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Semin Reprod Med 2007; 25(5): 368-378
DOI: 10.1055/s-2007-984743
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Mutations in the Human Gonadotropin-Releasing Hormone Receptor: Insights into Receptor Biology and Function

Grégoy Y. Bédécarrats1 , Ursula B. Kaiser2
  • 1Department of Animal and Poultry Science, Ontario Agricultural College, University of Guelph, Guelph, Ontario, Canada
  • 2Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Further Information

Publication History

Publication Date:
20 August 2007 (online)

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ABSTRACT

Pulsatile hypothalamic release of GnRH tightly controls reproduction by activating a specific cell membrane receptor (GnRHR) on the surface of pituitary gonadotrophs to stimulate luteinizing hormone and follicle-stimulating hormone secretion. During the last 10 years, 21 loss-of-function GNRHR mutations have been identified in patients with idiopathic hypogonadotropic hypogonadism. Although most patients with hypogonadotropic hypogonadism can be treated by delivery of exogenous pulsatile GnRH, in several cases, patients with GNRHR mutations fail to respond efficiently to GnRH treatment. The impact of each mutation on GnRHR function has been studied extensively in vitro, but correlation with clinical phenotype is not always evident. By combining recent advances into the molecular mechanisms controlling ligand binding and receptor activation with data accumulated from clinical studies, this review summarizes the overall structure-function relationships of the human GnRH receptor, with an emphasis on the impact of naturally occurring mutations. Furthermore, given that it was recently demonstrated that pharmacological chaperones can rescue altered receptor function in vitro, potential therapeutic approaches are also discussed.

KEYWORDS

Gonadotropin-releasing hormone - gonadotropin-releasing hormone receptor - luteinizing hormone - follicle-stimulating hormone - hypogonadotropic hypogonadism - mutations

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Ursula B KaiserM.D. 

Associate Professor of Medicine, Chief, Division of Endocrinology, Diabetes, and Hypertension

Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

Email: ukaiser@partners.org