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Genetically determined dosage of follicle-stimulating hormone (FSH) affects male reproductive parameters.

Grigorova M, Punab M, Zilaitienė B, Erenpreiss J, Ausmees K, Matuleviĉius V, Tsarev I, Jørgensen N, Laan M - J. Clin. Endocrinol. Metab. (2011)

Bottom Line: We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, -211 bp from the mRNA start) and significantly reduced male serum FSH.Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10(-6); T-allele effect, -0.41 IU/liter), inhibin-B (P = 2.16 × 10(-3); T-allele effect, -14.67 pg/ml), and total testosterone (P = 9.30 × 10(-3); T-allele effect, -1.46 nmol/liter).The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations.

View Article: PubMed Central - PubMed

Affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.

ABSTRACT

Context: The detailed role of FSH in contributing to male testicular function and fertility has been debated. We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, -211 bp from the mRNA start) and significantly reduced male serum FSH.

Objective: In the current study, the T-allele carriers of the FSHB -211 G/T single nucleotide polymorphism represented a natural model for documenting downstream phenotypic consequences of insufficient FSH action.

Design and subjects: We genotyped rs10835638 in the population-based Baltic cohort of young men (n = 1054; GG carriers, n = 796; GT carriers, n = 244; TT carriers, n = 14) recruited by Andrology Centres in Tartu, Estonia; Riga, Latvia; and Kaunas, Lithuania. Marker-trait association testing was performed using linear regression (additive, recessive models) adjusted by age, body mass index, smoking, and recruitment center.

Results: Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10(-6); T-allele effect, -0.41 IU/liter), inhibin-B (P = 2.16 × 10(-3); T-allele effect, -14.67 pg/ml), and total testosterone (P = 9.30 × 10(-3); T-allele effect, -1.46 nmol/liter). Parameters altered only among TT homozygotes were reduced testicular volume (recessive model, P = 1.19 × 10(-4); TT genotype effect, -9.47 ml) and increased serum LH (P = 2.25 × 10(-2); TT genotype effect, 1.07 IU/liter). The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations.

Conclusion: We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels (inhibin-B, total testosterone, LH), and affected male reproductive potential.

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Related in: MedlinePlus

Box-and-whisker diagrams for the distribution of serum FSH (A), inhibin-B (B), LH (C), total testosterone (D), testis volume (E), and sperm concentration (F) in the Baltic young men cohort subgrouped according to their FSHB promoter SNP rs10835638 genotype (GG, n = 796; GT, n = 244; TT, n = 14). The boxes represent the 25th and 75th percentiles; the whiskers cover the 5th to 95th percentiles of the raw data. Circles represent the outlier values. The confounder adjusted median value is denoted as the dotted line that bisects the boxes. For each boxplot, P value of multiple linear regression (additive or recessive genetic model) and effect size (β) of the FSHB rs10835638 T-allele or T-allele homozygosity are shown.
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Figure 1: Box-and-whisker diagrams for the distribution of serum FSH (A), inhibin-B (B), LH (C), total testosterone (D), testis volume (E), and sperm concentration (F) in the Baltic young men cohort subgrouped according to their FSHB promoter SNP rs10835638 genotype (GG, n = 796; GT, n = 244; TT, n = 14). The boxes represent the 25th and 75th percentiles; the whiskers cover the 5th to 95th percentiles of the raw data. Circles represent the outlier values. The confounder adjusted median value is denoted as the dotted line that bisects the boxes. For each boxplot, P value of multiple linear regression (additive or recessive genetic model) and effect size (β) of the FSHB rs10835638 T-allele or T-allele homozygosity are shown.

Mentions: Stratification of the study sample based on the genotypes of the rs10835638 distinguished three categories of reproductive parameters in respect to the effect of the FSHB promoter −211 G/T SNP (Table 2 and Fig. 1). The first group consisted of parameters showing a gradient from the lowest measurements among TT-genotype carriers to the highest level in the GG group (TT<GT<GG). The dosage of the T-allele was robustly associated with reduced serum FSH level (linear regression additive model, P = 1.11 × 10−6), followed by the association with decreased serum inhibin-B (P = 2.16 × 10−3). Both associations were resistant to stringent Bonferroni correction for multiple testing. Compared with the GG-homozygote group (adjusted median, 2.3 IU/liter), the GT-heterozygote (2.0 IU/liter), and TT-homozygote (1.8 IU/liter) men had approximately 13 and 22% reduced FSH levels, respectively. Serum inhibin-B levels in TT-homozygotes (adjusted median, 142 pg/ml) and GT-heterozygotes (172 pg/ml) were 4.5 and 21% lower than among GG-homozygotes (180 pg/ml), respectively. The inhibin-B/FSH ratio was not affected by the carrier status of rs10835638, indicating that the decrease in both hormone levels is in high correlation. Statistically significant associations were also detected between T-allele carrier status and reduced total serum testosterone (TT group, 23 nmol/liter; vs. GT group, 24 nmol/liter; vs. GG group, 25 nmol/liter; P = 9.30 × 10−3), testosterone/LH ratio (P = 1.24 × 10−3), and testosterone/estradiol ratio (P = 6.02 × 10−3).


Genetically determined dosage of follicle-stimulating hormone (FSH) affects male reproductive parameters.

Grigorova M, Punab M, Zilaitienė B, Erenpreiss J, Ausmees K, Matuleviĉius V, Tsarev I, Jørgensen N, Laan M - J. Clin. Endocrinol. Metab. (2011)

Box-and-whisker diagrams for the distribution of serum FSH (A), inhibin-B (B), LH (C), total testosterone (D), testis volume (E), and sperm concentration (F) in the Baltic young men cohort subgrouped according to their FSHB promoter SNP rs10835638 genotype (GG, n = 796; GT, n = 244; TT, n = 14). The boxes represent the 25th and 75th percentiles; the whiskers cover the 5th to 95th percentiles of the raw data. Circles represent the outlier values. The confounder adjusted median value is denoted as the dotted line that bisects the boxes. For each boxplot, P value of multiple linear regression (additive or recessive genetic model) and effect size (β) of the FSHB rs10835638 T-allele or T-allele homozygosity are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298437&req=5

Figure 1: Box-and-whisker diagrams for the distribution of serum FSH (A), inhibin-B (B), LH (C), total testosterone (D), testis volume (E), and sperm concentration (F) in the Baltic young men cohort subgrouped according to their FSHB promoter SNP rs10835638 genotype (GG, n = 796; GT, n = 244; TT, n = 14). The boxes represent the 25th and 75th percentiles; the whiskers cover the 5th to 95th percentiles of the raw data. Circles represent the outlier values. The confounder adjusted median value is denoted as the dotted line that bisects the boxes. For each boxplot, P value of multiple linear regression (additive or recessive genetic model) and effect size (β) of the FSHB rs10835638 T-allele or T-allele homozygosity are shown.
Mentions: Stratification of the study sample based on the genotypes of the rs10835638 distinguished three categories of reproductive parameters in respect to the effect of the FSHB promoter −211 G/T SNP (Table 2 and Fig. 1). The first group consisted of parameters showing a gradient from the lowest measurements among TT-genotype carriers to the highest level in the GG group (TT<GT<GG). The dosage of the T-allele was robustly associated with reduced serum FSH level (linear regression additive model, P = 1.11 × 10−6), followed by the association with decreased serum inhibin-B (P = 2.16 × 10−3). Both associations were resistant to stringent Bonferroni correction for multiple testing. Compared with the GG-homozygote group (adjusted median, 2.3 IU/liter), the GT-heterozygote (2.0 IU/liter), and TT-homozygote (1.8 IU/liter) men had approximately 13 and 22% reduced FSH levels, respectively. Serum inhibin-B levels in TT-homozygotes (adjusted median, 142 pg/ml) and GT-heterozygotes (172 pg/ml) were 4.5 and 21% lower than among GG-homozygotes (180 pg/ml), respectively. The inhibin-B/FSH ratio was not affected by the carrier status of rs10835638, indicating that the decrease in both hormone levels is in high correlation. Statistically significant associations were also detected between T-allele carrier status and reduced total serum testosterone (TT group, 23 nmol/liter; vs. GT group, 24 nmol/liter; vs. GG group, 25 nmol/liter; P = 9.30 × 10−3), testosterone/LH ratio (P = 1.24 × 10−3), and testosterone/estradiol ratio (P = 6.02 × 10−3).

Bottom Line: We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, -211 bp from the mRNA start) and significantly reduced male serum FSH.Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10(-6); T-allele effect, -0.41 IU/liter), inhibin-B (P = 2.16 × 10(-3); T-allele effect, -14.67 pg/ml), and total testosterone (P = 9.30 × 10(-3); T-allele effect, -1.46 nmol/liter).The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations.

View Article: PubMed Central - PubMed

Affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.

ABSTRACT

Context: The detailed role of FSH in contributing to male testicular function and fertility has been debated. We have previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, -211 bp from the mRNA start) and significantly reduced male serum FSH.

Objective: In the current study, the T-allele carriers of the FSHB -211 G/T single nucleotide polymorphism represented a natural model for documenting downstream phenotypic consequences of insufficient FSH action.

Design and subjects: We genotyped rs10835638 in the population-based Baltic cohort of young men (n = 1054; GG carriers, n = 796; GT carriers, n = 244; TT carriers, n = 14) recruited by Andrology Centres in Tartu, Estonia; Riga, Latvia; and Kaunas, Lithuania. Marker-trait association testing was performed using linear regression (additive, recessive models) adjusted by age, body mass index, smoking, and recruitment center.

Results: Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 × 10(-6); T-allele effect, -0.41 IU/liter), inhibin-B (P = 2.16 × 10(-3); T-allele effect, -14.67 pg/ml), and total testosterone (P = 9.30 × 10(-3); T-allele effect, -1.46 nmol/liter). Parameters altered only among TT homozygotes were reduced testicular volume (recessive model, P = 1.19 × 10(-4); TT genotype effect, -9.47 ml) and increased serum LH (P = 2.25 × 10(-2); TT genotype effect, 1.07 IU/liter). The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations.

Conclusion: We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels (inhibin-B, total testosterone, LH), and affected male reproductive potential.

Show MeSH
Related in: MedlinePlus