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A Genetic Basis for Functional Hypothalamic Amenorrhea

Lookup NU author(s): Caroline Martin, Dr Richard Quinton, Katherine Martin

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Abstract

Background: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. Methods: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. Results: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. Conclusions: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.) N Engl J Med 2011;364:215-25.


Publication metadata

Author(s): Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, Seminara SB, Boepple PA, Sidis Y, Crowley WF, Martin KA, Hall JE, Pitteloud N

Publication type: Article

Publication status: Published

Journal: New England Journal of Medicine

Year: 2011

Volume: 364

Issue: 3

Pages: 215-225

Print publication date: 01/01/2011

Date deposited: 16/02/2011

ISSN (print): 0028-4793

ISSN (electronic): 1533-4406

Publisher: Massachusetts Medical Society

URL: http://dx.doi.org/10.1056/NEJMoa0911064

DOI: 10.1056/NEJMoa0911064


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Funding

Funder referenceFunder name
Pew Latin American Fellows Program in the Biomedical Sciences
Newcastle University Teaching Hospitals Special Trustees
1R01HD056264Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH)
1 UL1 RR025758-01National Center for Research Resources
5R01HD015788Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH)
5R01HD42708Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH)
5U54HD028138Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH)
M01-RR-01066National Center for Research Resources

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