Genetics May Play a Role in Hypothalamic Amenorrhea

Rare variants of genes involved in idiopathic hypogonadotropic hypogonadism contribute to the occurrence of functional hypothalamic amenorrhea in some women. Predisposing factors such as weight loss, excessive exercise, eating disorders, and psychological distress can lead to functional hypothalamic amenorrhea, a reversible form of gonadotropin-releasing hormone (GnRH) deficiency, according to a study reported in the New England Journal of Medicine [2011;364(3):215-225]. Researchers from Massachusetts General Hospital analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women diagnosed with hypothalamic amenorrhea and 422 control women. The 55 women presented to the Massachusetts General Hospital or Newcastle upon Tyne Hospital with a history of secondary amenorrhea for ≥6 months, low or normal gonadotropin levels, and low serum estradiol levels. Furthermore, all had at least 1 predisposing factor. All 55 women had completed puberty spontaneously. The mean age at diagnosis was 22.4±6.1 years, the mean body mass index (BMI) was 19.4±2.2, and the mean age at menarche was 13.5±1.8 years. The control group from the greater Boston area, which was recruited by means of advertising, had undergone normal puberty, had a normal menstrual cycle for the previous 2 years, and a BMI between 18 and 35. A total of 6 heterozygous mutations were identified in 7 of the 55 women (13%, 95% confidence interval, 5-24). There were 2 variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), 2 in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), 1 in the GnRH receptor gene GNRHR (R262Q), and 1 in the Kallmann syndrome 1 sequence gene KAL1 (V371I). These genetic variants were absent among the controls without risk factors for hypothalamic amenorrhea (n=375) and among those who exercised >5 hours per week (n=47). All 7 patients with hypothalamic amenorrhea who had mutations had secondary amenorrhea for at least 6 months and at least 1 risk factor for hypothalamic amenorrhea. Of the 7 women with gene variants, 4 reported a family history of hypothalamic amenorrhea or delayed puberty. Four of the 7 patients had attempted to conceive; 3 of the attempts were successful, with 1 patient conceiving without assisted reproductive treatment. Two of the 7 women continued to receive long-term hormone replacement therapy. The other 5 women discontinued hormonal therapy and had recovery of menses. In vitro assays found that the FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H variants led to loss of function. This had been previously demonstrated for the PROKR2 L173R and GNRHR R262Q variants. “We speculate that such heterozygous mutations, while not sufficient to cause idiopathic hypogonadotropic hypogonadism, could set a lower threshold for functional inhibition of the hypothalamicpituitary-gonadal axis under adverse hormonal, nutritional, or psychological conditions and thereby lead to hypothalamic amenorrhea,” wrote the researchers. This study demonstrated that rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea. These mutations may contribute to individual susceptibility to functional changes in GnRH secretion. “Our observations provide evidence for the role of rare variants in common multifactorial disease,” the researchers concluded. A limitation noted by the authors was the small cohort with hypothalamic amenorrhea. To elucidate the genetics of hypothalamic amenorrhea more completely, the authors noted the importance of a comprehensive sequencing of genes associated with idiopathic hypogonadotropic hypogonadism in larger cohorts of patients with hypothalamic amenorrhea. Given the limited size of the cohort, the researchers cautioned against women with hypothalamic amenorrhea being “routinely screened for mutations at loci known to underlie idiopathic hypogonadotropic hypogonadism, except in cases of clear familial inheritance of hypothalamic amenorrhea or idiopathic hypogonadotropic hypogonadism.”