Circulating testosterone and SHBG concentrations are heritable in women: the Framingham Heart Study
Open accessAbstract
CONTEXT: Many factors influence the concentration of circulating testosterone and its primary binding protein, SHBG. However, little is known about the genetic contribution to their circulating concentrations in women, and their heritability in women is not well established. OBJECTIVE: Our objective was to estimate the heritability of circulating total testosterone (TT), free testosterone (FT), and SHBG in women in families from the Framingham Heart Study. METHODS: Women in the Framingham Heart Study who were not pregnant, had not undergone bilateral oophorectomy, and were not using exogenous hormones were eligible for this investigation. TT was measured using liquid chromatography tandem mass spectrometry and SHBG using an immunofluorometric assay (Delfia-Wallac), and FT was calculated. Heritability estimates were calculated using variance-components methods in Sequential Oligogenic Linkage Analysis Routines (SOLAR) and were adjusted for age, age(2), body mass index (BMI), BMI(2), diabetes, smoking, and menopausal status. Bivariate analyses were done to assess genetic correlation between TT, FT, and SHBG. RESULTS: A total of 2685 women were studied including 868 sister pairs and 688 mother-daughter pairs. Multivariable adjusted heritability estimates were 0.26 ± 0.05 for FT, 0.26 ± 0.05 for TT, and 0.56 ± 0.05 for SHBG (P < 1.0 × 10(-7) for all). TT was genetically correlated with SHBG [genetic correlation coefficient (ρG) = 0.31 ± 0.10] and FT (ρG = 0.54 ± 0.09), whereas SHBG was inversely correlated with FT (ρG = -0.60 ± 0.08). CONCLUSION: Circulating TT, FT, and SHBG concentrations in women are significantly heritable, underscoring the importance of further work to identify the specific genes that contribute significantly to variation in sex steroid concentrations in women. The strong shared genetic component among pairs of TT, FT, and SHBG concentrations suggests potential pleiotropic effects for some of the underlying genes.
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Evidence from twin studies demonstrates that adult testosterone as well as its bioavailability demonstrate significant additive genetic effects.
“Further, evidence from twin studies of serum testosterone or hormonally mediated digit ratio measurements demonstrates that adult testosterone as well as its bioavailability demonstrate significant additive genetic effects, indicating that women who produce more testosterone will have offspring who also produce higher testosterone (Coviello et al., 2011; Hiraishi et al., 2012; Paul et al., 2006;”
From Endometriosis and polycystic ovary syndrome are diametric disorders (2021) · cites this paper as Coviello et al., 2011
The Results (page unavailable) report significant heritability of total and free testosterone in women, supporting the genetic-effects point. But this was a family study, not a twin study: it analyzed sister and mother–daughter pairs. Its heritability estimates do not establish that every woman with higher testosterone will have offspring with higher testosterone. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe genetic contribution to variability in muscle mass and strength may be explained by the equally high genetic contributions to circulating testosterone.
“Among the nonhormonal factors, genetics explains a large proportion [∼50% to 60% from pooled twin studies (156)] of the variability in muscle mass and strength (157, 158) and may be explained in turn by the equally high genetic contributions to circulating testosterone (37, 38).”
From Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance (2018) · cites this paper as [38]
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1 retracted
Shaw, L. J., Bairey Merz, C. N., Azziz, R., Stanczyk, F. Z., Sopko, G., Braunstein, G. D., Kelsey, S. F., Kip, K. E., Cooper-DeHoff, R. M., Johnson, B. D., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0425 · Cited by 427 · see citing works
RetractedWriting Group for the Women's Health Initiative Investigators (2002) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.288.3.321 · Cited by 15,889 · see citing works
Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees
Almasy, L. A., & Blangero, J. (1998) · The American Journal of Human Genetics · doi:10.1086/301844 · Cited by 3,007 · see citing works
Androgen Levels in Adult Females: Changes with Age, Menopause, and Oophorectomy
Davison, S. L., Bell, R., Donath, S., Montalto, J. G., & Davis, S. R. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0212 · Cited by 998 · see citing works
Splansky, G. L., Corey, D., Yang, Q., Atwood, L. D., Cupples, L. A., Benjamin, E. J., D'Agostino, R. B., Fox, C. S., Larson, M. G., Murabito, J. M., et al. (2007) · American Journal of Epidemiology · doi:10.1093/aje/kwm021 · Cited by 860 · see citing works
Self-citationSex hormone-binding globulin and risk of type 2 diabetes in women and men
Ding, E. L., Song, Y., Manson, J. E., Hunter, D. J., Lee, C. C., Rifai, N., Buring, J. E., Gaziano, J. M., & Liu, S. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0804381 · Cited by 726 · see citing works
Role of Endocytosis in Cellular Uptake of Sex Steroids
Hammes, A., Andreassen, T. K., Spoelgen, R., Raila, J., Hubner, N., Schulz, H., Metzger, J., Schweigert, F. J., Luppa, P. B., Nykjaer, A., et al. (2005) · Cell · doi:10.1016/j.cell.2005.06.032 · Cited by 413 · see citing works
Sir-Petermann, T., Codner, E., Pérez, V., Echiburú, B., Maliqueo, M., Ladrón de Guevara, A., Preisler, J., Crisosto, N., Sánchez, F., Cassorla, F., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2836 · Cited by 260 · see citing works
Self-citationPerry, J. R. B., Weedon, M. N., Langenberg, C., Jackson, A. U., Lyssenko, V., Sparsø, T., Thorleifsson, G., Grallert, H., Ferrucci, L., Maggio, M., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddp522 · Cited by 217 · see citing works
Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study
Ding, E. L., Song, Y., Manson, J. E., Rifai, N., Buring, J. E., & Liu, S. (2007) · Diabetologia · doi:10.1007/s00125-007-0785-y · Cited by 208 · see citing works
Mazer, N. A. (2009) · Steroids · doi:10.1016/j.steroids.2009.01.008 · Cited by 189 · see citing works
Kalyani, R. R., Franco, M., Dobs, A. S., Ouyang, P., Vaidya, D., Bertoni, A., Gapstur, S. M., & Golden, S. H. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0910 · Cited by 179 · see citing works
Hryb, D. J., Khan, M., Romas, N. A., & Rosner, W. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)39289-0 · Cited by 171 · see citing works
Laughlin, G. A., Vivian Goodell, A., & Barrett-Connor, E. L. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1693 · Cited by 140 · see citing works
Patel, S. M., Ratcliffe, S. J., Reilly, M. P., Weinstein, R., Bhasin, S., Blackman, M. R., Cauley, J. A., Sutton-Tyrrell, K., Robbins, J., Fried, L. P., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0740 · Cited by 132 · see citing works
Self-citationHeritability of plasma sex hormones and hormone binding globulin in adult male twins
Ring, H. Z., Lessov, C. N., Reed, T., Marcus, R., Holloway, L., Swan, G. E., & Carmelli, D. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1025 · Cited by 117 · see citing works
Meikle, A. W., Bishop, D. T., Stringham, J. D., & West, D. W. (1986) · Metabolism · doi:10.1016/0026-0495(86)90020-x · Cited by 115 · see citing works
Menopause and modifiable coronary heart disease risk factors: A population based study
Agrinier, N., Cournot, M., Dallongeville, J., Arveiler, D., Ducimetière, P., Ruidavets, J., & Ferrières, J. (2009) · Maturitas · doi:10.1016/j.maturitas.2009.11.023 · Cited by 91 · see citing works
Lee, J. S., LaCroix, A. Z., Wu, L., Cauley, J. A., Jackson, R. D., Kooperberg, C. L., LeBoff, M. S., Robbins, J. A., Lewis, C. E., Bauer, D. C., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2358 · Cited by 80 · see citing works
Maggio, M., Lauretani, F., Basaria, S., Ceda, G. P., Bandinelli, S., Metter, E. J., Bos, A. J., Ruggiero, C., Ceresini, G., Paolisso, G., et al. (2008) · Journal of Endocrinological Investigation · doi:10.1007/bf03345608 · Cited by 77 · see citing works
Jaquish, C. E., Blangero, J., Haffner, S. M., D, M. P. S. M., & MacCluer, J. W. (1997) · Metabolism · doi:10.1016/s0026-0495(97)90266-3 · Cited by 31 · see citing works
Stone, J., Folkerd, E. J., Doody, D., Schroen, C., Treloar, S. A., Giles, G. G., Pike, M. C., English, D. R., Southey, M. C., Hopper, J. L., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0713 · Cited by 24 · see citing works
Shakir, Y. A., Samsioe, G., Nyberg, P., Lidfeldt, J., Nerbrand, C., & Agardh, C. (2007) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.11.111 · Cited by 18 · see citing works
Shahar, E., Burke, G. L., Cushman, M., Heckbert, S. R., Ouyang, P., & Szklo, M. (2007) · Preventive Medicine · doi:10.1016/j.ypmed.2007.12.013 · Cited by 9 · see citing works
Flagged first, then by citations
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- [22]22. Coviello AD, Vasan RS, Pencina M, D'Agostino R, Zhang A, Ulloor J, Bhasin S. 2007. Free testosterone is positively associated with diabetes, metabolic syndrome, and dyslipidemia in women: the Framingham Offspring Study. J Womens Health 16:1113 [Google Scholar]
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Coviello, A. D., Haring, R., Wellons, M., Vaidya, D., Lehtimäki, T., Keildson, S., Lunetta, K. L., He, C., Fornage, M., Lagou, V., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002805 · Cited by 250 · see citing works
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“…adult testosterone as well as its bioavailability demonstrate significant additive genetic effects, indicating that women who produce more testosterone will have offspring who also produce higher testosterone (Coviello et al., 2011; Hiraishi et al., 2012; Paul et al., 2006; Stone et al., 2009).”
BackgroundPrescott, J., Thompson, D. J., Kraft, P., Chanock, S. J., Audley, T., Brown, J. D., Leyland, J., Folkerd, E. J., Doody, D., Hankinson, S. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037815 · Cited by 64 · see citing works
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Varghese, J. S., Smith, P. L., Folkerd, E. J., Brown, J. D., Leyland, J., Audley, T., Warren, R. M. L., Dowsett, M., Easton, D. F., & Thompson, D. J. (2012) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-12-0789 · Cited by 23 · see citing works
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Fishman, R., Kralj‐Fišer, S., Marglit, S., Koren, L., & Vortman, Y. (2024) · Hormones and Behavior · doi:10.1016/j.yhbeh.2024.105525 · Cited by 3 · see citing works
Petrela, R. B., Chhetri, C. D., Najafi, A., Zhang, Z., Rinkoski, T. A., Wieben, E. D., Fautsch, M. P., Chakraborty, S., Millen, A. E., & Patel, S. P. (2025) · BMJ Open Ophthalmology · doi:10.1136/bmjophth-2024-001884 · Cited by 3 · see citing works
Palomba, S., Costanzi, F., Seminara, G., Caserta, D., & Aversa, A. (2026) · Human Reproduction Open · doi:10.1093/hropen/hoag005 · Cited by 1 · see citing works
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- Authors
- Coviello, A. D., Zhuang, W. V., Lunetta, K. L., Bhasin, S., Ulloor, J., Zhang, A., Karasik, D., Kiel, D. P., Vasan, R. S., & Murabito, J. M.
- Affiliations
- Boston University (US)
- Harvard University (US)
- Framingham Heart Study (US)
- Corresponding author
- Coviello, A. D.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2011-09
- Volume
- 96
- Issue
- 9
- Pages
- E1491-E1495
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3167671
- OpenAlex
- W2049000159
- Cited by
- 33
- References
- 24
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 2 · 2022: 5 · 2021: 1 · 2020: 1 · 2018: 3 · 2014: 1 · 2013: 3 · 2012: 4
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG031206, R01AR/AG 41398, R21AG032598)
- National Heart, Lung, and Blood Institute (R01HL094755)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- circulating testosterone, sex hormone-binding globulin, free testosterone, heritability, genetic correlation, sex steroids, women, genetic architecture, pleiotropy, Framingham Heart Study
- MeSH terms
- Adult, Aged, Female, Humans, Middle Aged, Sex Hormone-Binding Globulin, Testosterone
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