Spontaneous Improvement of Hypogonadotropic Hypogonadism in a Patient with PCSK1 and HS6ST1 Mutations: A Case Report

TL;DR

A man with Kallmann syndrome experienced spontaneous recovery of testosterone production after stopping androgen therapy, despite ongoing anosmia.

Contribution

This case report presents a rare instance of spontaneous improvement in hypogonadotropic hypogonadism linked to specific genetic mutations.

Findings

The patient's testosterone levels normalized after stopping androgen therapy without additional hormonal agents.

Genetic testing revealed heterozygous mutations in PCSK1 and HS6ST1, genes associated with GnRH regulation and KS.

Spontaneous recovery occurred without olfactory improvement, indicating independent restoration of reproductive function.

Abstract

Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism (HH) characterized by gonadotropin-releasing hormone (GnRH) deficiency and anosmia due to defective neuronal migration. While traditionally considered irreversible, cases of spontaneous improvement of HH have been reported, suggesting residual GnRH neuronal function in some individuals. We present a case of a 29-year-old man with KS who exhibited spontaneous recovery of endogenous testosterone production following the cessation of long-term androgen therapy without the use of alternative hormonal agents. After ceasing testosterone therapy for several months, the patient’s total testosterone levels normalized (407–424 ng/dL), accompanied by increased secondary sexual characteristics, stable gonadotropin levels, and normal testicular volume. Persistent anosmia was noted, suggesting that restoration of reproductive endocrine function can occur independently of olfactory recovery. Genetic testing identified heterozygous mutations in PCSK1 and HS6ST1, genes implicated in GnRH regulation and KS pathogenesis. This case highlights the potential role of genetic variation in spontaneous HH improvement and underscores the need for individualized management strategies, including periodic reassessment of gonadal function and fertility potential. Further research is needed to elucidate the mechanisms driving spontaneous HH improvement, identify predictive biomarkers of reversibility, and explore therapeutic strategies that may promote endogenous GnRH activity in select patients with KS.