Gonadotropin therapy for mini-puberty induction in male infants with hypogonadotropic hypogonadism

S. Rhys-Evans; F. d; E.C. Alexander; I.F. Dinah; S. Heger; A. Nordenstrom; J. Rohayem; S.R. Howard

doi:10.1530/ey.22.1.8

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 1.8 | DOI: 10.1530/ey.22.1.8

ESPEYB25 1. Pituitary and Neuroendocrinology New Treatments and Hopes (5 abstracts)

1.8. Gonadotropin therapy for mini-puberty induction in male infants with hypogonadotropic hypogonadism

S. Rhys-Evans , F. d’Aniello , E.C. Alexander , I.F. Dinah , S. Heger , A. Nordenstrom , J. Rohayem & S.R. Howard

J Clin Endocrinol Metab 110(4) (2025) e921-e931.PMID: 39673783

Brief Summary: This systematic review and meta-analysis examined the induction of mini-puberty using exogenous gonadotropins in male infants with congenital hypogonadotropic hypogonadism (CHH). The evidence supports the efficacy of this clinical therapeutic approach to induce mini puberty.

Mini-puberty, the transient activation of the hypothalamic-pituitary-gonadal (HPG) axis during the first few months of life, plays a critical role in male genital development, Sertoli and Leydig cell maturation, and potential future fertility. In CHH, this window is missed, with consequences including micropenis, undescended testes, and impaired testicular function.

This multicenter systematic meta-analyses review suggests that combined recombinant human LH and FSH therapy mimics the physiological patterns of mini-puberty. The findings indicate improvements in genital development (notably penile length and testicular descent) and biochemical responses: elevated testosterone, AMH, and inhibin B, suggesting functional activation of Leydig and Sertoli cells.

Strengths of the study are its well-structured design and use of validated clinical and biochemical endpoints. Moreover, the inclusion of longitudinal follow-up enhances the relevance of the data to future fertility considerations.

This study supports a shift towards earlier, targeted intervention during infancy, potentially improving future fertility outcomes by rescuing early testicular development. While the sample size reflects the rarity of CHH, the biochemical and anatomical responses were consistent and clinically meaningful. This work raises important considerations: What are the long-term reproductive outcomes of early gonadotropin exposure? Should all boys with CHH routinely offer this therapy? And how can we standardize early diagnosis to allow timely initiation of treatment? Future studies will provide with important clinical data supporting the treatment for CHH during mini-puberty.