This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Themmen, A. P. N. Articles by Huhtaniemi, I. T. Search for Related Content PubMed PubMed Citation Articles by Themmen, A. P. N. Articles by Huhtaniemi, I. T.

Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function

Department of Endocrinology and Reproduction (A.P.N.T.), Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands; and Department of Physiology (I.T.H.), University of Turku, 20520 Turku, Finland

The recent unraveling of structures of genes for the gonadotropin subunits and gonadotropin receptors has provided reproductive endocrinologists with new tools to study normal and pathological functions of the hypothalamic-pituitary-gonadal axis. Rare inactivating mutations that produce distinctive phenotypes of isolated LH or FSH deficiency have been discovered in gonadotropin subunit genes. In addition, there is a common polymorphism in the LHß subunit gene with possible clinical significance as a contributing factor to pathologies of LH-dependent gonadal functions. Both activating and inactivating mutations have been detected in the gonadotropin receptor genes, a larger number in the LH receptor gene, but so far only a few in the gene for the FSH receptor. These mutations corroborate and extend our knowledge of clinical consequences of gonadotropin resistance and inappropriate gonadotropin action. The information obtained from human mutations has been complemented by animal models with disrupted or inappropriately activated gonadotropin ligand or receptor genes. These clinical and experimental genetic disease models form a powerful tool for exploring the physiology and pathophysiology of gonadotropin function and provide an excellent example of the power of molecular biological approaches in the study of pathogenesis of diseases.

This article has been cited by other articles:

				M. Bruysters, S. Christin-Maitre, M. Verhoef-Post, C. Sultan, J. Auger, I. Faugeron, L. Larue, S. Lumbroso, A.P.N. Themmen, and P. Bouchard A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister Hum. Reprod., August 1, 2008; 23(8): 1917 - 1923. [Abstract] [Full Text] [PDF]

				R. A. L. Bayne, T. Forster, S. T. G. Burgess, M. Craigon, M. J. Walton, D. T. Baird, P. Ghazal, and R. A. Anderson Molecular Profiling of the Human Testis Reveals Stringent Pathway-Specific Regulation of RNA Expression Following Gonadotropin Suppression and Progestogen Treatment J Androl, July 1, 2008; 29(4): 389 - 403. [Abstract] [Full Text] [PDF]

				D. Thevenin and T. Lazarova Stable interactions between the transmembrane domains of the adenosine A2A receptor Protein Sci., July 1, 2008; 17(7): 1188 - 1199. [Abstract] [Full Text] [PDF]

				S. Mueller, G. Kleinau, H. Jaeschke, R. Paschke, and G. Krause Extended Hormone Binding Site of the Human Thyroid Stimulating Hormone Receptor: DISTINCTIVE ACIDIC RESIDUES IN THE HINGE REGION ARE INVOLVED IN BOVINE THYROID STIMULATING HORMONE BINDING AND RECEPTOR ACTIVATION J. Biol. Chem., June 27, 2008; 283(26): 18048 - 18055. [Abstract] [Full Text] [PDF]

				S. M. HAWKINS and M. M. MATZUK The Menstrual Cycle: Basic Biology Ann. N.Y. Acad. Sci., June 1, 2008; 1135(1): 10 - 18. [Abstract] [Full Text] [PDF]

				P. J. O'Shaughnessy, P. J. Baker, A. Monteiro, S. Cassie, S. Bhattacharya, and P. A. Fowler Developmental Changes in Human Fetal Testicular Cell Numbers and Messenger Ribonucleic Acid Levels during the Second Trimester J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4792 - 4801. [Abstract] [Full Text] [PDF]

				M. Zhang, Y.-X. Tao, G. L. Ryan, X. Feng, F. Fanelli, and D. L. Segaloff Intrinsic Differences in the Response of the Human Lutropin Receptor Versus the Human Follitropin Receptor to Activating Mutations J. Biol. Chem., August 31, 2007; 282(35): 25527 - 25539. [Abstract] [Full Text] [PDF]

				A. Lofrano-Porto, G. B. Barra, L. A. Giacomini, P. P. Nascimento, A. C. Latronico, L. A. Casulari, and F. d. A. da Rocha Neves Luteinizing Hormone Beta Mutation and Hypogonadism in Men and Women N. Engl. J. Med., August 30, 2007; 357(9): 897 - 904. [Abstract] [Full Text] [PDF]

				S. Bhasin Experiments of Nature -- A Glimpse into the Mysteries of the Pubertal Clock N. Engl. J. Med., August 30, 2007; 357(9): 929 - 932. [Full Text] [PDF]

				K. Shiraishi and M. Ascoli Lutropin/Choriogonadotropin Stimulate the Proliferation of Primary Cultures of Rat Leydig Cells through a Pathway that Involves Activation of the Extracellularly Regulated Kinase 1/2 Cascade Endocrinology, July 1, 2007; 148(7): 3214 - 3225. [Abstract] [Full Text] [PDF]

				J.-H. Choi, A. S. T. Wong, H.-F. Huang, and P. C. K. Leung Gonadotropins and Ovarian Cancer Endocr. Rev., June 1, 2007; 28(4): 440 - 461. [Abstract] [Full Text] [PDF]

				R P Amann and D N R Veeramachaneni Cryptorchidism in common eutherian mammals Reproduction, March 1, 2007; 133(3): 541 - 561. [Abstract] [Full Text] [PDF]

				N. Andric and M. Ascoli A Delayed Gonadotropin-Dependent and Growth Factor-Mediated Activation of the Extracellular Signal-Regulated Kinase 1/2 Cascade Negatively Regulates Aromatase Expression in Granulosa Cells Mol. Endocrinol., December 1, 2006; 20(12): 3308 - 3320. [Abstract] [Full Text] [PDF]

				S. Mueller, G. Kleinau, H. Jaeschke, S. Neumann, G. Krause, and R. Paschke Significance of Ectodomain Cysteine Boxes 2 and 3 for the Activation Mechanism of the Thyroid-stimulating Hormone Receptor J. Biol. Chem., October 20, 2006; 281(42): 31638 - 31646. [Abstract] [Full Text] [PDF]

				J. Van Durme, F. Horn, S. Costagliola, G. Vriend, and G. Vassart GRIS: Glycoprotein-Hormone Receptor Information System Mol. Endocrinol., September 1, 2006; 20(9): 2247 - 2255. [Abstract] [Full Text] [PDF]

				K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws Ovarian follicle development and transgenic mouse models Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555. [Abstract] [Full Text] [PDF]

				M. Poutanen Toward understanding the endocrine regulation of gonadal somatic cells. Endocrinology, August 1, 2006; 147(8): 3662 - 3665. [Full Text] [PDF]

				H. F. Vischer, J. C. M. Granneman, and J. Bogerd Identification of Follicle-Stimulating Hormone-Selective {beta}-Strands in the N-Terminal Hormone-Binding Exodomain of Human Gonadotropin Receptors Mol. Endocrinol., August 1, 2006; 20(8): 1880 - 1893. [Abstract] [Full Text] [PDF]

				M. J. Walton, R. A. L. Bayne, I. Wallace, D. T. Baird, and R. A. Anderson Direct Effect of Progestogen on Gene Expression in the Testis during Gonadotropin Withdrawal and Early Suppression of Spermatogenesis J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2526 - 2533. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]

				D. Piersma, E. M. J. J. Berns, M. Verhoef-Post, A. G. Uitterlinden, I. Braakman, H. A. P. Pols, and A. P. N. Themmen A Common Polymorphism Renders the Luteinizing Hormone Receptor Protein More Active by Improving Signal Peptide Function and Predicts Adverse Outcome in Breast Cancer Patients J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1470 - 1476. [Abstract] [Full Text] [PDF]

				T. Mizutani, K. Shiraishi, T. Welsh, and M. Ascoli Activation of the Lutropin/Choriogonadotropin Receptor in MA-10 Cells Leads to the Tyrosine Phosphorylation of the Focal Adhesion Kinase by a Pathway that Involves Src Family Kinases Mol. Endocrinol., March 1, 2006; 20(3): 619 - 630. [Abstract] [Full Text] [PDF]

				P. Lamba, M. M Santos, D. P Philips, and D. J Bernard Acute regulation of murine follicle-stimulating hormone {beta} subunit transcription by activin A J. Mol. Endocrinol., February 1, 2006; 36(1): 201 - 220. [Abstract] [Full Text] [PDF]

				D. PUETT, Y. LI, K. ANGELOVA, G. DEMARS, T. P. MEEHAN, F. FANELLI, and P. NARAYAN Structure-Function Relationships of the Luteinizing Hormone Receptor Ann. N.Y. Acad. Sci., December 1, 2005; 1061(1): 41 - 54. [Abstract] [Full Text] [PDF]

				P. Hallast, L. Nagirnaja, T. Margus, and M. Laan Segmental duplications and gene conversion: Human luteinizing hormone/chorionic gonadotropin {beta} gene cluster Genome Res., November 1, 2005; 15(11): 1535 - 1546. [Abstract] [Full Text] [PDF]

				I. Huhtaniemi Focus on gonadotrophin signalling Reproduction, September 1, 2005; 130(3): 261 - 262. [Full Text] [PDF]

				A. P N Themmen An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms Reproduction, September 1, 2005; 130(3): 263 - 274. [Abstract] [Full Text] [PDF]

				S. Costagliola, E. Urizar, F. Mendive, and G. Vassart Specificity and promiscuity of gonadotropin receptors Reproduction, September 1, 2005; 130(3): 275 - 281. [Abstract] [Full Text] [PDF]

				S. B Rulli and I. Huhtaniemi What have gonadotrophin overexpressing transgenic mice taught us about gonadal function? Reproduction, September 1, 2005; 130(3): 283 - 291. [Abstract] [Full Text] [PDF]

				T R. Kumar What have we learned about gonadotropin function from gonadotropin subunit and receptor knockout mice? Reproduction, September 1, 2005; 130(3): 293 - 302. [Abstract] [Full Text] [PDF]

				F. X. Donadeu and M. Ascoli The Differential Effects of the Gonadotropin Receptors on Aromatase Expression in Primary Cultures of Immature Rat Granulosa Cells Are Highly Dependent on the Density of Receptors Expressed and the Activation of the Inositol Phosphate Cascade Endocrinology, September 1, 2005; 146(9): 3907 - 3916. [Abstract] [Full Text] [PDF]

				M. Ascoli Learning New Tricks from an Old Dog: The Processing of the Intracellular Precursor of the Luteinizing Hormone Receptor (LHR) into the Mature Cell-Surface LHR Is a Regulated Process Endocrinology, August 1, 2005; 146(8): 3221 - 3223. [Full Text] [PDF]

				B. P. Hermann and L. L. Heckert Silencing of Fshr Occurs through a Conserved, Hypersensitive Site in the First Intron Mol. Endocrinol., August 1, 2005; 19(8): 2112 - 2131. [Abstract] [Full Text] [PDF]

				S. Yamashita, K. Nakamura, Y. Omori, K. Tsunekawa, M. Murakami, and T. Minegishi Association of Human Follitropin (FSH) Receptor with Splicing Variant of Human Lutropin/Choriogonadotropin Receptor Negatively Controls the Expression of Human FSH Receptor Mol. Endocrinol., August 1, 2005; 19(8): 2099 - 2111. [Abstract] [Full Text] [PDF]

				M. Zhang, D. Mizrachi, F. Fanelli, and D. L. Segaloff The Formation of a Salt Bridge Between Helices 3 and 6 Is Responsible for the Constitutive Activity and Lack of Hormone Responsiveness of the Naturally Occurring L457R Mutation of the Human Lutropin Receptor J. Biol. Chem., July 15, 2005; 280(28): 26169 - 26176. [Abstract] [Full Text] [PDF]

				C. Galet and M. Ascoli The Differential Binding Affinities of the Luteinizing Hormone (LH)/Choriogonadotropin Receptor for LH and Choriogonadotropin Are Dictated by Different Extracellular Domain Residues Mol. Endocrinol., May 1, 2005; 19(5): 1263 - 1276. [Abstract] [Full Text] [PDF]

				T. P Meehan, B. G Harmon, M. E Overcast, K. K Yu, S. A Camper, D. Puett, and P. Narayan Gonadal defects and hormonal alterations in transgenic mice expressing a single chain human chorionic gonadotropin-lutropin receptor complex J. Mol. Endocrinol., April 1, 2005; 34(2): 489 - 503. [Abstract] [Full Text] [PDF]

				H. Valdes-Socin, R. Salvi, A. F. Daly, R. C. Gaillard, P. Quatresooz, P.-M. Tebeu, F. P. Pralong, and A. Beckers Hypogonadism in a Patient with a Mutation in the Luteinizing Hormone Beta-Subunit Gene N. Engl. J. Med., December 16, 2004; 351(25): 2619 - 2625. [Abstract] [Full Text] [PDF]

				X. Ma, Y. Dong, M. M. Matzuk, and T. R. Kumar Targeted disruption of luteinizing hormone {beta}-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility PNAS, December 7, 2004; 101(49): 17294 - 17299. [Abstract] [Full Text] [PDF]

				G. Kleinau, H. Jaschke, S. Neumann, J. Lattig, R. Paschke, and G. Krause Identification of a Novel Epitope in the Thyroid-stimulating Hormone Receptor Ectodomain Acting as Intramolecular Signaling Interface J. Biol. Chem., December 3, 2004; 279(49): 51590 - 51600. [Abstract] [Full Text] [PDF]

				M. Saint-Dizier, F. Foulon-Gauze, F. Lecompte, Y. Combarnous, and M. Chopineau Cloning and functional expression of the equine luteinizing hormone/chorionic gonadotrophin receptor J. Endocrinol., December 1, 2004; 183(3): 551 - 559. [Abstract] [Full Text] [PDF]

				D. D. Elsholz, V. Padmanabhan, R. L. Rosenfield, P. R. Olton, D. J. Phillips, and C. M. Foster GnRH agonist stimulation of the pituitary-gonadal axis in children: age and sex differences in circulating inhibin-B and activin-A Hum. Reprod., December 1, 2004; 19(12): 2748 - 2758. [Abstract] [Full Text] [PDF]

				A. Richter-Unruh, M. Verhoef-Post, S. Malak, J. Homoki, B. P. Hauffa, and A. P. N. Themmen Leydig Cell Hypoplasia: Absent Luteinizing Hormone Receptor Cell Surface Expression Caused by a Novel Homozygous Mutation in the Extracellular Domain J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5161 - 5167. [Abstract] [Full Text] [PDF]

				M. Jiang, M.-L. Savontaus, H. Simonsen, C. Williamson, R. Mullenbach, J. Gromoll, N. Terwort, M. Alevizaki, and I. Huhtaniemi Absence of the genetic variant Val79Met in human chorionic gonadotropin-beta gene 5 in five European populations Mol. Hum. Reprod., October 1, 2004; 10(10): 763 - 766. [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]

				L. Montanelli, J. J. J. Van Durme, G. Smits, M. Bonomi, P. Rodien, E. J. Devor, K. Moffat-Wilson, L. Pardo, G. Vassart, and S. Costagliola Modulation of Ligand Selectivity Associated with Activation of the Transmembrane Region of the Human Follitropin Receptor Mol. Endocrinol., August 1, 2004; 18(8): 2061 - 2073. [Abstract] [Full Text] [PDF]

				D. Mizrachi and D. L. Segaloff Intracellularly Located Misfolded Glycoprotein Hormone Receptors Associate with Different Chaperone Proteins than Their Cognate Wild-Type Receptors Mol. Endocrinol., July 1, 2004; 18(7): 1768 - 1777. [Abstract] [Full Text] [PDF]

				C. M. Foster, P. R. Olton, M. S. Racine, D. J. Phillips, and V. Padmanabhan Sex differences in FSH-regulatory peptides in pubertal age boys and girls and effects of sex steroid treatment Hum. Reprod., July 1, 2004; 19(7): 1668 - 1676. [Abstract] [Full Text] [PDF]

				R. Roberts, J. Stark, A. Iatropoulou, D. L. Becker, S. Franks, and K. Hardy Energy Substrate Metabolism of Mouse Cumulus-Oocyte Complexes: Response to Follicle-Stimulating Hormone Is Mediated by the Phosphatidylinositol 3-Kinase Pathway and Is Associated with Oocyte Maturation Biol Reprod, July 1, 2004; 71(1): 199 - 209. [Abstract] [Full Text] [PDF]

				F. Fanelli, M. Verhoef-Post, M. Timmerman, A. Zeilemaker, J. W. M. Martens, and A. P. N. Themmen Insight into Mutation-Induced Activation of the Luteinizing Hormone Receptor: Molecular Simulations Predict the Functional Behavior of Engineered Mutants at M398 Mol. Endocrinol., June 1, 2004; 18(6): 1499 - 1508. [Abstract] [Full Text] [PDF]

				K. Nakamura, S. Yamashita, Y. Omori, and T. Minegishi A Splice Variant of the Human Luteinizing Hormone (LH) Receptor Modulates the Expression of Wild-Type Human LH Receptor Mol. Endocrinol., June 1, 2004; 18(6): 1461 - 1470. [Abstract] [Full Text] [PDF]

				K. Kawamura, J. Kumagai, S. Sudo, S.-Y. Chun, M. Pisarska, H. Morita, J. Toppari, P. Fu, J. D. Wade, R. A. D. Bathgate, et al. Paracrine regulation of mammalian oocyte maturation and male germ cell survival PNAS, May 11, 2004; 101(19): 7323 - 7328. [Abstract] [Full Text] [PDF]

				C. M. Allan, A. Garcia, J. Spaliviero, F.-P. Zhang, M. Jimenez, I. Huhtaniemi, and D. J. Handelsman Complete Sertoli Cell Proliferation Induced by Follicle-Stimulating Hormone (FSH) Independently of Luteinizing Hormone Activity: Evidence from Genetic Models of Isolated FSH Action Endocrinology, April 1, 2004; 145(4): 1587 - 1593. [Abstract] [Full Text] [PDF]

				I. Beau, M.-T. Groyer-Picard, A. Desroches, E. Condamine, J. Leprince, J.-P. Tome, P. Dessen, H. Vaudry, and M. Misrahi The Basolateral Sorting Signals of the Thyrotropin and Luteinizing Hormone Receptors: An Unusual Family of Signals Sharing an Unusual Distal Intracellular Localization, but Unrelated in Their Structures Mol. Endocrinol., March 1, 2004; 18(3): 733 - 746. [Abstract] [Full Text] [PDF]

				J.-F. Mouillet, C. Sonnenberg-Hirche, X. Yan, and Y. Sadovsky p300 Regulates the Synergy of Steroidogenic Factor-1 and Early Growth Response-1 in Activating Luteinizing Hormone-{beta} Subunit Gene J. Biol. Chem., February 27, 2004; 279(9): 7832 - 7839. [Abstract] [Full Text] [PDF]

				F.-P. Zhang, T. Pakarainen, M. Poutanen, J. Toppari, and I. Huhtaniemi The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis PNAS, November 11, 2003; 100(23): 13692 - 13697. [Abstract] [Full Text] [PDF]

				P. G. McDONOUGH Molecular Abnormalities of FSH and LH Action Ann. N.Y. Acad. Sci., November 1, 2003; 997(1): 22 - 34. [Abstract] [Full Text] [PDF]

				T. Hirakawa and M. Ascoli The Lutropin/Choriogonadotropin Receptor-Induced Phosphorylation of the Extracellular Signal-Regulated Kinases in Leydig Cells Is Mediated by a Protein Kinase A-Dependent Activation of Ras Mol. Endocrinol., November 1, 2003; 17(11): 2189 - 2200. [Abstract] [Full Text] [PDF]

				S. B. Rulli, P. Ahtiainen, S. Makela, J. Toppari, M. Poutanen, and I. Huhtaniemi Elevated Steroidogenesis, Defective Reproductive Organs, and Infertility in Transgenic Male Mice Overexpressing Human Chorionic Gonadotropin Endocrinology, November 1, 2003; 144(11): 4980 - 4990. [Abstract] [Full Text] [PDF]

				H. F. Vischer, J. C. M. Granneman, and J. Bogerd Opposite Contribution of Two Ligand-Selective Determinants in the N-Terminal Hormone-Binding Exodomain of Human Gonadotropin Receptors Mol. Endocrinol., October 1, 2003; 17(10): 1972 - 1981. [Abstract] [Full Text] [PDF]

K. H. Burns, G. E. Owens, S. C. Ogbonna, J. H. Nilson, and M. M. Matzuk Expression Profiling Analyses of Gonadotropin Responses and Tumor Development in the Absence of Inhibins Endocrinology, October 1, 2003; 144(10): 4492 - 4507. [Abstract] [Full Text] [PDF]