Comparative efficacy of HCG-based versus testosterone regimens for simulating mini-puberty in infants with congenital hypogonadotropic hypogonadism (CHH)

Background: Mini-puberty is a transient but vital phase of hypothalamic-pituitary-gonadal (HPG) axis activation occurring during the first 3–6 months of life, essential for normal testicular development, Sertoli cell maturation, and future fertility. In infants with congenital hypogonadotropic hypogonadism (CHH), the absence of this activation results in macropains, cryptorchidism, and underdeveloped gonads. Therapeutic simulation of mini-puberty using either testosterone or gonadotropin-based regimens (HCG ± RFSH) is employed to mitigate these deficits, yet comparative data remain limited.

Objectives

This review aims to

• Compare the clinical efficacy of testosterone monotherapy versus HCG-based combination regimens in penile growth, testicular volume, and testis descent.
• Evaluate hormonal responses, including serum testosterone, LH, FSH, and inhibin B changes.
• Assess the safety, practicality, and long-term reproductive implications of each approach.

Methods: A structured review of literature from 2000 to 2024 was performed across PubMed, Scopus, and Cochrane Library. Twelve clinical studies involving 168 male infants with CHH were included. Regimens involved testosterone monotherapy or combinations of HCG, RFSH, and/or RLH. Outcomes analyzed included genital growth, hormonal profiles, and side effects. Quality was appraised via the Cochrane Risk of Bias tool.

Results: HCG + FSH regimens outperformed testosterone monotherapy in achieving penile length gains (up to 233% increase), testicular descent (70–80% in most studies), and testicular volume growth. Only gonadotropin regimens achieved comprehensive hormonal restoration with increased levels of LH, FSH, testosterone, and inhibin B. In contrast, testosterone therapy elevated serum testosterone but suppressed gonadotropins and did not stimulate Sertoli cell activity. Most regimens were well tolerated, with only mild local side effects reported. Comparative figures and forest plots demonstrated consistent positive treatment effects, especially in injection-based gonadotropin protocols. Non-CHH populations with macropains/cryptorchidism also showed benefit with HCG-based therapies.

Conclusion: HCG + FSH therapy most effectively replicates physiological mini-puberty by stimulating both Leydig and Sertoli cells, thus enhancing genital development and preserving fertility potential. Testosterone alone, while effective for penile growth, fails to support full gonadal maturation. Early initiation (<6 months) of gonadotropin therapy is critical. These findings support the adoption of HCG + FSH as the preferred regimen in CHH infants and highlight the need for longitudinal follow-up to assess long-term reproductive outcomes.