SHBG Gene Promoter Polymorphisms in Men Are Associated with Serum Sex Hormone-Binding Globulin, Androgen and Androgen Metabolite Levels, and Hip Bone Mineral Density
Abstract
Context: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. Objective: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)n microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. Design and Study Subjects: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n ≅ 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). Main Outcome Measures: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5α-androstane-3α,17β-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. Results: In both cohorts, (TAAAA)n and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5α-androstane-3α,17β-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. Conclusions: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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The number of (TAAAA)n repeats is inversely related to SHBG levels.
“Furthermore, the number of (TAAAA)n repeats was also inversely related to SHBG levels [69, 70].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [69]
For the rare homozygous AA genotype of rs1799941, an increase in both serum SHBG and T was observed as opposed to the reference genotype.
“Second, for the rare homozygous AA genotype of rs1799941, an increase in both serum SHBG and T was observed as opposed to the reference genotype [66, 69, 72, 73].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [69]
Total T, and not free T, was elevated in subjects with six repeats compared to seven or more repeats of the (TAAAA)n repeat polymorphism, independently from SHBG levels.
“First, total T, and not free T, was elevated in subjects with six repeats, as compared to seven or more, of the (TAAAA)n repeat polymorphism. This effect occurred independently from SHBG levels [69].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [69]
The (TAAAA)n repeat and rs1799941 were confirmed as independent predictors of BMD at the hip.
“In addition, forementioned genetic studies on polymorphisms in the promotor region of SHBG confirmed the (TAAAA)n repeat and rs1799941 as independent predictors of BMD at the hip [69].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [69]
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- Authors
- Eriksson, A. L., Lorentzon, M., Mellström, D., Vandenput, L., Swanson, C., Andersson, N., Hammond, G. L., Jakobsson, J., Rane, A., Orwoll, E. S., Ljunggren, O., Johnell, O., Labrie, F., Windahl, S. H., & Ohlsson, C.
- Affiliations
- University of Gothenburg (SE)
- Center for Bone Research at the Sahlgrenska Academy (A.L.E., M.L., D.M., L.V., C.S., N.A., S.H.W., C.O.), Departments of Internal Medicine and Geriatrics, Göteborg University, SE-413 45 Göteborg, Sweden
- University of British Columbia (CA)
- Karolinska University Hospital (SE)
- Oregon Health & Science University (US)
- Department of Medical Sciences (Ö.L.), University of Uppsala, SE-751 85 Uppsala, Sweden
- Department of Orthopaedics (O.J.), Malmö General Hospital, SE-20502 Malmö, Sweden
- Université Laval (CA)
- Corresponding author
- Ohlsson, C.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2006-12-01
- Volume
- 91
- Issue
- 12
- Pages
- 5029-5037
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2125128734
- Cited by
- 101
- References
- 6
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 6 · 2013: 8 · 2012: 6
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- sex hormone-binding globulin, androgen metabolism, dihydrotestosterone, testosterone, estradiol, hip bone density, genetic association, men, older men, young men, bone mass
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Androgens, Animals, Genotype, Hip, Humans, Male, Mice, Transgenic, Polymorphism, Genetic, Promoter Regions, Genetic, Sex Hormone-Binding Globulin, Bone Density, Microsatellite Repeats, Mice
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