Cited by 256Hypothalamic control of reproductive hormonesPituitary Gland Disorders and TreatmentsReproductive Biology and Fertility

A genetic basis for functional hypothalamic amenorrhea

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Caronia, Lisa M., Martin, Cecilia, Welt, Corrine K., Sykiotis, Gerasimos P., Quinton, Richard, Thambundit, Apisadaporn, Avbelj, Magdalena, Dhruvakumar, Sadhana +9 more·2011·New England Journal of Medicine

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.).

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Authors
Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Martin, K. A., Hall, J. E., & Pitteloud, N.
Affiliations
  • Harvard University (US)
  • Newcastle University (GB)
Venue
New England Journal of Medicine
Published
2011-01-20
Volume
364
Issue
3
Pages
215-225
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
OpenAlex
W2343831581
Cited by
256
References
49
Citations by year
2026: 3 · 2025: 12 · 2024: 15 · 2023: 11 · 2022: 15 · 2021: 17 · 2020: 18 · 2019: 23 · 2018: 13 · 2017: 14 · 2016: 13 · 2015: 15 · 2014: 15 · 2013: 24 · 2012: 26
FWCI
29.30
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
  • IRIS (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Harvard Catalyst (1UL1RR025758, 1 UL1 RR 025758‐01, UL1-RR025758, UL1 RR025758-01, RR025758, M01RR01066)
  • Newcastle University
  • National Institutes of Health (UL1RR02575801)
  • National Institute on Aging (R01AG013241)
  • National Institute of Child Health and Human Development
  • National Center for Research Resources (UL1RR025758, M01RR001066, M01-RR01066)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD015788, R01HD043341, 5R01HD42708, R01HD042708, R01HD056264, U54HD028138)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
functional hypothalamic amenorrhea, idiopathic hypogonadotropic hypogonadism, GnRH deficiency, genetic susceptibility, FGFR1, PROKR2, GnRH receptor, KAL1, rare variants, loss-of-function mutations, Kallmann syndrome, reproductive axis
MeSH terms
Amenorrhea, Female, Humans, Hypogonadism, Hypothalamic Diseases, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Mutation, Nerve Tissue Proteins, Protein Precursors, Receptors, LHRH, Gene Expression, Extracellular Matrix Proteins, Sequence Analysis, DNA, Receptors, Peptide, Genetic Predisposition to Disease, Receptors, G-Protein-Coupled, Receptor, Fibroblast Growth Factor, Type 1

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