The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor.

Mutations in the GnRH receptor (GnRH-R) gene have been reported to cause idiopathic hypogonadotropic hypogonadism (IHH). Herein, we describe a 26-yr-old male with a mild phenotypic form of IHH, the fertile eunuch syndrome (IHH in the presence of normal testicular size and some degree of spermatogenesis), associated with a homozygous mutation (Gln106Arg) in the GnRH-R. This mutation, located in the first extracellular loop of the GnRH-R, has been previously shown to decrease but not eliminate GnRH binding. The proband had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and a normal adult male testicular size of 17 mL at baseline. After only 4 months of treatment with hCG alone, he developed sperm in his ejaculate and his wife conceived. Following cessation of hCG therapy, the patient demonstrated reversal of his hypogonadotropism as evidenced by normal adult male testosterone levels and the appearance of pulsatile luteinizing hormone secretion. This case thus expands the emerging clinical spectrum of GnRH-R mutations, provides the first genetic basis for the fertile eunuch variant of IHH and documents the occurrence of reversible IHH in a patient with a GnRH-R mutation.