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Expanding the Phenotype and Genotype of Female GnRH Deficiency

Lookup NU author(s): Dr Richard Quinton


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Context: GnRH deficiency is a rare genetic disorder of absent or partial pubertal development. The clinical and genetic characteristics of GnRH-deficient women have not been well-described. Objective: Todetermine the phenotypic and genotypic spectrum of a large series of GnRH-deficient women. Design, Setting, and Subjects: Retrospective study of 248 females with GnRH deficiency evaluated at an academic medical center between 1980 and 2010. Main Outcome Measures: Clinical presentation, baseline endogenous GnRH secretory activity, and DNA sequence variants in 11 genes associated with GnRH deficiency. Results: Eighty-eight percent had undergone pubarche, 51% had spontaneous thelarche, and 10% had 1-2 menses. Women with spontaneous thelarche were more likely to demonstrate normal pubarche (P = 0.04). In 27% of women, neuroendocrine studies demonstrated evidence of some endogenous GnRH secretory activity. Thirty-six percent (a large excess relative to controls) harbored a rare sequence variant in a gene associated with GnRH deficiency (87% heterozygous and 13% biallelic), with variants in FGFR1 (15%), GNRHR (6.6%), and PROKR2 (6.6%) being most prevalent. One woman had a biallelic variant in the X-linked gene, KAL1, and nine women had heterozygous variants. Conclusions: The clinical presentation of female GnRH deficiency varies from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this cohort, rare sequence variants were present in all of the known genes associated with GnRH deficiency, including the novel identification of GnRH-deficient women with KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive development requires further investigation. (J Clin Endocrinol Metab 96: E566-E576, 2011)

Publication metadata

Author(s): Shaw ND, Seminara SB, Welt CK, Au MG, Plummer L, Hughes VA, Dwyer AA, Martin KA, Quinton R, Mericq V, Merino PM, Gusella JF, Crowley WF, Pitteloud N, Hall JE

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2011

Volume: 96

Issue: 3

Pages: E566-E576

Print publication date: 01/03/2011

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: The Endocrine Society


DOI: 10.1210/jc.2010-2292


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Funder referenceFunder name
Harvard University
5T32 HD007396National Institutes of Health
M01-RR-01066National Institutes of Health/National Center for Research Resources, General Clinical Research Centers
GM061354Developmental Genome Anatomy Project
R01 HD42708Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health
UL1 RR 025758Harvard Clinical and Translational Science Center
U54 HD028138Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health