This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pitteloud, N. Articles by Hayes, F. J. Search for Related Content PubMed PubMed Citation Articles by Pitteloud, N. Articles by Hayes, F. J.

The Fertile Eunuch Variant of Idiopathic Hypogonadotropic Hypogonadism: Spontaneous Reversal Associated with a Homozygous Mutation in the Gonadotropin-Releasing Hormone Receptor¹

Reproductive Endocrine Unit of the Department of Medicine and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Nelly Pitteloud, M.D., Reproductive Endocrine Unit and National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: npitteloud{at}partners.org

Abstract

Mutations in the GnRH receptor (GnRH-R) gene have been reported to cause idiopathic hypogonadotropic hypogonadism (IHH). Herein, we describe a 26-yr-old male with a mild phenotypic form of IHH, the fertile eunuch syndrome (IHH in the presence of normal testicular size and some degree of spermatogenesis), associated with a homozygous mutation (Gln106Arg) in the GnRH-R. This mutation, located in the first extracellular loop of the GnRH-R, has been previously shown to decrease but not eliminate GnRH binding. The proband had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and a normal adult male testicular size of 17 mL at baseline. After only 4 months of treatment with hCG alone, he developed sperm in his ejaculate and his wife conceived. Following cessation of hCG therapy, the patient demonstrated reversal of his hypogonadotropism as evidenced by normal adult male testosterone levels and the appearance of pulsatile luteinizing hormone secretion.

This case thus expands the emerging clinical spectrum of GnRH-R mutations, provides the first genetic basis for the fertile eunuch variant of IHH and documents the occurrence of reversible IHH in a patient with a GnRH-R mutation.

This article has been cited by other articles:

				A. A. Sinisi, R. Asci, G. Bellastella, L. Maione, D. Esposito, A. Elefante, A. De Bellis, A. Bellastella, and A. Iolascon Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: Case Report Hum. Reprod., October 1, 2008; 23(10): 2380 - 2384. [Abstract] [Full Text] [PDF]

				T. Raivio, J. Falardeau, A. Dwyer, R. Quinton, F. J. Hayes, V. A. Hughes, L. W. Cole, S. H. Pearce, H. Lee, P. Boepple, et al. Reversal of Idiopathic Hypogonadotropic Hypogonadism N. Engl. J. Med., August 30, 2007; 357(9): 863 - 873. [Abstract] [Full Text] [PDF]

				L. Lin, G. S. Conway, N. R. Hill, M. T. Dattani, P. C. Hindmarsh, and J. C. Achermann A Homozygous R262Q Mutation in the Gonadotropin-Releasing Hormone Receptor Presenting as Constitutional Delay of Growth and Puberty with Subsequent Borderline Oligospermia J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5117 - 5121. [Abstract] [Full Text] [PDF]

				F. Cerrato, J. Shagoury, M. Kralickova, A. Dwyer, J. Falardeau, M. Ozata, G. Van Vliet, P. Bouloux, J. E Hall, F. J Hayes, et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S3 - S10. [Abstract] [Full Text] [PDF]

				A. Antelli, L. Baldazzi, A. Balsamo, P. Pirazzoli, A. Nicoletti, M. Gennari, and A. Cicognani Two novel GnRHR gene mutations in two siblings with hypogonadotropic hypogonadism. Eur. J. Endocrinol., August 1, 2006; 155(2): 201 - 205. [Abstract] [Full Text] [PDF]

				F. Lanfranco, J. Gromoll, S. von Eckardstein, E. M Herding, E. Nieschlag, and M. Simoni Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism Eur. J. Endocrinol., December 1, 2005; 153(6): 845 - 852. [Abstract] [Full Text] [PDF]

				C. K. Cheng and P. C. K. Leung Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans Endocr. Rev., April 1, 2005; 26(2): 283 - 306. [Abstract] [Full Text] [PDF]

				N. Pitteloud, J. S. Acierno Jr., A. U. Meysing, A. A. Dwyer, F. J. Hayes, and W. F. Crowley Jr. Reversible Kallmann Syndrome, Delayed Puberty, and Isolated Anosmia Occurring in a Single Family with a Mutation in the Fibroblast Growth Factor Receptor 1 Gene J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1317 - 1322. [Abstract] [Full Text] [PDF]

				A. U. Meysing, H. Kanasaki, G. Y. Bedecarrats, J. S. Acierno Jr., P. M. Conn, K. A. Martin, S. B. Seminara, J. E. Hall, W. F. Crowley Jr., and U. B. Kaiser GNRHR Mutations in a Woman with Idiopathic Hypogonadotropic Hypogonadism Highlight the Differential Sensitivity of Luteinizing Hormone and Follicle-Stimulating Hormone to Gonadotropin-Releasing Hormone J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3189 - 3198. [Abstract] [Full Text] [PDF]

				R. P. Millar, Z.-L. Lu, A. J. Pawson, C. A. Flanagan, K. Morgan, and S. R. Maudsley Gonadotropin-Releasing Hormone Receptors Endocr. Rev., April 1, 2004; 25(2): 235 - 275. [Abstract] [Full Text] [PDF]

				S. P. Brothers, J. A. Janovick, and P. M. Conn Unexpected Effects of Epitope and Chimeric Tags on Gonadotropin-Releasing Hormone Receptors: Implications for Understanding the Molecular Etiology of Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6107 - 6112. [Abstract] [Full Text] [PDF]

				Y. Bo-Abbas, J. S. Acierno Jr., J. K. Shagoury, W. F. Crowley Jr., and S. B. Seminara Autosomal Recessive Idiopathic Hypogonadotropic Hypogonadism: Genetic Analysis Excludes Mutations in the Gonadotropin-Releasing Hormone (GnRH) and GnRH Receptor Genes J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2730 - 2737. [Abstract] [Full Text] [PDF]

				B. Karges, W. Karges, M. Mine, L. Ludwig, R. Kuhne, E. Milgrom, and N. de Roux Mutation Ala171Thr Stabilizes the Gonadotropin-Releasing Hormone Receptor in Its Inactive Conformation, Causing Familial Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1873 - 1879. [Abstract] [Full Text] [PDF]

				G. Y. Bedecarrats, K. D. Linher, and U. B. Kaiser Two Common Naturally Occurring Mutations in the Human Gonadotropin-Releasing Hormone (GnRH) Receptor Have Differential Effects on Gonadotropin Gene Expression and on GnRH-Mediated Signal Transduction J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 834 - 843. [Abstract] [Full Text] [PDF]

				N. Pitteloud, F. J. Hayes, A. Dwyer, P. A. Boepple, H. Lee, and W. F. Crowley Jr. Predictors of Outcome of Long-Term GnRH Therapy in Men with Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4128 - 4136. [Abstract] [Full Text] [PDF]

				L. F. G. Silveira, P. M. Stewart, M. Thomas, D. A. Clark, P. M. G. Bouloux, and G. S. MacColl Novel Homozygous Splice Acceptor Site GnRH Receptor (GnRHR) Mutation: Human GnRHR "Knockout" J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2973 - 2977. [Abstract] [Full Text] [PDF]

				N. Pitteloud, F. J. Hayes, P. A. Boepple, S. DeCruz, S. B. Seminara, D. T. MacLaughlin, and W. F. Crowley Jr. The Role of Prior Pubertal Development, Biochemical Markers of Testicular Maturation, and Genetics in Elucidating the Phenotypic Heterogeneity of Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 152 - 160. [Abstract] [Full Text] [PDF]