This Article Full Text Full Text (PDF) Alert me when this article is cited 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 Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seminara, S. B. Articles by Crowley, W. F. Search for Related Content PubMed PubMed Citation Articles by Seminara, S. B. Articles by Crowley, W. F., Jr.

Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann’s Syndrome): Pathophysiological and Genetic Considerations

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

I. Introduction

II. Ontogeny of Normal GnRH Secretion

A. Fetal life

B. Neonatal and childhood periods

C. Puberty

D. Adulthood

III. Historical Perspective

IV. Clinical Presentation of GnRH Deficiency

A. Congenital GnRH deficiency

B. Adult-onset GnRH deficiency

C. Variant or partial forms of GnRH deficiency

D. Associated anomalies in KS

E. Differential diagnosis

V. Approaches to Studying GnRH Secretion

A. Animal and in vitro studies

B. Human studies

VI. Patterns of GnRH Secretion in Men with GnRH Deficiency

VII. Patterns of GnRH Secretion in Women with GnRH Deficiency

VIII. Genetic Studies

IX. X-Linked Genes Controlling GnRH Secretion

A. Kallmann’s syndrome gene

B. Adrenal hypoplasia congenita (AHC) gene product

X. Autosomal Genes Controlling GnRH Secretion

A. The genetics of autosomal inheritance

B. GnRH gene

C. GnRH receptor gene

D. Other autosomal genes

XI. Conclusion

This article has been cited by other articles:

				N. A. Ciccone, S. Xu, C. T. Lacza, R. S. Carroll, and U. B. Kaiser Frequency-Dependent Regulation of Follicle-Stimulating Hormone {beta} by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors Mol. Cell. Biol., February 15, 2010; 30(4): 1028 - 1040. [Abstract] [Full Text] [PDF]

				T. Raivio, Y. Sidis, L. Plummer, H. Chen, J. Ma, A. Mukherjee, E. Jacobson-Dickman, R. Quinton, G. Van Vliet, H. Lavoie, et al. Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4380 - 4390. [Abstract] [Full Text] [PDF]

				M. Koenigkam-Santos, A.C. Santos, T. Borduqui, B.R. Versiani, J.E.C. Hallak, J.A.S. Crippa, and M. Castro Whole-Brain Voxel-Based Morphometry in Kallmann Syndrome Associated with Mirror Movements AJNR Am. J. Neuroradiol., October 1, 2008; 29(9): 1799 - 1804. [Abstract] [Full Text] [PDF]

				A. P. Abreu, E. B. Trarbach, M. de Castro, E. M. Frade Costa, B. Versiani, M. T. Matias Baptista, H. M. Garmes, B. B. Mendonca, and A. C. Latronico Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4113 - 4118. [Abstract] [Full Text] [PDF]

				L. W. Cole, Y. Sidis, C. Zhang, R. Quinton, L. Plummer, D. Pignatelli, V. A. Hughes, A. A. Dwyer, T. Raivio, F. J. Hayes, et al. Mutations in Prokineticin 2 and Prokineticin receptor 2genes in Human Gonadotrophin-Releasing Hormone Deficiency: Molecular Genetics and Clinical Spectrum J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3551 - 3559. [Abstract] [Full Text] [PDF]

				N. Pitteloud, A. A. Dwyer, S. DeCruz, H. Lee, P. A. Boepple, W. F. Crowley Jr., and F. J. Hayes The Relative Role of Gonadal Sex Steroids and Gonadotropin-Releasing Hormone Pulse Frequency in the Regulation of Follicle-Stimulating Hormone Secretion in Men J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2686 - 2692. [Abstract] [Full Text] [PDF]

				L. M. Cotton, M. K. O'Bryan, and B. T. Hinton Cellular Signaling by Fibroblast Growth Factors (FGFs) and Their Receptors (FGFRs) in Male Reproduction Endocr. Rev., April 1, 2008; 29(2): 193 - 216. [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]

				R. S. Ribeiro, T. C. Vieira, and J. Abucham Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review Eur. J. Endocrinol., March 1, 2007; 156(3): 285 - 290. [Abstract] [Full Text] [PDF]

				S. P Brothers, J. A. Janovick, and P M. Conn Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression J. Mol. Endocrinol., December 1, 2006; 37(3): 479 - 488. [Abstract] [Full Text] [PDF]

				E. B. Trarbach, E. M. F. Costa, B. Versiani, M. de Castro, M. T. M. Baptista, H. M. Garmes, B. B. de Mendonca, and A. C. Latronico Novel Fibroblast Growth Factor Receptor 1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism with and without Anosmia J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4006 - 4012. [Abstract] [Full Text] [PDF]

				N. Pitteloud, J. S. Acierno Jr., A. Meysing, A. V. Eliseenkova, J. Ma, O. A. Ibrahimi, D. L. Metzger, F. J. Hayes, A. A. Dwyer, V. A. Hughes, et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism PNAS, April 18, 2006; 103(16): 6281 - 6286. [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]

				A. Cariboni, S. Rakic, A. Liapi, R. Maggi, A. Goffinet, and J. G. Parnavelas Reelin provides an inhibitory signal in the migration of gonadotropin-releasing hormone neurons Development, November 1, 2005; 132(21): 4709 - 4718. [Abstract] [Full Text] [PDF]

				G. Pinto, V. Abadie, R. Mesnage, J. Blustajn, S. Cabrol, J. Amiel, L. Hertz-Pannier, A. M. Bertrand, S. Lyonnet, R. Rappaport, et al. CHARGE Syndrome Includes Hypogonadotropic Hypogonadism and Abnormal Olfactory Bulb Development J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5621 - 5626. [Abstract] [Full Text] [PDF]

				M. M. Grumbach A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3122 - 3127. [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]

				J. S. Jorgensen, C. C. Quirk, and J. H. Nilson Multiple and Overlapping Combinatorial Codes Orchestrate Hormonal Responsiveness and Dictate Cell-Specific Expression of the Genes Encoding Luteinizing Hormone Endocr. Rev., August 1, 2004; 25(4): 521 - 542. [Abstract] [Full Text] [PDF]

				S. P. Brothers, A. Cornea, J. A. Janovick, and P. M. Conn Human Loss-of-Function Gonadotropin-Releasing Hormone Receptor Mutants Retain Wild-Type Receptors in the Endoplasmic Reticulum: Molecular Basis of the Dominant-Negative Effect Mol. Endocrinol., July 1, 2004; 18(7): 1787 - 1797. [Abstract] [Full Text] [PDF]

				I. Fahmy, A. Kamal, R. Shamloul, R. Mansour, G. Serour, and M. Aboulghar ICSI using testicular sperm in male hypogonadotrophic hypogonadism unresponsive to gonadotrophin therapy Hum. Reprod., July 1, 2004; 19(7): 1558 - 1561. [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]

				A. Ulloa-Aguirre, J. A. Janovick, A. Leanos-Miranda, and P. M. Conn Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism Hum. Reprod. Update, March 1, 2004; 10(2): 177 - 192. [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]

				S. B. Seminara, S. Messager, E. E. Chatzidaki, R. R. Thresher, J. S. Acierno Jr., J. K. Shagoury, Y. Bo-Abbas, W. Kuohung, K. M. Schwinof, A. G. Hendrick, et al. The GPR54 Gene as a Regulator of Puberty N. Engl. J. Med., October 23, 2003; 349(17): 1614 - 1627. [Abstract] [Full Text] [PDF]

				N. de Roux, E. Genin, J.-C. Carel, F. Matsuda, J.-L. Chaussain, and E. Milgrom Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 PNAS, September 16, 2003; 100(19): 10972 - 10976. [Abstract] [Full Text] [PDF]

				N. Massin, C. Pecheux, C. Eloit, J.-L. Bensimon, J. Galey, F. Kuttenn, J.-P. Hardelin, C. Dode, and P. Touraine X Chromosome-Linked Kallmann Syndrome: Clinical Heterogeneity in Three Siblings Carrying an Intragenic Deletion of the KAL-1 Gene J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2003 - 2008. [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]

				C. P. Leo, S. Y. Hsu, and A. J. W. Hsueh Hormonal Genomics Endocr. Rev., June 1, 2002; 23(3): 369 - 381. [Abstract] [Full Text] [PDF]

				J. C. Achermann, G. Ozisik, J. J. Meeks, and J. L. Jameson Genetic Causes of Human Reproductive Disease J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2447 - 2454. [Full Text] [PDF]

				I. L. Sedlmeyer and M. R. Palmert Delayed Puberty: Analysis of a Large Case Series from an Academic Center J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1613 - 1620. [Abstract] [Full Text] [PDF]

				M. P. Allen, D. A. Linseman, H. Udo, M. Xu, J. B. Schaack, B. Varnum, E. R. Kandel, K. A. Heidenreich, and M. E. Wierman Novel Mechanism for Gonadotropin-Releasing Hormone Neuronal Migration Involving Gas6/Ark Signaling to p38 Mitogen-Activated Protein Kinase Mol. Cell. Biol., January 15, 2002; 22(2): 599 - 613. [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]

				M. R. Palmert and P. A. Boepple Variation in the Timing of Puberty: Clinical Spectrum and Genetic Investigation J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2364 - 2368. [Abstract] [Full Text] [PDF]

				N. Pitteloud, P. A. Boepple, S. DeCruz, S. B. Valkenburgh, W. F. Crowley Jr., and F. J. Hayes The Fertile Eunuch Variant of Idiopathic Hypogonadotropic Hypogonadism: Spontaneous Reversal Associated with a Homozygous Mutation in the Gonadotropin-Releasing Hormone Receptor J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2470 - 2475. [Abstract] [Full Text] [PDF]

				A. P. N. Themmen and I. T. Huhtaniemi Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function Endocr. Rev., October 1, 2000; 21(5): 551 - 583. [Abstract] [Full Text]

				M.-L. Kottler, S. Chauvin, N. Lahlou, C. E. Harris, C. J. Johnston, J.-P. Lagarde, P. Bouchard, N. R. Farid, and R. Counis A New Compound Heterozygous Mutation of the Gonadotropin-Releasing Hormone Receptor (L314X, Q106R) in a Woman with Complete Hypogonadotropic Hypogonadism: Chronic Estrogen Administration Amplifies the Gonadotropin Defect J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3002 - 3008. [Abstract] [Full Text]

				R. Maggi, F. Pimpinelli, L. Molteni, M. Milani, L. Martini, and F. Piva Immortalized Luteinizing Hormone-Releasing Hormone Neurons Show a Different Migratory Activity in Vitro Endocrinology, June 1, 2000; 141(6): 2105 - 2112. [Abstract] [Full Text] [PDF]

				Mutational Analysis of DAX1 in Patients with Hypogonadotropic Hypogonadism or Pubertal Delay J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4497 - 4500. [Abstract] [Full Text]

				J. C. Achermann and J. L. Jameson Fertility and Infertility: Genetic Contributions from the Hypothalamic-Pituitary- Gonadal Axis Mol. Endocrinol., June 1, 1999; 13(6): 812 - 818. [Full Text]