Journal of Clinical Endocrinology & Metabolism, Vol 81, 3722-3726, Copyright © 1996 by Endocrine Society

ARTICLES

Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene

K Aittomaki, R Herva, UH Stenman, K Juntunen, P Ylostalo, O Hovatta and A de la Chapelle
Department of Medical Genetics, University of Helsinki, Finland. kristiina.aittomaki@helsinki.fi

The recent finding that a mutation in the FSH receptor gene causes ovarian dysgenesis prompted the present study to determine the phenotype caused by this mutation. Twenty-two patients with ovarian dysgenesis and a 566C-->T mutation in the FSH receptor gene (designated FSH-resistant ovaries or FSHRO) were compared with 30 clinically similar patients with ovarian dysgenesis (designated ODG) who did not have this mutation. The genealogical studies suggested a founder effect of the FSH receptor gene mutation in Finland. Clinically, both groups of patients were characterized by primary or early secondary amenorrhea, variable development of secondary sex characteristics, and high serum levels of FSH and LH. Notable differences were observed in median adult height (FSHRO patients were shorter) and the occurrence of follicles judged by transvaginal sonography (observed in 6 of 8 FSHRO vs. 1 of 11 ODG) and ovarian histology (present in all 9 FSHRO vs. 1 of 4 ODG). These findings suggest that a subset of ovarian dysgenesis patients with the FSH receptor mutation 566C-->T is pathogenetically distinct, possibly due to residual receptor activity, and that these patients can be tentatively identified by demonstrating the presence of ovarian follicles and confirmed by mutation analysis.

This article has been cited by other articles:

				M.E. Rubio-Gozalbo, C.S. Gubbels, J.A. Bakker, P.P.C.A. Menheere, W.K.W.H. Wodzig, and J.A. Land Gonadal function in male and female patients with classic galactosemia Hum. Reprod. Update, September 30, 2009; (2009) dmp038v1. [Abstract] [Full Text] [PDF]

				A. L. Chand, G. T. Ooi, C. A. Harrison, A. N. Shelling, and D. M. Robertson Functional analysis of the human inhibin {alpha} subunit variant A257T and its potential role in premature ovarian failure Hum. Reprod., December 1, 2007; 22(12): 3241 - 3248. [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]

				M. Kaare, J. N. Painter, V.-M. Ulander, R. Kaaja, and K. Aittomaki Variations of the Amnionless gene in recurrent spontaneous abortions Mol. Hum. Reprod., January 1, 2006; 12(1): 25 - 29. [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]

				C. M. Foster, P. R. Olton, and V. Padmanabhan Diurnal changes in FSH-regulatory peptides and their relationship to gonadotrophins in pubertal girls Hum. Reprod., February 1, 2005; 20(2): 543 - 548. [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]

				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]

				N. Massin, A. Gougeon, G. Meduri, E. Thibaud, K. Laborde, C. Matuchansky, E. Constancis, M.C. Vacher-Lavenu, B. Paniel, J.R. Zorn, et al. Significance of ovarian histology in the management of patients presenting a premature ovarian failure Hum. Reprod., November 1, 2004; 19(11): 2555 - 2560. [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]

				Y.-M. Zhang and S. K. Roy Downregulation of Follicle-Stimulating Hormone (FSH)-Receptor Messenger RNA Levels in the Hamster Ovary: Effect of the Endogenous and Exogenous FSH Biol Reprod, June 1, 2004; 70(6): 1580 - 1588. [Abstract] [Full Text] [PDF]

				N. C. Zachos, R. B. Billiar, E. D. Albrecht, and G. J. Pepe Developmental Regulation of Follicle-Stimulating Hormone Receptor Messenger RNA Expression in the Baboon Fetal Ovary Biol Reprod, May 1, 2003; 68(5): 1911 - 1917. [Abstract] [Full Text] [PDF]

				L. A. Allen, J. C. Achermann, P. Pakarinen, T. J. Kotlar, I. T. Huhtaniemi, J. L. Jameson, T. D. Cheetham, and S. G. Ball A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics Hum. Reprod., February 1, 2003; 18(2): 251 - 256. [Abstract] [Full Text] [PDF]

				N. Danilovich, D. Javeshghani, W. Xing, and M. R. Sairam Endocrine Alterations and Signaling Changes Associated with Declining Ovarian Function and Advanced Biological Aging in Follicle-Stimulating Hormone Receptor Haploinsufficient Mice Biol Reprod, August 1, 2002; 67(2): 370 - 378. [Abstract] [Full Text] [PDF]

				S. B. Seminara and W. F. Crowley Jr. Genetic Approaches to Unraveling Reproductive Disorders: Examples of Bedside to Bench Research in the Genomic Era Endocr. Rev., June 1, 2002; 23(3): 382 - 392. [Abstract] [Full Text] [PDF]

				S. N. Kalantaridou and G. P. Chrousos Monogenic Disorders of Puberty J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2481 - 2494. [Full Text] [PDF]

				A. Rannikko, P. Pakarinen, P. R. Manna, I. Beau, M. Misrahi, K. Aittomaki, and I. Huhtaniemi Functional characterization of the human FSH receptor with an inactivating Ala189Val mutation Mol. Hum. Reprod., April 1, 2002; 8(4): 311 - 317. [Abstract] [Full Text] [PDF]

				E. Doherty, P. Pakarinen, A. Tiitinen, A. Kiilavuori, I. Huhtaniemi, S. Forrest, and K. Aittomaki A Novel Mutation in the FSH Receptor Inhibiting Signal Transduction and Causing Primary Ovarian Failure J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1151 - 1155. [Abstract] [Full Text] [PDF]

				L C Layman Human gene mutations causing infertility J. Med. Genet., March 1, 2002; 39(3): 153 - 161. [Abstract] [Full Text] [PDF]

				R. B. Barnes, A. B. Namnoum, R. L. Rosenfield, and L. C. Layman The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: Clinical studies in a patient with isolated FSH deficiency and multicystic ovaries: Case report Hum. Reprod., January 1, 2002; 17(1): 88 - 91. [Abstract] [Full Text] [PDF]

				O. Hovatta, V. Soderstrom-Anttila, T. Foudila, L. Tuomivaara, K. Juntunen, A. Tiitinen, and K. Aittomaki Pregnancies after oocyte donation in women with ovarian failure caused by an inactivating mutation in the follicle stimulating hormone receptor Hum. Reprod., January 1, 2002; 17(1): 124 - 127. [Abstract] [Full Text] [PDF]

				S. K. Roy and L. Albee Requirement for Follicle-Stimulating Hormone Action in the Formation of Primordial Follicles during Perinatal Ovarian Development in the Hamster Endocrinology, December 1, 2000; 141(12): 4449 - 4456. [Abstract] [Full Text] [PDF]

				N. Danilovich, P. S. Babu, W. Xing, M. Gerdes, H. Krishnamurthy, and M. R. Sairam Estrogen Deficiency, Obesity, and Skeletal Abnormalities in Follicle-Stimulating Hormone Receptor Knockout (FORKO) Female Mice Endocrinology, November 1, 2000; 141(11): 4295 - 4308. [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]

				H. Louhio, O. Hovatta, J. Sjoberg, and T. Tuuri The effects of insulin, and insulin-like growth factors I and II on human ovarian follicles in long-term culture Mol. Hum. Reprod., August 1, 2000; 6(8): 694 - 698. [Abstract] [Full Text] [PDF]

				P. Touraine, I. Beau, A. Gougeon, G. Meduri, A. Desroches, C. Pichard, M. Detoeuf, B. Paniel, M. Prieur, J-R Zorn, et al. New Natural Inactivating Mutations of the Follicle-Stimulating Hormone Receptor: Correlations between Receptor Function and Phenotype Mol. Endocrinol., November 1, 1999; 13(11): 1844 - 1854. [Abstract] [Full Text]

				K. Vendola, J. Zhou, J. Wang, O. A. Famuyiwa, M. Bievre, and C. A. Bondy Androgens Promote Oocyte Insulin-Like Growth Factor I Expression and Initiation of Follicle Development in the Primate Ovary Biol Reprod, August 1, 1999; 61(2): 353 - 357. [Abstract] [Full Text]

				J. F. Strauss III and A. Dunaif Molecular Mysteries of Polycystic Ovary Syndrome Mol. Endocrinol., June 1, 1999; 13(6): 800 - 805. [Full Text]

				C.S. Wright, O. Hovatta, R. Margara, G. Trew, R.M.L. Winston, S. Franks, and K. Hardy Effects of follicle-stimulating hormone and serum substitution on the in-vitro growth of human ovarian follicles Hum. Reprod., June 1, 1999; 14(6): 1555 - 1562. [Abstract] [Full Text] [PDF]

				J. W. Persson, K. Humphrey, C. Watson, P. Taylor, D. Leigh, B. McDonald, and I. S. Fraser Investigation of a unique male and female sibship with Kallmann's syndrome and 46,XX gonadal dysgenesis with short stature Hum. Reprod., May 1, 1999; 14(5): 1207 - 1212. [Abstract] [Full Text] [PDF]

				E. Y. Adashi and J. D. Hennebold Single-Gene Mutations Resulting in Reproductive Dysfunction in Women N. Engl. J. Med., March 4, 1999; 340(9): 709 - 718. [Full Text] [PDF]

				P. Caron, S. Chauvin, S. Christin-Maitre, A. Bennet, N. Lahlou, R. Counis, P. Bouchard, and M.-L. Kottler Resistance of Hypogonadic Patients with Mutated GnRH Receptor Genes to Pulsatile GnRH Administration J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 990 - 996. [Abstract] [Full Text]

				M. Jiang, K. Aittomäki, C. Nilsson, P. Pakarinen, A. Iitiä, T. Torresani, H. Simonsen, V. Goh, K. Pettersson, A. de la Chapelle, et al. The Frequency of an Inactivating Point Mutation (566C->T) of the Human Follicle-Stimulating Hormone Receptor Gene in Four Populations Using Allele-Specific Hybridization and Time-Resolved Fluorometry J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4338 - 4343. [Abstract] [Full Text]

				A. Dierich, M. R. Sairam, L. Monaco, G. M. Fimia, A. Gansmuller, M. LeMeur, and P. Sassone-Corsi Impairing follicle-stimulating hormone (FSH) signaling in vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance PNAS, November 10, 1998; 95(23): 13612 - 13617. [Abstract] [Full Text] [PDF]

				M. Simoni, J. Gromoll, and E. Nieschlag The Follicle-Stimulating Hormone Receptor: Biochemistry, Molecular Biology, Physiology, and Pathophysiology Endocr. Rev., December 1, 1997; 18(6): 739 - 773. [Abstract] [Full Text]

				C. Matthews and V. K. Chatterjee Isolated Deficiency of Follicle-Stimulating Hormone Re-Revisited N. Engl. J. Med., August 28, 1997; 337(9): 642 - 642. [Full Text]