Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle‐aged and elderly men

Vanbillemont, Griet; Bogaert, Veerle; Bacquer, Dirk De; Lapauw, Bruno; Goemaere, Stefan; Toye, Kaatje; Steen, Kristel Van; Taes, Youri; Kaufman, Jean‐Marc

doi:10.1111/j.1365-2265.2008.03365.x

Cited by 45 publications

(34 citation statements)

References 38 publications

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“…Although in vitro studies have shown that the (TAAAA) 6 allele reduces SHBG gene expression (22), opposite in vivo findings in men are consistent. Our findings confirm the three previous findings on higher SHBG levels in association with shorter TAAAA repeats (28,34,35), but not a very recent finding on their association with rs6259 (37). The association of the two CYP19A1 polymorphisms (rs11575899 and rs727479) with lower E 2 levels and elevated levels of free and bioavailable T matches well because the potent negative feedback action of E 2 on LH secretion should be suppressed, resulting in elevated T level (38).…”

Section: Discussionsupporting

confidence: 81%

“…The Asp356Asn (GAC 3 AAC) mutation in exon 8 of SHBG (rs6259) induces an additional consensus site for N-glycosylation, increasing circulatory half-life of the variant SHBG protein without affecting its steroid-binding affinity (33) or steady-state plasma levels (34), which our findings confirmed. Variable associations of this polymorphism, depending on age of men, were recently reported between SHBG and T levels (35). The only significant association we found with this polymorphism was the slightly but significantly (P Ͻ 0.01) elevated level of free T in heterozygotes.…”

Section: Discussioncontrasting

confidence: 35%

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

Huhtaniemi

Pye

Holliday

et al. 2010

The Journal of Clinical Endocrinology & Metabolism

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, and the European Male Aging Study Group* † Context: Polymorphisms in genes involved in regulation, biosynthesis, metabolism, and actions of testicular sex hormones may influence hormone balance and phenotype of aging men. Objective:We investigated the relationships between polymorphisms in genes related to pituitarytesticular endocrine function and health status. Design and Setting:Using cross-sectional baseline data, we conducted a multinational prospective cohort observational study consisting of a population survey of community-dwelling men.Participants: A total of 2748 men, aged 40 -79 (mean Ϯ SD, 60.2 ϩ 11.2) yr, were randomly recruited from eight European centers. Forty-three polymorphisms were genotyped in the following genes: androgen receptor (AR), estrogen receptor-␣ and -␤ (ESR1 and ESR2), steroid 5␣-reductase type II (SRD5A2), 17␣-hydroxylase/17,20-lyase (CYP17A1), aromatase (CYP19A1), sex hormone-binding globulin (SHBG), LH ␤-subunit (LHB), and LH receptor (LHCGR). Main Outcome Measures:We measured the associations between gene polymorphisms and endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Several polymorphisms in SHBG, ESR2, AR, CYP19A1, and LHB were significantly associated with circulating levels of SHBG, LH, total, free, and bioavailable testosterone and estradiol, the LH ϫ testosterone product, and indices of insulin sensitivity. Apart from several previously reported associations between genes affecting estrogen levels and heel ultrasound parameters, no associations existed between polymorphisms and nonhormonal variables (anthropometry, blood lipids, blood pressure, hemoglobin, prostate symptoms, prostate-specific antigen, sexual dysfunction, cognition). Conclusion:In aging men, polymorphisms in genes related to the pituitary-testicular endocrine function significantly influence circulating LH, testosterone, and estradiol levels, but the downstream effects may be too small to influence secondary phenotypic parameters. (J Clin Endocrinol Metab 95:

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Section: Discussionsupporting

confidence: 81%

Section: Discussioncontrasting

confidence: 35%

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

Huhtaniemi

Pye

Holliday

et al. 2010

The Journal of Clinical Endocrinology & Metabolism

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“…Alternatively, calculated concentrations of circulating free sex steroid may not accurately reflect local bioavailability of these hormones at the target tissue level (55)(56)(57). Calculation of free sex steroid concentrations assumes that the binding affinity between both sex steroids and SHBG is constant in the entire population and does not vary with age while, in reality, it may be affected by genetic variants or isoforms of SHBG, age and levels of other SHBG-binding steroids (54,(58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Influence of bone remodelling rate on quantitative ultrasound parameters at the calcaneus and DXA BMDa of the hip and spine in middle-aged and elderly European men: the European Male Ageing Study (EMAS)

Boonen

Pye

O'Neill

et al. 2011

European Journal of Endocrinology

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Objective: To assess the influence of sex hormones on markers of bone turnover and to explore the association between these markers and bone health in middle-aged and elderly European men. Design: A cross-sectional population-based survey. Methods: Men aged 40-79 years were recruited from population registers in eight European centres. Subjects completed a postal questionnaire which included questions concerning lifestyle and were invited to undergo quantitative ultrasound (QUS) of the calcaneus and to provide a fasting blood sample from which the bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (b C-terminal cross-linked telopeptide (b-cTX)), total testosterone, total oestradiol (E 2 ), sex hormone-binding globulin (SHBG) and insulin-like growth factor 1 (IGF1) were measured. Dualenergy X-ray absorptiometry (DXA) of the hip and lumbar spine was performed in two centres. Results: A total of 3120, mean age 59.9 years (S.D.Z11.0) were included. After adjustment for centre, age, height, weight, lifestyle factors, season and other hormones, total and free E 2 were negatively associated with b-cTX but not P1NP while SHBG, IGF1 and parathyroid hormone (PTH) were positively associated with both b-cTX and P1NP. Total or free testosterone was not independently associated with either bone marker. After the same adjustments, higher levels of both bone markers were significantly associated with lower QUS parameters and lower DXA-assessed bone density at the total hip and lumbar spine. Conclusions: E 2 , SHBG, IGF1 and PTH contribute significantly to the regulation/rate of bone turnover in middle-aged and older European men. Higher rates of bone remodelling are negatively associated with male bone health.

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“…Cousin et al (2004) studied a population of French women with hirsutism and found that homozygous patients for the six TAAAA repeat allele had higher serum SHBG levels compared with patients being homozygous for the nine TAAAA repeat allele, while SHBG levels of homozygous patients for the eight TAAAA allele lay between the two. This association between the six TAAAA allele and elevated SHBG levels was also found in healthy men (Turk et al, 2007;Eriksson et al, 2006;Vanbillemont et al, 2009).…”

Section: The (Taaaa)n Repeat Polymorphism In Shbg Promotermentioning

confidence: 55%

Genetic variants of sex hormone-binding globulin and their biological consequences

Xita¹,

Tsatsoulis²

2010

Molecular and Cellular Endocrinology

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To cite this version:Nectaria Xita, Agathocles Tsatsoulis. Genetic variants of sex hormone-binding globulin and their biological consequences. Molecular and Cellular Endocrinology, Elsevier, 2009, 316 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ABSTRACTSeveral hormonal and metabolic factors have been found to influence the production of sex hormone-binding globulin (SHBG). In addition, twin studies have suggested that genetic factors may also contribute to variation in SHBG levels. Given the clinical significance of SHBG in regulating bioavailable sex steroid hormones, a number of studies examined the potential association between polymorphisms of SHBG gene and serum SHBG levels as well as their possible contribution in the pathogenesis of common diseases. Thus, polymorphisms of SHBG, altering either the production or the metabolism of the protein, may represent part of the genetic background of sex steroid hormone activity in humans. There is considerable heterogeneity in the results of these studies indicating the multiplicity of the factors influencing SHBG variation. However, the weight of evidence suggests that some common genetic variants of SHBG may influence SHBG levels and in part contribute to the phenotypic expression of human diseases.

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Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle‐aged and elderly men

Abstract: Our findings show that and the (TAAAA)(n)-repeat and the Asp327Asn polymorphism contribute to the genetically determined interindividual variation in total serum T levels in healthy men through variation in SHBG concentrations.

Cited by 45 publications

References 38 publications

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

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

Influence of bone remodelling rate on quantitative ultrasound parameters at the calcaneus and DXA BMDa of the hip and spine in middle-aged and elderly European men: the European Male Ageing Study (EMAS)

Genetic variants of sex hormone-binding globulin and their biological consequences

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