Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

Huhtaniemi, Ilpo; Pye, Stephen R.; Holliday, Kate L.; Thomson, Wendy; O'Neill, Terence W; Platt, Hazel; Payne, Debbie; John, Sally; Jiang, Min; Bártfai, György; Boonen, Steven; Casanueva, Felipe F.; Finn, Joseph D.; Forti, Gianni; Giwercman, Aleksander; Han, Thang S.; Kula, Krzysztof; Lean, Michael E. J.; Pendleton, Neil; Punab, Margus; Silman, Alan J.; Vanderschueren, Dirk; Labrie, Fernand; Wu, Frederick C. W.

doi:10.1210/jc.2009-2071

Cited by 38 publications

(29 citation statements)

References 45 publications

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“…In contrast, in a cohort of middle‐aged and elderly men ( n = 2748; mean age: 60.2 ± 11.2 year) significantly lower serum LH levels among V‐LH carriers compared to the WT‐LH homozygotes were reported (Huhtaniemi et al ., 2010). During ageing, the changes in hormonal pattern gradually lead to primary testicular dysfunction with declining testosterone levels and an associated elevation of LH (Araujo & Wittert, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The two SNPs coding for V‐LH (A‐>G, rs1800447; A‐>G, rs34349826) are located in the LHB exon 2 and exhibit complete linkage disequilibrium (LD) (Nilsson et al ., 1998). V‐LH seems to be a universally common variant with the average minor allele frequency among Europeans 8% (range 7.34–11.8%; Huhtaniemi et al ., 2010). The change from isoleucine to threonine (Ile15Thr) creates an extra glycosylation site Asn 13 ‐Ala‐Thr in V‐LH compared to the wild‐type (WT) LH (four vs. three oligosaccharide chains) (Suganuma et al ., 1996).…”

Section: Introductionmentioning

confidence: 99%

“…A small‐scale study ( n = 49) investigating the onset and progression of puberty in healthy boys reported slower progression of puberty and lower testes volume in V‐LH carriers (Raivio et al ., 1996). In a European cohort of middle‐aged and elderly men (EMAS study: n = 2748 men, eight European countries), V‐LH was associated with reduced levels of serum LH (Huhtaniemi et al ., 2010). In female patients, several studies have associated V‐LH with subfertility because of ovulatory disorders (Furui et al ., 1994; Takahashi et al ., 1998, 1999; Du et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

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‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

et al. 2015

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SummaryLuteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V‐LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH β‐subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V‐LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V‐LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V‐LH was detected by genotyping of the underlying DNA polymorphisms using PCR‐RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta‐analysis. No significant difference was detected between young men and infertility patients for the V‐LH allele frequency (11.0 vs. 9.3%, respectively). V‐LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta‐analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V‐LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB ‐211G/T, FSHR Asn680Ser, FSHR ‐29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V‐LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V‐LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

et al. 2015

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“…The testosterone and sex hormone binding globulin (SHBG) analyses were centralized and the methods used for measuring hormone concentrations have previously been described (21).…”

Section: Hormone and Psa Assessmentmentioning

confidence: 99%

“…This variant has been linked to androgenetic alopecia in Caucasian populations, where the minor allele (rs6152A) in these populations was associated with a decreased risk (18)(19)(20). In a previous EMAS analysis, carriers of the rs6152A variant were also found to have significantly lower estradiol levels than those with rs6152G (21).…”

Section: Introductionmentioning

confidence: 95%

Androgen Receptor Polymorphism-Dependent Variation in Prostate-Specific Antigen Concentrations of European Men

Holgersson

Giwercman

Bjartell

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Androgens acting via the androgen receptor (AR) stimulate production of PSA, which is a clinical marker of prostate cancer. Because genetic variants in the AR may have a significant impact on the risk of being diagnosed with prostate cancer, the aim was to investigate whether AR variants were associated with the risk of having PSA above clinically used cutoff thresholds of 3 or 4 ng/mL in men without prostate cancer.Methods: Men without prostate cancer history (n ¼ 1,744) were selected from the European Male Ageing Study cohort of 40 to 79-year-old men from eight different European centers. Using linear and logistic regression models, with age and center as covariates, we investigated whether AR variants (CAG repeatlength and/or SNP genotype) were associated with having serum PSA concentrations above 3 or 4 ng/mL, which often are set as cutoff concentrations for further investigation of prostate cancer.Results: Carriers of the SNP rs1204038 A-allele (16% of the men) were more likely to have PSA>3 and 4 ng/mL (OR; 95% confidence intervals, 1.65; 1.13-2.40 and 1.87; 1.18-2.96, respectively) than G-allele carriers. They also had shorter CAG repeats (median 20 vs. 23, P < 0.0005), but CAG repeat length per se did not affect the PSA concentrations.Conclusion: The A-allele of the SNP rs1204038 gives a 65% higher risk of having PSA above 3 ng/mL than the G-allele in men without prostate cancer, and thereby an increased risk of being referred for further examination on suspicion of prostate cancer.Impact: Serum PSA as a clinical marker could be improved by adjustment for AR-genotype. Cancer Epidemiol Biomarkers Prev; 23(10); 2048-56. Ó2014 AACR.

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Associations between Salivary Testosterone Levels, Androgen-Related Genetic Polymorphisms, and Self-Estimated Ejaculation Latency Time

et al. 2014

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IntroductionRecently, testosterone (T) has been shown to be associated with premature ejaculation (PE) symptoms in the literature. Furthermore, studies suggest that the etiology of PE is partly under genetic control.AimThe aim of this study was to reassess findings suggesting an association between testosterone (T) and a key symptom of PE, ejaculation latency time (ELT), as well as exploratively investigating associations between six androgen-related genetic polymorphisms and ELT.Materials and MethodsStatistical analyses were performed on a population-based sample of 1,429 Finnish men aged 18–45 years (M = 26.9, SD = 4.7). Genotype information was available for 1,345–1,429 of these (depending on the polymorphism), and salivary T samples were available from 384 men. Two androgen receptor gene-linked, two 5-alpha-reductase type 2-gene-linked, and two sex hormone-binding globuline gene-linked polymorphisms were genotyped.Main Outcome MeasuresEjaculatory function was assessed using self-reported ELT.ResultsWe found no association between salivary T levels and ELT. We found a nominally significant association between a 5-alpha-reductase type 2-gene-linked polymorphism (rs2208532) and ELT, but this association did not remain significant after correction for multiple testing. One single nucleotide polymorphism in the sex hormone-binding globulin gene (rs1799941) moderated (significantly after correction for multiple testing) the association between salivary T and ELT, so that A:A genotype carriers had significantly lower salivary T levels as a function of increasing ELT compared with other genotype groups.ConclusionsWe were unable to find support for the hypothesis suggesting an association between T levels and ELT, possibly because of the low number of phenotypically extreme cases (the sample used in the present study was population based). Our results concerning genetic associations should be interpreted with caution until replication studies have been conducted. Jern P, Westberg L, Ankarberg-Lindgren C, Johansson A, Gunst A, Sandnabba NK, and Santtila P. Associations between salivary testosterone levels, androgen-related genetic polymorphisms, and self-estimated ejaculation latency time. Sex Med 2014;2:107–114.

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Effect of Polymorphisms in Selected Genes Involved in Pituitary-Testicular Function on Reproductive Hormones and Phenotype in Aging Men

Cited by 38 publications

References 45 publications

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

Androgen Receptor Polymorphism-Dependent Variation in Prostate-Specific Antigen Concentrations of European Men

Associations between Salivary Testosterone Levels, Androgen-Related Genetic Polymorphisms, and Self-Estimated Ejaculation Latency Time

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