Analysis

Abstract

Purpose: Pulsatile gonadotropin-releasing hormone (GnRH) therapy and gonadotropin therapy (GT) were widely used for male patients with congenital hypogonadotropic hypogonadism (CHH), but their efficacy was not well compared before. We conducted this meta-analysis to compare the efficacy of restoring fertility using these two therapies.

Materials and methods: PubMed, Web of Science, and Scopus were systematically searched for comparative studies evaluating the efficiency of GnRH therapy and GT for male patients with CHH. For continuous outcomes, the weighted mean difference (WMD) was used to measure the difference, whereas the risk ratio with 95% confidence interval was calculated for binary variables.

Results: Overall, eight articles from seven studies with 420 patients enrolled were included in the analysis. Patients from the two different groups were determined to be comparable in age, proportion with Kallmann syndrome, percentage of cryptorchidism and pretreatment hormones (follicular-stimulating hormone, luteinizing hormone, and testosterone). GnRH therapy was related to a larger testicular volume (standardized mean difference=-1.43; p=0.01) and earlier spermatogenesis (WMD=-5.30 months; p=0.004) compared to GT. However, the difference in the rate of positive sperm detection (p=0.08), sperm concentration (p=0.37), and pregnancy rate (p=0.11) were not significant. Allergic reactions mostly occurred during GnRH therapy, while GT was related to a higher incidence of gynecomastia and acne.

Conclusions: Compared to GT, GnRH was related to earlier spermatogenesis and less estradiol-related adverse reactions, although there were no significant differences in spermatogenesis rate, sperm concentration, and pregnancy rate. High-quality randomized controlled trials are needed for future research.

Keywords: Chorionic gonadotropin; Gonadotropin-releasing hormone; Idiopathic hypogonadotropic hypogonadism; Kallmann syndrome; Spermatogenesis.

Fig. 1. PRISMA flow chart of the screening of eligible studies. ^aOf the eight articles included, two articles reported the outcomes of the same study [1220].

Fig. 2. The risk of bias graph of included studies based on the ROBINS-1 method.

Fig. 3. Forest plots of posttreatment physiological parameters of patients after gonadotropin-releasing hormone (GnRH) or gonadotropin therapy (GT). (A) Forest plot of posttreatment testosterone of patients after GnRH or GT. The posttreatment testosterone level of the GnRH group was significantly lower than that of the GT group. (B) Forest plot of posttreatment testicular volume of patients after GnRH or GT. GnRH therapy was related to larger posttreatment testicular volume. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, SD: standard deviation, CI: confidence interval, df: degree of freedom.

Fig. 4. Forest plots of spermatogenesis of patients after gonadotropin-releasing hormone (GnRH) compared to gonadotropin therapy (GT). (A) Forest plot of rate of spermatogenesis of patients after GnRH compared to GT. The spermatogenesis rates of the two groups were not significantly different. (B) Forest plot of time to first sperm detection of patients after GnRH compared to GT. GnRH therapy was related to earlier spermatogenesis. (C) Forest plot of sperm count of patients after GnRH compared to GT. No significant difference was detected. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, M–H: Mantel–Haenszel, CI: confidence interval, df: degree of freedom, SD: standard deviation.

Fig. 5. Forest plot of pregnancy rate after gonadotropin-releasing hormone (GnRH) compared to gonadotropin therapy. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, M–H: Mantel–Haenszel, CI: confidence interval, df: degree of freedom.

Fig. 6. Forest plots of adverse reaction events after gonadotropin-releasing hormone (GnRH) or gonadotropin therapy (GT). (A) Forest plot of total adverse reaction events after GnRH or GT. The incidences of adverse reactions were similar in two groups. (B) Forest plot of allergy events after GnRH or GT. Allergies occurred only in the GnRH group, and the difference was significant. (C) Forest plot of incidence of gynecomastia and acne after GnRH or GT. GnRH therapy resulted in more estradiol-related adverse reactions, including gynecomastia and acne. HCG: human chorionic gonadotropin, HMG: human menopausal gonadotropin, M–H: Mantel–Haenszel, CI: confidence interval, df: degree of freedom.