Abstract
Associations of total testosterone (T) and calculated free T with cardiovascular disease (CVD) remain poorly understood. Particularly how these associations vary according to race and ethnicity in a nationally representative sample of men. Data included 7058 men (≥20 years) from NHANES. CVD was defined as any reported diagnosis of heart failure (HF), coronary artery disease (CAD), myocardial infarction (MI), and stroke. Total T (ng/mL) was obtained among males who participated in the morning examination. Weighted multivariable-adjusted logistic regression models were conducted. We found associations of low T (OR = 1.57, 95% CI = 1.17–2.11), low calculated free T (OR = 1.53, 95% CI = 1.10–2.17), total T (Q1 vs Q5), and calculated free T (Q1 vs Q5) with CVD after adjusting for estradiol and SHBG. In disease specific analysis, low T increased prevalence of MI (OR = 1.72, 95% CI = 1.08–2.75) and HF (OR = 1.74, 95% CI = 1.08–2.82), but a continuous increment of total T reduced the prevalence of CAD. Similar inverse associations were identified among White and Mexican Americans, but not Blacks (OR = 0.93, 95% CI = 0.49–1.76). Low levels of T and calculated free T were associated with an increased prevalence of overall CVD and among White and Mexican Americans. Associations remained in the same direction with specific CVD outcomes in the overall population.
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Data availability
All data generated or analyzed in this study was provided by the National Center for Health Statistics (NCHS) of the US Centers for Disease Control and Prevention (CDC)- https://www.cdc.gov/nchs/nhanes/index.htm. For further data inquiries, please contact the corresponding author of this paper (DSL).
References
van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab. 2000;85:3276–82.
Rohrmann S, Shiels MS, Lopez DS, Rifai N, Nelson WG, Kanarek N, et al. Body fatness and sex steroid hormone concentrations in US men: results from NHANES III. Cancer Causes Control. 2011;22:1141–51.
Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–75.
Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200:423–32.
Wang J, Fan X, Yang M, Song M, Wang K, Giovannucci E, et al. Sex-specific associations of circulating testosterone levels with all-cause and cause-specific mortality. Eur J Endocrinol. 2021;184:723–32.
Le M, Flores D, May D, Gourley E, Nangia AK. Current Practices of Measuring and Reference Range Reporting of Free and Total Testosterone in the United States. J Urol. 2016;195:1556–61.
Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012;97:179–89.
Travison TG, Araujo AB, O’Donnell AB, Kupelian V, McKinlay JB. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92:196–202.
Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92:4241–7.
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pr. 2006;60:762–9.
Malik RD, Lapin B, Wang CE, Lakeman JC, Helfand BT. Are we testing appropriately for low testosterone?: Characterization of tested men and compliance with current guidelines. J Sex Med. 2015;12:66–75.
Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care. 2011;34:1669–75.
Kloner RA, Carson C 3rd, Dobs A, Kopecky S, Mohler ER 3rd. Testosterone and Cardiovascular Disease. J Am Coll Cardiol. 2016;67:545–57.
Trost LW, Mulhall JP. Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials. J Sex Med. 2016;13:1029–46.
Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374:611–24.
Derby CA, Zilber S, Brambilla D, Morales KH, McKinlay JB. Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf). 2006;65:125–31.
U.S. Census Bureau. Overview of Race and Hispanic Origin: 2010. http://www.census.gov/prod/cen2010/briefs/c2010br-02.pdf. 2010.
Rohrmann S, Nelson WG, Rifai N, Brown TR, Dobs A, Kanarek N, et al. Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans. J Clin Endocrinol Metab. 2007;92:2519–25.
Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021;143:e254–e743.
Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. National Health and Nutrition Examination Survey: Overview. Accessed January 2020. https://www.cdc.gov/nchs/data/nhanes/nhanes_13_14/NHANES_Overview_Brochure.pdf.
National Center for Health Statistics 1994. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988-94. Series 1: programs and collection procedures. Vital- Health Stat. 1994;1:1–407.
Sodergard R, Backstrom T, Shanbhag V, Carstensen H. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem. 1982;16:801–10.
Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–72.
Paduch DA, Brannigan, RD, Fuchs EF, Kim ED, Marmar JL, Sandlow JI. The Laboratory Diagnosis of Testosterone Deficiency. http://university.auanet.org/common/pdf/education/clinical-guidance/Testosterone-Deficiency-WhitePaper.pdf. 2017.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.
Mazidi M, Mikhailidis DP, Banach M. Associations between risk of overall mortality, cause-specific mortality and level of inflammatory factors with extremely low and high high-density lipoprotein cholesterol levels among American adults. Int J Cardiol. 2019;276:242–7.
Menke A, Guallar E, Rohrmann S, Nelson WG, Rifai N, Kanarek N, et al. Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol. 2010;171:583–92.
Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011;165:687–701.
Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:3007–19.
Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011;97:870–5.
Yeap BB, Marriott RJ, Antonio L, Raj S, Dwivedi G, Reid CM, et al. Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men. Ann Intern Med. 2022;175:159–70.
Schafer S, Aydin MA, Appelbaum S, Kuulasmaa K, Palosaari T, Ojeda F, et al. Low testosterone concentrations and prediction of future heart failure in men and in women: evidence from the large FINRISK97 study. ESC Heart Fail. 2021;8:2485–91.
Marriott RJ, Harse J, Murray K, Yeap BB. Systematic review and meta-analyses on associations of endogenous testosterone concentration with health outcomes in community-dwelling men. BMJ Open. 2021;11:e048013. -2020-048013
Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies. J Sex Med. 2018;15:1260–71.
Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011;58:1674–81.
Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007;116:2694–701.
Khurana KK, Navaneethan SD, Arrigain S, Schold JD, Nally JV, Shoskes DA. Serum testosterone levels and mortality in men with CKD stages 3-4. Am J Kidney Dis. 2014;64:367–74.
Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94:2482–8.
Arnlov J, Pencina MJ, Amin S, Nam BH, Benjamin EJ, Murabito JM, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med. 2006;145:176–84.
Pye SR, Huhtaniemi IT, Finn JD, Lee DM, O’Neill TW, Tajar A, et al. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014;99:1357–66.
Mazur A. The age-testosterone relationship in black, white, and Mexican-American men, and reasons for ethnic differences. Aging Male. 2009;12:66–76.
Watts EL, Appleby PN, Perez-Cornago A, Bueno-de-Mesquita HB, Chan JM, Chen C, et al. Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies. Eur Urol. 2018;74:585–94.
Pool LR, Ning H, Lloyd-Jones DM, Allen NB. Trends in Racial/Ethnic Disparities in Cardiovascular Health Among US Adults From 1999-2012. J Am Heart Assoc. 2017;6:https://doi.org/10.1161/JAHA.117.006027.
Selvin E, Feinleib M, Zhang L, Rohrmann S, Rifai N, Nelson WG, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care. 2007;30:234–8.
Tsilidis KK, Rohrmann S, McGlynn KA, Nyante SJ, Lopez DS, Bradwin G, et al. Association between endogenous sex steroid hormones and inflammatory biomarkers in US men. Andrology. 2013;1:919–28.
Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96:939–49.
Zhao D, Guallar E. Testosterone and Cardiovascular Disease in Men. Ann Intern Med. 2022;175:287–8.
Duello TM, Rivedal S, Wickland C, Weller A. Race and genetics versus ‘race’ in genetics: a systematic review of the use of African ancestry in genetic studies. Evol Med Public Health. 2021;9:232–45.
Garcia-Ortiz H, Barajas-Olmos F, Contreras-Cubas C, Cid-Soto MA, Cordova EJ, Centeno-Cruz F, et al. The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas. Nat Commun. 2021;12:5942. -021-26188
Funding
DSL was supported by the National Institutes of Health (NIH) and National Institute on Aging, Grant #: P30 AG059301; and the Cancer Prevention and Research Institute of Texas (CPRIT), Grant #: RP210130.
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DSL, ST, and KKT contributed to the study design, interpretation of the data, writing and critical discussion of the paper draft. ST and SG contributed to the statistical analysis of the study. All other authors contributed to the interpretation, discussion and editing of the paper draft.
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Association of Total and Free Testosterone with Cardiovascular Disease in a Nationally Representative Sample of White, Black, and Mexican American men
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Lopez, D.S., Taha, S., Gutierrez, S. et al. Association of total and free testosterone with cardiovascular disease in a nationally representative sample of white, black, and Mexican American men. Int J Impot Res (2022). https://doi.org/10.1038/s41443-022-00660-7
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DOI: https://doi.org/10.1038/s41443-022-00660-7