Reversal of Congenital Hypogonadotropic Hypogonadism.

Approximately 10% of male individuals with CHH undergo reversal with sustained hypothalamic-pituitary-gonadal axis activation and/or fertility after discontinuing hormonal treatment.

• Reversal is defined by sustained HPG axis activation and/or fertility after discontinuing hormonal treatment.
• The authors conducted a structured, systematic literature search identifying relevant articles published up to 2025.
• 31 articles reporting reversal of CHH in males were identified.
• Cases included those with severe GnRH deficiency and individuals harboring pathogenic variants in CHH genes.

Reversal of CHH is distinct from delayed puberty, and olfactory phenotype does not predict HPG axis recovery.

• Anosmia (absent sense of smell) does not predict whether an individual will experience HPG axis recovery.
• The distinction from delayed puberty is an important clinical consideration noted by the authors.
• Cases exist on a continuum from normosmic individuals with severe GnRH deficiency to milder cases with partial spontaneous puberty (Pasqualini syndrome subtype).

In males, reversal universally occurs after achieving normal serum testosterone levels on hormone therapy.

• Testicular growth on testosterone replacement is described as a hallmark of HPG axis activation.
• Reversal is not always lasting after it occurs.
• The authors note that achieving normal serum testosterone levels on hormone therapy appears to be a prerequisite for reversal.

Specific genetic variants in CHH-associated genes differentially predict likelihood of HPG axis reversal.

• Pathogenic variants in GNRHR favor reversal of CHH.
• ANOS1 variants virtually exclude HPG axis recovery.
• Genetic testing is recommended alongside clinical signs to identify patients who may benefit from close surveillance of reversal.

Insights from CHH reversal have helped shape the first tailored approach to managing CHH.

• The reversal phenomenon has expanded understanding of the regulation of human reproduction.
• Precise mechanisms underlying reversal have yet to be elucidated.
• Clinicians can use clinical signs and genetic testing to identify patients who may benefit from close surveillance.