Correspondence
Isolated Deficiency of Follicle-Stimulating Hormone Re-Revisited
N Engl J Med 1997; 337:642August 28, 1997
- Article
To the Editor:
In 1972, Rabin et al. described the case of an Israeli woman with primary amenorrhea due to an isolated deficiency of follicle-stimulating hormone.1 They “revisited” the case in 1979 and reported that treatment with gonadotropin had induced ovulation and resulted in pregnancy.2
In 1993, we elucidated the genetic basis of an isolated follicle-stimulating hormone deficiency in an unrelated Italian woman. She was homozygous for a two-nucleotide deletion in the coding region of the gene for the β subunit of follicle-stimulating hormone, which caused a shift in the reading frame and a premature termination codon, resulting in a 25-amino-acid truncation of the predicted polypeptide.3 This woman also conceived after treatment with follicle-stimulating hormone.
We have now re-revisited the first case and found that the Israeli woman is homozygous for the same mutation as the Italian woman. The Israeli woman is of European Jewish parentage, but there is no evidence of shared ancestry or consanguinity in either family. Nevertheless, given the genetic alteration, it seems unlikely that these two cases represent separate mutational events.
The mother of the Italian patient had difficulty conceiving, prompting us to hypothesize that fertility may also be impaired in women who are heterozygous for the mutation. We therefore studied several relatives of the Israeli woman. Both her 18-year-old daughter and her sister are heterozygous for the genetic defect, but both have normal serum follicle-stimulating hormone concentrations and regular menstrual cycles, and the sister has had three normal pregnancies. These findings suggest that reproductive function is not compromised in female heterozygotes.
At the time of the initial investigation, the Israeli woman underwent an ovarian biopsy, which showed normal primordial and preantral follicles,1 and primordial follicles were also demonstrable by ultrasonography in the Italian woman. Women with hypergonadotropic amenorrhea who are homozygous for an inactivating mutation in the gene for the follicle-stimulating hormone receptor also have normal primordial follicles on biopsy.4 Moreover, in female mice with a targeted deletion of the follicle-stimulating hormone β-subunit gene, follicular development occurs until the preantral stage.5 Together, these findings suggest that early follicular development is not dependent on signaling through the follicle-stimulating hormone pathway.
5 ReferencesClare Matthews, M.D., Ph.D.
V. Krishna Chatterjee, M.D.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom1
Rabin D ,Spitz I ,Bercovici B , et al. Isolated deficiency of follicle-stimulating hormone: clinical and laboratory features. N Engl J Med 1972;287:1313-1317
Full Text | Web of Science | Medline2
Rabinowitz D ,Benveniste R ,Lindner J ,Lorber D ,Daniell J . Isolated follicle-stimulating hormone deficiency revisited: ovulation and conception in presence of circulating antibody to follicle-stimulating hormone. N Engl J Med 1979;300:126-128
Full Text | Web of Science | Medline3
Matthews CH ,Borgato S ,Beck-Peccoz P , et al. Primary amenorrhoea and infertility due to a mutation in the β-subunit of follicle-stimulating hormone. Nat Genet 1993;5:83-86
CrossRef | Web of Science | Medline4
Aittomaki K ,Herva R ,Stenman U-H , et al. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab 1996;81:3722-3726
CrossRef | Web of Science | Medline5
Kumar TJ ,Wang Y ,Lu N ,Matzuk MM . Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 1997;15:201-204
CrossRef | Web of Science | Medline
- Citing Articles (17)
Citing Articles
1
Lawrence C. Layman. 2012. Disorders of the Hypothalamic–Pituitary–Gonadal Axis. , 659-683.
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Brian J. Arey, Francisco J. López. (2011) Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications. Reviews in Endocrine and Metabolic Disorders 12:4, 275-288
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Alejandro Martinez-Aguayo, Mehul T Dattani, John C Achermann. 2011. Gonadotropin Hormones: Disorders. .
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M.E. Rubio-Gozalbo, C.S. Gubbels, J.A. Bakker, P.P.C.A. Menheere, W.K.W.H. Wodzig, J.A. Land. (2010) Gonadal function in male and female patients with classic galactosemia. Human Reproduction Update 16:2, 177-188
CrossRef5
M. L. Kottler, N. Richard, O. Chabre, S. Alain, J. Young. (2009) FSHβ gene mutation in a female with delayed puberty and hypogonadism: response to recombinant human FSH. Folia Histochemica et Cytobiologica 47:5, S55-S58
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Ericka Barbosa Trarbach, Leticia Gontijo Silveira, Ana Claudia Latronico. (2007) Genetic insights into human isolated gonadotropin deficiency. Pituitary 10:4, 381-391
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Karina Berger, Haroldo Souza, Vinicius Nahime Brito, Catarina Brasil d'Alva, Berenice Bilharinho Mendonca, Ana Claudia Latronico. (2005) Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH beta-subunit gene mutations in both sexes. Fertility and Sterility 83:2, 466-470
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Lawrence C Layman. (2003) Genetic causes of human infertility. Endocrinology & Metabolism Clinics of North America 32:3, 549-572
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C GRACIA, D DRISCOLL. (2003) Molecular basis of pubertal abnormalities. Obstetrics and Gynecology Clinics of North America 30:2, 261-277
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Andrew D Clark, Lawrence C Layman. (2003) Analysis of the Cys82Arg mutation in follicle-stimulating hormone beta (FSHβ) using a novel FSH expression vector. Fertility and Sterility 79:2, 379-385
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Cathy Hay, Frederick Wu. (2002) Genetics and hypogonadotrophic hypogonadism. Current Opinion in Obstetrics and Gynecology 14:3, 303-308
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Ilpo T. Huhtaniemi. (2002) The role of mutations affecting gonadotrophin secretion and action in disorders of pubertal development. Best Practice & Research Clinical Endocrinology & Metabolism 16:1, 123-138
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John C Achermann, Jeffrey Weiss, Eun-Jig Lee, J.Larry Jameson. (2001) Inherited disorders of the gonadotropin hormones. Molecular and Cellular Endocrinology 179:1-2, 89-96
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Lawrence C Layman, Paul G McDonough. (2000) Mutations of follicle stimulating hormone-β and its receptor in human and mouse: genotype/phenotype. Molecular and Cellular Endocrinology 161:1-2, 9-17
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J Levallet. (1999) Follicle-Stimulating Hormone Ligand and Receptor Mutations, and Gonadal Dysfunction. Archives of Medical Research 30:6, 486-494
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Juha S Tapanainen, Tommi Vaskivuo, Kristiina Aittomäki, Ilpo T Huhtaniemi. (1998) Inactivating FSH receptor mutations and gonadal dysfunction. Molecular and Cellular Endocrinology 145:1-2, 129-135
CrossRef17
Göran Lindstedt, Ernst Nyström, Clare Matthews, Ingrid Ernest, Per Olof Janson, Krishna Chatterjee. (1998) Follitropin (FSH) Deficiency in an Infertile Male due to FSHβ Gene Mutation. A Syndrome of Normal Puberty and Virilization but Under-developed Testicles with Azoospermia, Low FSH but High Lutropin and Normal Serum Testosterone Concentrations. Clinical Chemistry and Laboratory Medicine 36:8, 663-665
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