Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.
Population studies suggest that low serum levels of endogenous testosterone are a risk factor for cardiovascular events, although these studies cannot establish causality or exclude reverse causality, and some of these associations might result from residual confounding.
Although many retrospective studies show no association, some retrospective studies of prescription databases have shown a higher risk of cardiovascular events in men receiving testosterone, with the risk increasing early after treatment initiation.
Meta-analyses of randomized, controlled trials of testosterone replacement therapy report conflicting findings, probably because the included trials lacked power or the duration was too short to assess cardiovascular events.
The TRAVERSE trial, the first trial of testosterone therapy that is adequately powered to assess cardiovascular events, began in 2018, and its findings might take a decade to become available.
Until the results of the TRAVERSE trial are available, clinicians should individualize testosterone treatment after having an informed discussion with their patients about the risks and benefits of testosterone replacement therapy.
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Basaria, S. Male hypogonadism. Lancet 383, 1250–1263 (2014).
Bhasin, S. et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 103, 1715–1744 (2018).
Wu, F. C. et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J. Clin. Endocrinol. Metab. 93, 2737–2745 (2008).
Bhasin, S. et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 96, 2430–2439 (2011).
Harman, S. M. et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).
Feldman, H. A. et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J. Clin. Endocrinol. Metab. 87, 589–598 (2002).
Wu, F. C. et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl. J. Med. 363, 123–135 (2010).
Snyder, P. J. et al. Effects of testosterone treatment in older men. N. Engl. J. Med. 374, 611–624 (2016).
Handelsman, D. J. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med. J. Aust. 199, 548–551 (2013).
Baillargeon, J., Urban, R. J., Ottenbacher, K. J., Pierson, K. S. & Goodwin, J. S. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA. Intern. Med. 173, 1465–1466 (2013).
Nguyen, C. P. et al. Testosterone and “age-related hypogonadism” — FDA concerns. N. Engl. J. Med. 373, 689–691 (2015).
Layton, J. B. et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J. Clin. Endocrinol. Metab. 99, 835–842 (2014).
Handelsman, D. J. Testosterone and male aging: faltering hope for rejuvenation. JAMA 317, 699–701 (2017).
Baillargeon, J., Kuo, Y. F., Westra, J. R., Urban, R. J. & Goodwin, J. S. Testosterone Prescribing in the United States, 2002–2016. JAMA 320, 200–202 (2018).
Yeap, B. B. et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J. Clin. Endocrinol. Metab. 94, 2353–2359 (2009).
Ohlsson, C. 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. 58, 1674–1681 (2011).
Soisson, V. et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 75, 282–288 (2013).
Yeap, B. B. et al. In older men, higher plasma testosterone or dihydrotestosterone is an independent predictor for reduced incidence of stroke but not myocardial infarction. J. Clin. Endocrinol. Metab. 99, 4565–4573 (2014).
Khaw, K. T. 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 116, 2694–2701 (2007).
Laughlin, G. A., Barrett-Connor, E. & Bergstrom, J. Low serum testosterone and mortality in older men. J. Clin. Endocrinol. Metab. 93, 68–75 (2008).
Haring, R. et al. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79. Eur. Heart J. 31, 1494–1501 (2010).
Vigen, R. et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310, 1829–1836 (2013).
Finkle, W. D. et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLOS ONE 9, e85805 (2014).
Etminan, M., Skeldon, S. C., Goldenberg, S. L., Carleton, B. & Brophy, J. M. Testosterone therapy and risk of myocardial infarction: a pharmacoepidemiologic study. Pharmacotherapy 35, 72–78 (2015).
Martinez, C. et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ 355, i5968 (2016).
Baillargeon, J. et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin. Proc. 90, 1038–1045 (2015).
Li, H., Benoit, K., Wang, W. & Motsko, S. Association between use of exogenous testosterone therapy and risk of venous thrombotic events among exogenous testosterone treated and untreated men with hypogonadism. J. Urol. 195, 1065–1072 (2016).
Sharma, R. et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the Veterans Administration Database. Chest 150, 563–571 (2016).
Shores, M. M., Smith, N. L., Forsberg, C. W., Anawalt, B. D. & Matsumoto, A. M. Testosterone treatment and mortality in men with low testosterone levels. J. Clin. Endocrinol. Metab. 97, 2050–2058 (2012).
Muraleedharan, V., Marsh, H., Kapoor, D., Channer, K. S. & Jones, T. H. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur. J. Endocrinol. 169, 725–733 (2013).
Baillargeon, J. et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann. Pharmacother. 48, 1138–1144 (2014).
Sharma, R. et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur. Heart J. 36, 2706–2715 (2015).
Tan, R. S., Cook, K. R. & Reilly, W. G. Myocardial infarction and stroke risk in young healthy men treated with injectable testosterone. Int. J. Endocrinol. 2015, 970750 (2015).
Anderson, J. L. et al. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system. Am. J. Cardiol. 117, 794–799 (2016).
Wallis, C. J. et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol. 4, 498–506 (2016).
Oni, O. A. et al. Normalization of testosterone levels after testosterone replacement therapy is not associated with reduced myocardial infarction in smokers. Mayo Clin. Proc. Innov. Qual. Outcomes 1, 57–66 (2017).
Cheetham, T. C. et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern. Med. 177, 491–499 (2017).
Sharma, R. et al. Normalization of testosterone levels after testosterone replacement therapy is associated with decreased incidence of atrial fibrillation. J. Am. Heart Assoc. 6, e004880 (2017).
Basaria, S. et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109–122 (2010).
Xu, L., Freeman, G., Cowling, B. J. & Schooling, C. M. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 11, 108 (2013).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03518034 (2019).
Wang, C., Catlin, D. H., Demers, L. M., Starcevic, B. & Swerdloff, R. S. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J. Clin. Endocrinol. Metab. 89, 534–543 (2004).
Sikaris, K. et al. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J. Clin. Endocrinol. Metab. 90, 5928–5936 (2005).
Handelsman, D. J. & Wartofsky, L. Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J. Clin. Endocrinol. Metab. 98, 3971–3973 (2013).
Shores, M. M. et al. Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study. Clin. Endocrinol. 81, 746–753 (2014).
Srinath, R., Gottesman, R. F., Hill Golden, S., Carson, K. A. & Dobs, A. Association between endogenous testosterone and cerebrovascular disease in the ARIC Study (Atherosclerosis Risk in Communities). Stroke 47, 2682–2688 (2016).
Magnani, J. W. et al. Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Circ. Arrhythm. Electrophysiol. 7, 307–312 (2014).
Rosenberg, M. A. et al. Serum androgens and risk of atrial fibrillation in older men: the Cardiovascular Health Study. Clin. Cardiol. 41, 830–836 (2018).
Zeller, T. et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women — results from the FINRISK study. Eur. J. Prev. Cardiol. 25, 1133–1139 (2018).
Ruige, J. B., Mahmoud, A. M., De Bacquer, D. & Kaufman, J. M. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 97, 870–875 (2011).
Haring, R. et al. Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality. Andrology 1, 17–23 (2013).
Shores, M. M., Matsumoto, A. M., Sloan, K. L. & Kivlahan, D. R. Low serum testosterone and mortality in male veterans. Arch. Intern. Med. 166, 1660–1665 (2006).
Tivesten, A. et al. Low serum testosterone and estradiol predict mortality in elderly men. J. Clin. Endocrinol. Metab. 94, 2482–2488 (2009).
Vikan, T., Schirmer, H., Njolstad, I. & Svartberg, J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur. J. Endocrinol. 161, 435–442 (2009).
Malkin, C. J. et al. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 96, 1821–1825 (2010).
Menke, A. et al. Sex steroid hormone concentrations and risk of death in US men. Am. J. Epidemiol. 171, 583–592 (2010).
Hyde, Z. et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J. Clin. Endocrinol. Metab. 97, 179–189 (2012).
Yeap, B. B. et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J. Clin. Endocrinol. Metab. 99, E9–E18 (2014).
Araujo, A. B. et al. Sex steroids and all-cause and cause-specific mortality in men. Arch. Intern. Med. 167, 1252–1260 (2007).
Szulc, P., Claustrat, B. & Delmas, P. D. Serum concentrations of 17beta-E2 and 25-hydroxycholecalciferol (25OHD) in relation to all-cause mortality in older men—the MINOS study. Clin. Endocrinol. 71, 594–602 (2009).
Haring, R. et al. Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study. Clin. Endocrinol. 78, 629–634 (2013).
Shores, M. M. et al. Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. J. Clin. Endocrinol. Metab. 99, 2061–2068 (2014).
Chan, Y. X. et al. Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non-fatal cardiovascular events, and mortality in men aged 17–97 years. Clin. Endocrinol. 85, 575–582 (2016).
Araujo, A. B. et al. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 96, 3007–3019 (2011).
Keating, N. L., O’Malley, A. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J. Clin. Oncol. 24, 4448–4456 (2006).
Azoulay, L. et al. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. Eur. Urol. 60, 1244–1250 (2011).
Keating, N. L., O’Malley, A. J., Freedland, S. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J. Natl Cancer Inst. 102, 39–46 (2010).
Martin-Merino, E., Johansson, S., Morris, T. & Garcia Rodriguez, L. A. Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-control study in UK primary care. Drug Saf. 34, 1061–1077 (2011).
Hu, J. C. et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur. Urol. 61, 1119–1128 (2012).
Maggi, M. et al. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Int. J. Clin. Pract. 70, 843–852 (2016).
Layton, J. B. et al. Comparative safety of testosterone dosage forms. JAMA Intern. Med. 175, 1187–1196 (2015).
Basaria, S. Need for standardising adverse event reporting in testosterone trials. Evid. Based Med. 19, 32–33 (2014).
Gluud, C. The Copenhagen Study Group for Liver Diseases. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 6, 807–813 (1986).
Basaria, S. et al. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. J. Gerontol. A 68, 153–160 (2013).
Newman, A. B. et al. Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 295, 2018–2026 (2006).
Newman, A. B. et al. Associations of subclinical cardiovascular disease with frailty. J. Gerontol. A 56, M158–M166 (2001).
Basaria, S. et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA 314, 570–581 (2015).
Resnick, S. M. et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 317, 717–727 (2017).
Budoff, M. J. et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA 317, 708–716 (2017).
Roy, C. N. et al. Association of testosterone levels with anemia in older men: a controlled clinical trial. JAMA Intern. Med. 177, 480–490 (2017).
Snyder, P. J. et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial. JAMA Intern. Med. 177, 471–479 (2017).
Meriggiola, M. C. et al. A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J. Clin. Endocrinol. Metab. 81, 3018–3023 (1996).
Bebb, R. A. et al. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J. Clin. Endocrinol. Metab. 81, 757–762 (1996).
Meriggiola, M. C., Bremner, W. J., Costantino, A., Di Cintio, G. & Flamigni, C. Low dose of cyproterone acetate and testosterone enanthate for contraception in men. Hum. Reprod. 13, 1225–1229 (1998).
Zhang, G. Y., Gu, Y. Q., Wang, X. H., Cui, Y. G. & Bremner, W. J. A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in normal Chinese men. J. Clin. Endocrinol. Metab. 84, 3642–3647 (1999).
Anawalt, B. D., Bebb, R. A., Bremner, W. J. & Matsumoto, A. M. A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations. J. Androl. 20, 407–414 (1999).
Wu, F. C., Balasubramanian, R., Mulders, T. M. & Coelingh-Bennink, H. J. Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. J. Clin. Endocrinol. Metab. 84, 112–122 (1999).
Anawalt, B. D. et al. Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression. Fertil. Steril. 74, 707–714 (2000).
Meriggiola, M. C., Costantino, A., Bremner, W. J. & Morselli-Labate, A. M. Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen. J. Androl. 23, 684–690 (2002).
Gu, Y. Q. et al. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J. Clin. Endocrinol. Metab. 88, 562–568 (2003).
Meriggiola, M. C. et al. Testosterone undecanoate maintains spermatogenic suppression induced by cyproterone acetate plus testosterone undecanoate in normal men. J. Clin. Endocrinol. Metab. 88, 5818–5826 (2003).
Herbst, K. L., Anawalt, B. D., Amory, J. K., Matsumoto, A. M. & Bremner, W. J. The male contraceptive regimen of testosterone and levonorgestrel significantly increases lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced by testosterone alone. J. Clin. Endocrinol. Metab. 88, 1167–1173 (2003).
Gu, Y. Q. et al. Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in chinese men. J. Clin. Endocrinol. Metab. 89, 2254–2262 (2004).
Anawalt, B. D. et al. Intramuscular testosterone enanthate plus very low dosage oral levonorgestrel suppresses spermatogenesis without causing weight gain in normal young men: a randomized clinical trial. J. Androl. 26, 405–413 (2005).
Meriggiola, M. C. et al. Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate. J. Clin. Endocrinol. Metab. 90, 2005–2014 (2005).
Qoubaitary, A. et al. Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in healthy men. J. Androl. 27, 853–867 (2006).
Wang, C. et al. Transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. J. Clin. Endocrinol. Metab. 92, 3292–3304 (2007).
Gu, Y. et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J. Clin. Endocrinol. Metab. 94, 1910–1915 (2009).
Nieschlag, E. et al. Hormonal male contraception in men with normal and subnormal semen parameters. Int. J. Androl. 34, 556–567 (2011).
Behre, H. M. et al. Efficacy and safety of an injectable combination hormonal contraceptive for men. J. Clin. Endocrinol. Metab. 101, 4779–4788 (2016).
Gonzalo, I. T. et al. Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination with transdermal and injectable testosterone. J. Clin. Endocrinol. Metab. 87, 3562–3572 (2002).
Handelsman, D. J., Conway, A. J., Howe, C. J., Turner, L. & Mackey, M. A. Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. J. Clin. Endocrinol. Metab. 81, 4113–4121 (1996).
Kinniburgh, D., Anderson, R. A. & Baird, D. T. Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced by addition of finasteride. J. Androl. 22, 88–95 (2001).
Anderson, R. A. et al. Investigation of hormonal male contraception in African men: suppression of spermatogenesis by oral desogestrel with depot testosterone. Hum. Reprod. 17, 2869–2877 (2002).
Kinniburgh, D. et al. Oral desogestrel with testosterone pellets induces consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men. Hum. Reprod. 17, 1490–1501 (2002).
Anderson, R. A., Kinniburgh, D. & Baird, D. T. Suppression of spermatogenesis by etonogestrel implants with depot testosterone: potential for long-acting male contraception. J. Clin. Endocrinol. Metab. 87, 3640–3649 (2002).
Turner, L. et al. Contraceptive efficacy of a depot progestin and androgen combination in men. J. Clin. Endocrinol. Metab. 88, 4659–4667 (2003).
Brady, B. M. et al. Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception. Hum. Reprod. 19, 2658–2667 (2004).
Wang, C. et al. Levonorgestrel implants enhanced the suppression of spermatogenesis by testosterone implants: comparison between Chinese and non-Chinese men. J. Clin. Endocrinol. Metab. 91, 460–470 (2006).
Walton, M. J., Kumar, N., Baird, D. T., Ludlow, H. & Anderson, R. A. 7alpha-methyl-19-nortestosterone (MENT) versus testosterone in combination with etonogestrel implants for spermatogenic suppression in healthy men. J. Androl. 28, 679–688 (2007).
Page, S. T. et al. Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist. J. Clin. Endocrinol. Metab. 91, 4374–4380 (2006).
Mahabadi, V. et al. Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men. J. Clin. Endocrinol. Metab. 94, 2313–2320 (2009).
Ilani, N. et al. A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. J. Clin. Endocrinol. Metab. 97, 3476–3486 (2012).
Calof, O. M. et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J. Gerontol. A 60, 1451–1457 (2005).
Haddad, R. M. et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin. Proc. 82, 29–39 (2007).
Fernandez-Balsells, M. M. et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 95, 2560–2575 (2010).
Albert, S. G. & Morley, J. E. Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. Clin. Endocrinol. 85, 436–443 (2016).
Alexander, G. C., Iyer, G., Lucas, E., Lin, D. & Singh, S. Cardiovascular risks of exogenous testosterone use among men: a systematic review and meta-analysis. Am. J. Med. 130, 293–305 (2017).
Corona, G. et al. Testosterone and cardiovascular risk: meta-analysis of interventional studies. J. Sex. Med. 15, 820–838 (2018).
Tunstall-Pedoe, H. et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 353, 1547–1557 (1999).
D’Agostino, R. B. Sr. et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 117, 743–753 (2008).
Kappert, K. et al. Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). Circulation 126, 934–941 (2012).
Kalin, M. F. & Zumoff, B. Sex hormones and coronary disease: a review of the clinical studies. Steroids 55, 330–352 (1990).
Alexandersen, P., Haarbo, J., Byrjalsen, I., Lawaetz, H. & Christiansen, C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ. Res. 84, 813–819 (1999).
Qiu, Y. et al. Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology 151, 3307–3316 (2010).
Larsen, B. A., Nordestgaard, B. G., Stender, S. & Kjeldsen, K. Effect of testosterone on atherogenesis in cholesterol-fed rabbits with similar plasma cholesterol levels. Atherosclerosis 99, 79–86 (1993).
Li, S., Li, X. & Li, Y. Regulation of atherosclerotic plaque growth and stability by testosterone and its receptor via influence of inflammatory reaction. Vascul. Pharmacol. 49, 14–18 (2008).
Nettleship, J. E., Jones, T. H., Channer, K. S. & Jones, R. D. Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor. Circulation 116, 2427–2434 (2007).
Bourghardt, J. et al. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology 151, 5428–5437 (2010).
Nathan, L. et al. Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc. Natl Acad. Sci. USA 98, 3589–3593 (2001).
Kelly, D. M., Sellers, D. J., Woodroofe, M. N., Jones, T. H. & Channer, K. S. Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model. Endocr. Res. 38, 125–138 (2012).
Hanke, H., Lenz, C., Hess, B., Spindler, K. D. & Weidemann, W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 103, 1382–1385 (2001).
Hatakeyama, H. et al. Testosterone inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells. FEBS Lett. 530, 129–132 (2002).
Mukherjee, T. K., Dinh, H., Chaudhuri, G. & Nathan, L. Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: implications in atherosclerosis. Proc. Natl Acad. Sci. USA 99, 4055–4060 (2002).
Cybulsky, M. I. & Gimbrone, M. A. Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251, 788–791 (1991).
O’Brien, K. D. et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J. Clin. Invest. 92, 945–951 (1993).
Cybulsky, M. I. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J. Clin. Invest. 107, 1255–1262 (2001).
McCrohon, J. A., Jessup, W., Handelsman, D. J. & Celermajer, D. S. Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1. Circulation 99, 2317–2322 (1999).
Son, B. K. et al. Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J. Biol. Chem. 285, 7537–7544 (2010).
Son, B. K. et al. Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circul. Res. 98, 1024–1031 (2006).
Son, B. K. et al. Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells. Eur. J. Pharmacol. 556, 1–8 (2007).
Zhu, D. et al. Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification. Sci. Rep. 6, 24807 (2016).
Langer, C. et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem. Biophys. Res. Commun. 296, 1051–1057 (2002).
Moverare-Skrtic, S. et al. Dihydrotestosterone treatment results in obesity and altered lipid metabolism in orchidectomized mice. Obesity 14, 662–672 (2006).
Herbst, K. L., Amory, J. K., Brunzell, J. D., Chansky, H. A. & Bremner, W. J. Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk. Am. J. Physiol. Endocrinol. Metab. 284, E1112–E1118 (2003).
Tan, K. C., Shiu, S. W., Pang, R. W. & Kung, A. W. Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins. Clin. Endocrinol. 48, 187–194 (1998).
Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).
Rubinow, K. B. et al. Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J. Lipid Res. 53, 1376–1383 (2012).
Rubinow, K. B., Vaisar, T., Chao, J. H., Heinecke, J. W. & Page, S. T. Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J. Clin. Lipidol. 12, 1072–1082 (2018).
Shahidi, N. T. Androgens and erythropoiesis. N. Engl. J. Med. 289, 72–80 (1973).
Shahani, S., Braga-Basaria, M., Maggio, M. & Basaria, S. Androgens and erythropoiesis: past and present. J. Endocrinol. Invest. 32, 704–716 (2009).
Bachman, E. et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J. Gerontol. A 69, 725–735 (2014).
Gagliano-Juca, T. et al. Mechanisms responsible for reduced erythropoiesis during androgen deprivation therapy in men with prostate cancer. Am. J. Physiol. Endocrinol. Metab. 315, E1185–E1193 (2018).
Guo, W. et al. The effects of short-term and long-term testosterone supplementation on blood viscosity and erythrocyte deformability in healthy adult mice. Endocrinology 156, 1623–1629 (2015).
Zhao, C., Moon du, G. & Park, J. K. Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits. Can. Urol. Assoc. J. 7, E221–E225 (2013).
Reinhart, W. H. The optimum hematocrit. Clin. Hemorheol. Microcircul. 64, 575–585 (2016).
Eugster, M. & Reinhart, W. H. The influence of the haematocrit on primary haemostasis in vitro. Thromb. Haemostasis 94, 1213–1218 (2005).
Ajayi, A. A., Mathur, R. & Halushka, P. V. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 91, 2742–2747 (1995).
Ajayi, A. A. & Halushka, P. V. Castration reduces platelet thromboxane A2 receptor density and aggregability. QJM 98, 349–356 (2005).
Yue, P., Chatterjee, K., Beale, C., Poole-Wilson, P. A. & Collins, P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 91, 1154–1160 (1995).
Deenadayalu, V. P., White, R. E., Stallone, J. N., Gao, X. & Garcia, A. J. Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel. Am. J. Physiol. Heart Circ. Physiol. 281, H1720–H1727 (2001).
Tep-areenan, P., Kendall, D. A. & Randall, M. D. Testosterone-induced vasorelaxation in the rat mesenteric arterial bed is mediated predominantly via potassium channels. Br. J. Pharmacol. 135, 735–740 (2002).
Chou, T. M. et al. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 94, 2614–2619 (1996).
Perusquia, M., Greenway, C. D., Perkins, L. M. & Stallone, J. N. Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R189–R195 (2015).
Bachetti, T. et al. Co-expression and modulation of neuronal and endothelial nitric oxide synthase in human endothelial cells. J. Mol. Cell. Cardiol. 37, 939–945 (2004).
Molinari, C. et al. The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs. J. Physiol. 543, 365–372 (2002).
Scragg, J. L., Jones, R. D., Channer, K. S., Jones, T. H. & Peers, C. Testosterone is a potent inhibitor of L-type Ca(2+) channels. Biochem. Biophys. Res. Commun. 318, 503–506 (2004).
Jones, R. D., English, K. M., Jones, T. H. & Channer, K. S. Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action. Clin. Sci. 107, 149–158 (2004).
Yu, J. et al. Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. Endocrinology 151, 1822–1828 (2010).
Campelo, A. E., Cutini, P. H. & Massheimer, V. L. Cellular actions of testosterone in vascular cells: mechanism independent of aromatization to estradiol. Steroids 77, 1033–1040 (2012).
Ruamyod, K., Watanapa, W. B. & Shayakul, C. Testosterone rapidly increases Ca2+-activated K+ currents causing hyperpolarization in human coronary artery endothelial cells. J. Steroid Biochem. Mol. Biol. 168, 118–126 (2017).
Ellison, K. E., Ingelfinger, J. R., Pivor, M. & Dzau, V. J. Androgen regulation of rat renal angiotensinogen messenger RNA expression. J. Clin. Invest. 83, 1941–1945 (1989).
Quan, A. et al. Androgens augment proximal tubule transport. Am. J. Physiol. Renal Physiol. 287, F452–F459 (2004).
Mackovic, M., Zimolo, Z., Burckhardt, G. & Sabolic, I. Isolation of renal brush-border membrane vesicles by a low-speed centrifugation; effect of sex hormones on Na+-H+ exchange in rat and mouse kidney. Biochim. Biophys. Acta 862, 141–152 (1986).
Loh, S. Y., Giribabu, N. & Salleh, N. Sub-chronic testosterone treatment increases the levels of epithelial sodium channel (ENaC)-alpha, beta and gamma in the kidney of orchidectomized adult male Sprague-Dawley rats. PeerJ 4, e2145 (2016).
Herak-Kramberger, C. M. et al. Sex-dependent expression of water channel AQP1 along the rat nephron. Am. J. Physiol. Renal Physiol. 308, F809–F821 (2015).
Bidoggia, H. et al. Sex differences on the electrocardiographic pattern of cardiac repolarization: possible role of testosterone. Am. Heart J. 140, 678–683 (2000).
Bai, C. X., Kurokawa, J., Tamagawa, M., Nakaya, H. & Furukawa, T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 112, 1701–1710 (2005).
Er, F. et al. Impact of testosterone on cardiac L-type calcium channels and Ca2+ sparks: acute actions antagonize chronic effects. Cell Calcium 41, 467–477 (2007).
Ridley, J. M., Shuba, Y. M., James, A. F. & Hancox, J. C. Modulation by testosterone of an endogenous hERG potassium channel current. J. Physiol. Pharmacol. 59, 395–407 (2008).
Golden, K. L., Marsh, J. D., Jiang, Y. & Moulden, J. Acute actions of testosterone on contractile function of isolated rat ventricular myocytes. Eur. J. Endocrinol. 152, 479–483 (2005).
Curl, C. L., Delbridge, L. M., Canny, B. J. & Wendt, I. R. Testosterone modulates cardiomyocyte Ca(2+) handling and contractile function. Physiol. Res. 58, 293–297 (2009).
Golden, K. L., Marsh, J. D., Jiang, Y., Brown, T. & Moulden, J. Gonadectomy of adult male rats reduces contractility of isolated cardiac myocytes. Am. J. Physiol. Endocrinol. Metab. 285, E449–E453 (2003).
Tsang, S., Wong, S. S., Wu, S., Kravtsov, G. M. & Wong, T. M. Testosterone-augmented contractile responses to alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart. Am. J. Physiol. Cell Physiol. 296, C766–C782 (2009).
Eleawa, S. M. et al. Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats. Acta Physiol. 209, 136–147 (2013).
Witayavanitkul, N., Woranush, W., Bupha-Intr, T. & Wattanapermpool, J. Testosterone regulates cardiac contractile activation by modulating SERCA but not NCX activity. Am. J. Physiol. Heart Circ. Physiol. 304, H465–H472 (2013).
Jaffe, M. D. Effect of testosterone cypionate on postexercise ST segment depression. Br. Heart J. 39, 1217–1222 (1977).
Webb, C. M., McNeill, J. G., Hayward, C. S., de Zeigler, D. & Collins, P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 100, 1690–1696 (1999).
English, K. M., Steeds, R. P., Jones, T. H., Diver, M. J. & Channer, K. S. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 102, 1906–1911 (2000).
Mathur, A. et al. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur. J. Endocrinol. 161, 443–449 (2009).
Webb, C. M. et al. Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. Am. J. Cardiol. 101, 618–624 (2008).
Smith, J. C. et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J. Clin. Endocrinol. Metab. 86, 4261–4267 (2001).
Dockery, F., Bulpitt, C. J., Agarwal, S., Vernon, C. & Rajkumar, C. Effect of androgen suppression compared with androgen receptor blockade on arterial stiffness in men with prostate cancer. J. Androl. 30, 410–415 (2009).
Johannsson, G., Gibney, J., Wolthers, T., Leung, K. C. & Ho, K. K. Independent and combined effects of testosterone and growth hormone on extracellular water in hypopituitary men. J. Clin. Endocrinol. Metab. 90, 3989–3994 (2005).
Stramba-Badiale, M., Spagnolo, D., Bosi, G. & Schwartz, P. J. Are gender differences in QTc present at birth? MISNES Investigators. Multicenter Italian Study on Neonatal Electrocardiography and Sudden Infant Death Syndrome. Am. J. Cardiol. 75, 1277–1278 (1995).
Alimurung, M. M., Joseph, L. G., Craige, E. & Massell, B. F. The Q-T interval in normal infants and children. Circulation 1, 1329–1337 (1950).
Rautaharju, P. M. et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can. J. Cardiol. 8, 690–695 (1992).
Zhang, Y. et al. Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis. Am. J. Epidemiol. 174, 403–411 (2011).
Junttila, M. J. et al. Relationship between testosterone level and early repolarization on 12-lead electrocardiograms in men. J. Am. Coll. Cardiol. 62, 1633–1634 (2013).
Vicente, J., Johannesen, L., Galeotti, L. & Strauss, D. G. Mechanisms of sex and age differences in ventricular repolarization in humans. Am. Heart J. 168, 749–756 (2014).
Gagliano-Juca, T. et al. Effects of testosterone replacement on electrocardiographic parameters in men: findings from two randomized trials. J. Clin. Endocrinol. Metab. 102, 1478–1485 (2017).
Schwartz, J. B. et al. Effects of testosterone on the Q-T interval in older men and older women with chronic heart failure. Int. J. Androl. 34, e415–e421 (2011).
Gagliano-Juca, T. et al. Androgen deprivation therapy is associated with prolongation of QTc interval in men with prostate cancer. J. Endocr. Soc. 2, 485–496 (2018).
Zhang, Y. et al. Electrocardiographic QT interval and mortality: a meta-analysis. Epidemiology 22, 660–670 (2011).
Noseworthy, P. A. et al. QT interval and long-term mortality risk in the Framingham Heart Study. Ann. Noninvasive Electrocardiol. 17, 340–348 (2012).
Nielsen, J. B. et al. Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population. Eur. Heart J. 35, 1335–1344 (2014).
Salem, J. E. et al. Hypogonadism as a reversible cause of torsades de pointes in men. Circulation 138, 110–113 (2018).
Buonanno, C. et al. Left ventricular function in men and women. Another difference between sexes. Eur. Heart J. 3, 525–528 (1982).
Hanley, P. C. et al. Gender-related differences in cardiac response to supine exercise assessed by radionuclide angiography. J. Am. Coll. Cardiol. 13, 624–629 (1989).
Merz, C. N., Moriel, M., Rozanski, A., Klein, J. & Berman, D. S. Gender-related differences in exercise ventricular function among healthy subjects and patients. Am. Heart J. 131, 704–709 (1996).
Traustadottir, T. et al. Long-term testosterone supplementation in older men attenuates age-related decline in aerobic capacity. J. Clin. Endocrinol. Metab. 103, 2861–2869 (2018).
Storer, T. W. et al. Testosterone attenuates age-related fall in aerobic function in mobility limited older men with low testosterone. J. Clin. Endocrinol. Metab. 101, 2562–2569 (2016).
Pugh, P. J., Jones, T. H. & Channer, K. S. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur. Heart J. 24, 909–915 (2003).
Malkin, C. J. et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur. Heart J. 27, 57–64 (2006).
Caminiti, G. et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J. Am. Coll. Cardiol. 54, 919–927 (2009).
Mortara, A. et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 96, 3450–3458 (1997).
Svartberg, J. et al. Low testosterone levels are associated with carotid atherosclerosis in men. J. Intern. Med. 259, 576–582 (2006).
Vikan, T., Johnsen, S. H., Schirmer, H., Njolstad, I. & Svartberg, J. Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromso study. Eur. J. Epidemiol. 24, 289–295 (2009).
Muller, M. et al. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 109, 2074–2079 (2004).
Soisson, V. et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis 223, 244–249 (2012).
Li, L. et al. Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian J. Androl. 14, 875–878 (2012).
Park, B. J., Shim, J. Y., Lee, Y. J., Lee, J. H. & Lee, H. R. Inverse relationship between bioavailable testosterone and subclinical coronary artery calcification in non-obese Korean men. Asian J. Androl. 14, 612–615 (2012).
Travison, T. G. et al. Circulating sex steroids and vascular calcification in community-dwelling men: the Framingham Heart Study. J. Clin. Endocrinol. Metab. 101, 2160–2167 (2016).
Khazai, B. et al. Association of endogenous testosterone with subclinical atherosclerosis in men: the multi-ethnic study of atherosclerosis. Clin. Endocrinol. 84, 700–707 (2016).
English, K. M. et al. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur. Heart J. 21, 890–894 (2000).
Tivesten, A. et al. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. J. Am. Coll. Cardiol. 50, 1070–1076 (2007).
Makinen, J. I. et al. Endogenous testosterone and serum lipids in middle-aged men. Atherosclerosis 197, 688–693 (2008).
Haffner, S. M., Mykkanen, L., Valdez, R. A. & Katz, M. S. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J. Clin. Endocrinol. Metab. 77, 1610–1615 (1993).
Zhang, N. et al. The relationship between endogenous testosterone and lipid profile in middle-aged and elderly Chinese men. Eur. J. Endocrinol. 170, 487–494 (2014).
Page, S. T. et al. Higher testosterone levels are associated with increased high-density lipoprotein cholesterol in men with cardiovascular disease: results from the Massachusetts Male Aging Study. Asian J. Androl. 10, 193–200 (2008).
Snyder, P. J. et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am. J. Med. 111, 255–260 (2001).
Whitsel, E. A., Boyko, E. J., Matsumoto, A. M., Anawalt, B. D. & Siscovick, D. S. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am. J. Med. 111, 261–269 (2001).
Mohler, E. R. 3rd et al. The effect of testosterone on cardiovacular biomarkers in the testosterone trials. J. Clin. Endocrinol. Metab. 103, 681–688 (2018).
Jones, T. H. et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34, 828–837 (2011).
Muller, M., Grobbee, D. E., den Tonkelaar, I., Lamberts, S. W. & van der Schouw, Y. T. Endogenous sex hormones and metabolic syndrome in aging men. J. Clin. Endocrinol. Metab. 90, 2618–2623 (2005).
Ding, E. L., Song, Y., Malik, V. S. & Liu, S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295, 1288–1299 (2006).
Chin, K. Y., Ima-Nirwana, S., Mohamed, I. N., Aminuddin, A. & Ngah, W. Z. Total testosterone and sex hormone-binding globulin are significantly associated with metabolic syndrome in middle-aged and elderly men. Exp. Clin. Endocrinol. Diabetes 121, 407–412 (2013).
Selvin, E. et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 30, 234–238 (2007).
Yeap, B. B. et al. Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study. Eur. J. Endocrinol. 161, 591–598 (2009).
Vikan, T., Schirmer, H., Njolstad, I. & Svartberg, J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur. J. Endocrinol. 162, 747–754 (2010).
Yialamas, M. A. et al. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 92, 4254–4259 (2007).
Braga-Basaria, M. et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J. Clin. Oncol. 24, 3979–3983 (2006).
Tsai, H. T. et al. Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer. J. Urol. 193, 1956–1962 (2015).
Shahani, S., Braga-Basaria, M. & Basaria, S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J. Clin. Endocrinol. Metab. 93, 2042–2049 (2008).
Basaria, S., Muller, D. C., Carducci, M. A., Egan, J. & Dobs, A. S. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 106, 581–588 (2006).
Gagliano-Juca, T. et al. Metabolic changes in androgen-deprived nondiabetic men with prostate cancer are not mediated by cytokines or aP2. J. Clin. Endocrinol. Metab. 103, 3900–3908 (2018).
Hsu, B. et al. Associations between circulating reproductive hormones and SHBG and prevalent and incident metabolic syndrome in community-dwelling older men: the Concord Health and Ageing in Men Project. J. Clin. Endocrinol. Metab. 99, E2686–E2691 (2014).
Antonio, L. et al. Associations between sex steroids and the development of metabolic syndrome: a longitudinal study in European men. J. Clin. Endocrinol. Metab. 100, 1396–1404 (2015).
Joyce, K. E. et al. Testosterone, dihydrotestosterone, sex hormone-binding globulin, and incident diabetes among older men: the Cardiovascular Health Study. J. Clin. Endocrinol. Metab. 102, 33–39 (2017).
Pitteloud, N. et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care 28, 1636–1642 (2005).
Dhindsa, S. et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 39, 82–91 (2016).
Boyanov, M. A., Boneva, Z. & Christov, V. G. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 6, 1–7 (2003).
Huang, G. et al. Long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels. J. Clin. Endocrinol. Metab. 103, 1678–1685 (2018).
Gianatti, E. J. et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. Diabetes Care 37, 2098–2107 (2014).
Willerson, J. T. & Ridker, P. M. Inflammation as a cardiovascular risk factor. Circulation 109, II2–10 (2004).
Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017).
Ridker, P. M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369 (2003).
Biasucci, L. M. et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99, 2079–2084 (1999).
Dunlay, S. M., Weston, S. A., Redfield, M. M., Killian, J. M. & Roger, V. L. Tumor necrosis factor-alpha and mortality in heart failure: a community study. Circulation 118, 625–631 (2008).
Pastuszak, A. W., Kohn, T. P., Estis, J. & Lipshultz, L. I. Low plasma testosterone is associated with elevated cardiovascular disease biomarkers. J. Sex. Med. 14, 1095–1103 (2017).
Zhang, Y. et al. Endogenous sex hormones and C-reactive protein in healthy Chinese men. Clin. Endocrinol. 78, 60–66 (2013).
Kaplan, S. A., Johnson-Levonas, A. O., Lin, J., Shah, A. K. & Meehan, A. G. Elevated high sensitivity C-reactive protein levels in aging men with low testosterone. Aging Male 13, 108–112 (2010).
Tsilidis, K. K. et al. Association between endogenous sex steroid hormones and inflammatory biomarkers in US men. Andrology 1, 919–928 (2013).
Haring, R. et al. Prospective inverse associations of sex hormone concentrations in men with biomarkers of inflammation and oxidative stress. J. Androl. 33, 944–950 (2012).
Maggio, M. et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J. Clin. Endocrinol. Metab. 91, 345–347 (2006).
Nakhai Pour, H. R., Grobbee, D. E., Muller, M. & van der Schouw, Y. T. Association of endogenous sex hormone with C-reactive protein levels in middle-aged and elderly men. Clin. Endocrinol. 66, 394–398 (2007).
Malkin, C. J. et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J. Clin. Endocrinol. Metab. 89, 3313–3318 (2004).
Abriel, H. & Zaklyazminskaya, E. V. Cardiac channelopathies: genetic and molecular mechanisms. Gene 517, 1–11 (2013).
Arnlov, J. et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann. Intern. Med. 145, 176–184 (2006).
Abbott, R. D. et al. Serum estradiol and risk of stroke in elderly men. Neurology 68, 563–568 (2007).
S.B. has previously consulted for AbbVie, Eli Lilly and Regeneron Pharmaceuticals. T.G.-J. declares no competing interests.
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Gagliano-Jucá, T., Basaria, S. Testosterone replacement therapy and cardiovascular risk. Nat Rev Cardiol 16, 555–574 (2019). https://doi.org/10.1038/s41569-019-0211-4
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