A Genetic Basis for Functional Hypothalamic Amenorrhea

Functional hypothalamic amenorrhea, a frequent cause of female infertility, is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency triggered by stressors, such as excessive exercise, nutritional deficits (weight loss, eating disorders), or psychological distress. These stressors suppress the hypothalamic-pituitary-gonadal axis (HPA) by inhibiting hypothalamic secretion of GnRH. Idiopathic hypogonadotropic hypogonadism is a congenital form of GnRH deficiency, with multiple genetic defects accounting for about 40% of the cases. It is unknown whether the variable susceptibility of women with hypothalamic amenorrhea to stressors reflects a genetic predisposition. This study tests the hypothesis that mutations in genes associated with idiopathic hypogonadotropic hypogonadism are causally related to the susceptibility to GnRH deficiency among women with hypothalamic amenorrhea. Genomic DNA from peripheral blood samples of 55 women with hypothalamic amenorrhea was analyzed for the presence of the known coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism. Among 7 of the 55 women with hypothalamic amenorrhea, 6 heterozygous mutations were identified: fibroblast growth factor receptor 1 gene contained 2 mutant variants (G260E and R756H), prokineticin receptor 2 gene (PROKR2) also had 2 variants (R85H and L173R), the GnRH receptor gene had 1 variant (R262Q), and the Kallmann syndrome 1 sequence gene also had 1 (V371I). A cohort of 422 control women with normal menstrual cycles contained no rare sequence variants. In vitro studies characterized the fibroblast growth factor receptor 1 gene mutants G260E and R756H, and the PROKR2 mutant R85H as loss-of-function mutations; previously, the PROKR2 mutant L173R and the GnRH receptor gene mutant R262Q had been reported as loss-of-function mutants. These findings show that genes mutated in patients with idiopathic hypogonadotropic hypogonadism are also mutated in those with hypothalamic amenorrhea. These mutations may account in part for the variable susceptibility of women to stressors leading to hypothalamic amenorrhea.