Reversal of Congenital Hypogonadotropic Hypogonadism

Congenital genetic disorders have been traditionally considered to be lifelong. An exception to this long-held view is the reversal of congenital hypogonadotropic hypogonadism (CHH). Approximately 10% of male individuals with CHH undergo reversal with sustained hypothalamic-pituitary-gonadal (HPG) axis activation and/or fertility after discontinuing hormonal treatment.

We conducted a structured, systematic literature search to identify relevant articles published on reversal of CHH in males (up to 2025). This mini-review provides a concise overview and synthesizes findings to inform clinical management of CHH.

We identified 31 articles reporting reversal of CHH in males, including cases of severe GnRH deficiency and individuals harboring pathogenic variants in CHH genes. Reversal is distinct from delayed puberty, and olfactory phenotype (ie, anosmia) does not predict HPG axis recovery. In males, reversal universally occurs after achieving normal serum testosterone levels on hormone therapy. Testicular growth on testosterone replacement is a hallmark of HPG axis activation-yet reversal is not always lasting. Cases exist on a continuum from normosmic individuals with severe GnRH deficiency to milder cases with partial spontaneous puberty (Pasqualini syndrome subtype). Pathogenic variants in GNRHR favor reversal while ANOS1 variants virtually exclude HPG axis recovery.

The reversal phenomenon in males has expanded our understanding of the regulation of human reproduction-yet precise mechanism(s) have yet to be elucidated. Clinicians can use clinical signs and genetic testing to identify patients who may benefit from close surveillance of reversal. Insights from reversal of CHH reversal have helped shape the first tailored approach managing CHH.