Dataset Information

Increased Prevalance of the -211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men.

ABSTRACT: CONTEXT:The human FSHB promoter polymorphism (rs10835638; -211 G/T) has been associated with serum FSH in a cohort of young Estonian men. The minor allele carriers had reduced serum FSH (15.7% in GT heterozygotes; 40% in TT homozygotes) compared with GG homozygotes. OBJECTIVE:Because FSH is essential for normal spermatogenesis and fertility, we speculated that abnormalities in FSH action could contribute to male infertility. We sought to study whether genetically inherited constitutively reduced FSH levels may affect male reproduction and replicate the association between rs10835638 and serum FSH among infertile male patients. DESIGN:Genotyping of rs10835638 in a cohort of infertile men (n = 1029; Andrology Center of the Tartu University Clinics, Estonia), including idiopathic infertility cases (IIFC; n = 750). PATIENTS:Patients included male partners (sperm concentration <20 x 10(6)/ml) of infertile couples failing to conceive a child for 12 months or longer. RESULTS:A significant excess of TT homozygotes (1.1 vs. 2.4%) as well as GT heterozygotes (22.4 vs. 25.1%) was detected among infertile men compared with the young male cohort (chi(2) test, P < 0.05). The T allele of rs10835638 was associated with reduced serum FSH (analysis of covariance; full cohort: P = 1.20 x 10(-6), F = 13.8; IIFC: P = 7.70 x 10(-7), F = 14.3) as well as with low FSH to LH ratio (full cohort: P = 1.52 x 10(-11), F = 25.6; IIFC: P = 3.25 x 10(-9), F = 20.4). The median serum FSH levels differed between the GG and TT carriers by 48.5%. All IIFC with TT genotype exhibited low (<1.8) FSH to LH ratio. CONCLUSIONS:In perspective, this genetic marker may have clinical significance in molecular diagnostics of male reproductive success and a potential to identify positive responders to FSH treatment.

SUBMITTER: Grigorova M

PROVIDER: S-EPMC2823301 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Increased Prevalance of the -211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men.

Grigorova Marina M Punab Margus M Poolamets Olev O Kelgo Piret P Ausmees Kristo K Korrovits Paul P Vihljajev Vladimir V Laan Maris M

The Journal of clinical endocrinology and metabolism 20091106 1

<h4>Context</h4>The human FSHB promoter polymorphism (rs10835638; -211 G/T) has been associated with serum FSH in a cohort of young Estonian men. The minor allele carriers had reduced serum FSH (15.7% in GT heterozygotes; 40% in TT homozygotes) compared with GG homozygotes.<h4>Objective</h4>Because FSH is essential for normal spermatogenesis and fertility, we speculated that abnormalities in FSH action could contribute to male infertility. We sought to study whether genetically inherited constit ...[more]

PMID: 19897680

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Project description:Genes critical for fertility are highly conserved in mammals. Interspecies DNA sequence variation, resulting in amino acid substitutions and post-transcriptional modifications, including alternative splicing, are a result of evolution and speciation. The mammalian follicle-stimulating hormone receptor (FSHR) gene encodes distinct species-specific forms by alternative splicing. Skipping of exon 2 of the human FSHR was reported in women of North American origin and correlated with low response to ovarian stimulation with exogenous follicle-stimulating hormone (FSH). To determine whether this variant correlated with low response in women of different genetic backgrounds, we performed a blinded retrospective observational study in a Turkish cohort. Ovarian response was determined as low, intermediate or high according to retrieved oocyte numbers after classifying patients in four age groups (<35, 35-37, 38-40, >40). Cumulus cells collected from 96 women undergoing IVF/ICSI following controlled ovarian hyperstimulation revealed four alternatively spliced FSHR products in seven patients (8%): exon 2 deletion in four patients; exon 3 and exons 2 + 3 deletion in one patient each, and a retention of an intron 1 fragment in one patient. In all others (92%) splicing was intact. Alternative skipping of exons 2, 3 or 2 + 3 were exclusive to low responders and was independent of the use of agonist or antagonist. Interestingly, skipping of exon 3 occurs naturally in the ovaries of domestic cats--a good comparative model for human fertility. We tested the signaling potential of human and cat variants after transfection in HEK293 cells and FSH stimulation. None of the splicing variants initiated cAMP signaling despite high FSH doses, unlike full-length proteins. These data substantiate the occurrence of FSHR exon skipping in a subgroup of low responders and suggest that species-specific regulation of FSHR splicing plays diverse roles in mammalian ovarian function.

Dataset Information

Increased Prevalance of the -211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men.

Publications

Increased Prevalance of the -211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men.

Similar Datasets

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