Background: The use of gonadotropins is a recent strategy for inducing puberty in adolescent males with hypogonadotropic hypogonadism (HH). Testosterone use has been discouraged in patients who desire to preserve fertility. Human chorionic gonadotropin (hCG) has been recommended for inducing puberty in HH; however, several clinicians administer hCG in combination with other gonadotropins. The benefits of using combination gonadotropin therapies (hCG+) over hCG monotherapy in pre-pubertal adolescent males with HH has not been clearly established. We performed a meta-analysis to assess the outcomes of hCG compared to hCG+ in terms of virilizing effects and testicular growth in peripubertal boys with HH.
Methods: We evaluated for heterogeneity among studies. We calculated pooled means for the post-treatment mean testicular volume (MTV), testosterone (T) level, and penile length for the hCG monotherapy and hCG+ treatment groups. We performed a meta-regression analysis to examine the contribution of various factors to post-treatment outcomes including baseline T level, age, treatment duration, and study quality.
Results: The meta-analysis included seven studies. All participants were prepubertal (age range: 13.3–25.9 years), with weighted mean treatment durations of 10.95 months for hCG monotherapy and 28.2 months for hCG. There was significant heterogeneity in baseline age (Q = 121.71; df = 1; P < 0.001) and T levels (Q = 436.74; df = 1; P < 0.001) between the two treatment groups. The hCG+ group had a larger post-treatment MTV, but it was not significantly different between the two groups (6.60 mL [95% CI, 3.18–10.02] for hCG monotherapy vs. 10.02 mL [95% CI, 8.30–11.75] for hCG+; P = 0.079). Post-treatment T levels differed significantly between the two groups (101.89 ng/dL [95% CI, 50.7–153.08] for hCG monotherapy vs. 424.10 ng/dL [95% CI, 304.59–543.62] for hCG+; P < 0.0001). A meta-regression analysis of post-treatment T levels showed that baseline age, baseline T level, and study grade did not contribute significantly to the difference between treatment groups. Treatment duration explained 3.04% of the difference between the two groups (P < 0.0001). After adjusting for treatment duration, the post-treatment T level remained significantly higher in the hCG+ group compared to the hCG monotherapy group. The hCG+ was also associated with better outcomes for post-treatment penile length, although these findings relied on data from only three studies.
Conclusion: Our study indicates that hCG+ therapies provide potential benefits over hCG monotherapy for pubertal induction in males with HH, regarding T levels and penile growth, with no difference in testicular growth between treatments. Prospective pediatric studies are needed to assess the benefits of these therapies in patients with HH and, ultimately, to establish guidelines for gonadotropin therapy in the adolescent population.