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Some, but not all, women develop hypothalamic amenorrhea (HA) in association with exercise and/or food restriction. We hypothesized that variants in genes associated with the more severe hypogonadotropic disorder, idiopathic hypogonadotropic hypogonadism (IHH), may contribute to a given woman’s susceptibility to HA when she is faced with a physiologic stressor. Indeed, rare sequence variants (RSVs) in IHH-associated genes were previously identified in women with HA that were absent in controls1. This study, however, used a variant-level, as opposed to the now preferred gene-level, approach and only examined 7 genes. To build upon these earlier findings and provide more definitive support for our hypothesis, we screened 106 women with HA and 477 controls for RSVs in a much larger IHH-gene panel (n=54 genes) using exome sequencing. Healthy controls were a convenience sample drawn from the ClinSeq Project2 who had originally been selected for a range of atherosclerosis risk phenotypes, but were unselected for reproductive phenotypes. We compared the frequency of RSVs (moderate- to high-impact, minor allele frequency [MAF] < 1%) across all 54 genes in HA compared with controls using a rare variant burden test (Fisher’s exact test. We identified 54 heterozygous RSVs (51 missense, 1 nonsense, 2 frameshift; 27.4% of alleles) in 46 HA women (1-3 RSVs/woman, 58 total RSVs, 12 subjects with >1 RSV) and 149 heterozygous RSVs (141 missense, 1 nonsense, 4 frameshift, 3 inframe indels; 18.8%) in 146 control women (1-4 RSVs/woman, 179 total RSVs, 28 subjects with >1 RSV) which represents a significantly increased burden of RSVs in HA (P = 0.006). A slightly greater proportion of RSVs in the HA group were considered damaging/deleterious by both Polyphen2 and SIFT vs controls (41.1% vs 36.0%), but this was not statistically significant. Thus, women with HA are significantly enriched for RSVs in genes that cause IHH as compared with controls. These results indicate that the risk of developing HA with exposure to physiologic stressors may indeed be increased in the presence of heterozygous protein-altering variants in genes related to the regulation of GnRH neuronal development and function. 1 Caronia LM, et al. N Engl J Med. 2011;364:215-25. 2 Biesecker LG, et al. Genome Res. 2009;19:1665-74. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO. |
