Reversible congenital hypogonadotropic hypogonadism: keys for clinical management.

Congenitalhypogonadotropic hypogonadism (CHH) is characterized by absent/incomplete puberty and a treatable form of male infertility resulting from deficient gonadotropin-releasing hormone (GnRH) secretion/action. Traditionally, CHH has been considered a permanent, lifelong condition. However, evidence indicates a subset men undergo reversal and recover reproductive axis function. We conducted a structured literature search (Medline, PubMed) using keywords to retrieve articles on CHH reversal (1975-2025). We synthesize the literature to provide a high-level overview of CHH and the reversal phenomenon in males. Particular focus is given to clinical aspects of CHH and reversal using a case vignette to highlight keys to management. Approximately 10-15% of males with CHH undergo reversal with sustained normalized testosterone levels and spermatogenesis off treatment. A key sign of reversal is testicular growth while on testosterone replacement therapy. Those men with some degree of spontaneous puberty (i.e., larger testicular volume), detectable follicle stimulating hormone levels , and/or pathogenic variants in GNRHR are more likely to undergo reversal. In contrast, severe GnRH deficiency, pathogenic ANOS1 and/or two or more combined pathogenic variants (oligogenicity) in CHH genes are less likely to recover reproductive axis function. Reversal is not lasting in all cases. The reversal phenomenon challenges the classical dogma that CHH is permanent and lifelong. Reversal cases highlight the plasticity of the neuroendocrine control of reproduction. Clinicians can tailor the approach to men with CHH using reversal predictors to guide supervise washout to identify reversal as well as long-term monitoring to assess potential relapse.