Testosterone and the heart: friend or foe?

References

• Stramba-Badiale M, Fox KM, Priori SG, et al. Cardiovascular diseases in women: a statement from the policy conference of the european society of cardiology. Eur Heart J. 2006;27(8):994–1005. doi: 10.1093/eurheartj/ehi819.
   PubMed Web of Science ®Google Scholar
• Gorodeski GI. Update on cardiovascular disease in post-menopausal women. Best Pract Res Clin Obstet Gynaecol. 2002;16(3):329–355. doi: 10.1053/beog.2002.0282.
   PubMed Web of Science ®Google Scholar
• Davis SR, Bell RJ, Robinson PJet al. Testosterone and estrone increase from the age of 70 years; findings from the sex hormones in older women study. J Clin Endocrinol Metab. 2019;104(12):6291–6300. doi: 10.1210/jc.2019-00743.
   PubMed Web of Science ®Google Scholar
• Davis SR, Panjari M, Stanczyk FZ. DHEA replacement for postmenopausal women. J Clin Endocrinol Metab. 2011;96(6):1642–1653. doi: 10.1210/jc.2010-2888.
   PubMed Web of Science ®Google Scholar
• Labrie F, Luu-The V, Labrie C, et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003;24(2):152–182. doi: 10.1210/er.2001-0031.
   PubMed Web of Science ®Google Scholar
• Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones. Binding of 21 endogenous steroids to both testosterone-binding globulin and cortico-steroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):58–68. doi: 10.1210/jcem-53-1-58.
   PubMed Web of Science ®Google Scholar
• Goldman AL, Bhasin S, Wu FCW, et al. A reappraisal of testosterone’s binding in circulation: physiological and clinical implications. Endocr Rev. 2017;38(4):302–324. doi: 10.1210/er.2017-00025.
   PubMed Web of Science ®Google Scholar
• Handelsman DJ. Free testosterone: pumping up the tires or ending the free ride? Endocr Rev. 2017;38(4):297–301. doi: 10.1210/er.2017-00171.
   PubMed Web of Science ®Google Scholar
• Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. Climacteric. 2019;22(5):429–434. doi: 10.1080/13697137.2019.1637079.
   PubMed Web of Science ®Google Scholar
• Skiba MA, Bell RJ, Islam RM, et al. Androgens during the reproductive years, what’s normal for women? J Clin Endocrinol Metab. 2019;104(11):5382–5392. doi: 10.1210/jc.2019-01357.
   PubMed Web of Science ®Google Scholar
• Davison SL, Bell R, Donath S, et al. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90(7):3847–3853. doi: 10.1210/jc.2005-0212.
   PubMed Web of Science ®Google Scholar
• Burger HG, Dudley EC, Robertson DM, et al. Hormonal changes in the menopause transition. Recent Prog Horm Res. 2002;57(1):257–275. doi: 10.1210/rp.57.1.257.
   PubMedGoogle Scholar
• Cappola AR, Ratcliffe SJ, Bhasin S, et al. Determinants of serum total and free testosterone levels in women over the age of 65 years. J Clin Endocrinol Metab. 2007;92(2):509–516. doi: 10.1210/jc.2006-1399.
   PubMed Web of Science ®Google Scholar
• Aribas E, Roeters van Lennep JE, De Rijke YB, et al. Sex steroids and sex steroid-binding globulin levels amongst middle-aged and elderly men and women from general population. Eur J Clin Invest. 2022;52(12):e13866. doi: 10.1111/eci.13866.
   PubMed Web of Science ®Google Scholar
• Islam RM, Bell RJ, Handelsman DJ, et al. Longitudinal changes over three years in sex steroid hormone levels in women aged 70 years and over. Clin Endocrinol. 2021;94(3):443–448. doi: 10.1111/cen.14401.
   PubMed Web of Science ®Google Scholar
• Biegelsen E, Loscalzo J. Endothelial function and atherosclerosis. Coron Artery Dis. 1999;10(4):241–256.
   PubMed Web of Science ®Google Scholar
• Meczekalski B, Katulski K, Czyzyk A, et al. Functional hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Invest. 2014;37(11):1049–1056. doi: 10.1007/s40618-014-0169-3.
   PubMed Web of Science ®Google Scholar
• Taddei S, Virdis A, Ghiadoni L, et al. Menopause is associated with endothelial dysfunction in women. Hypertension. 1996;28(4):576–582. doi: 10.1161/01.hyp.28.4.576.
   PubMed Web of Science ®Google Scholar
• Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev. 2002;23(5):665–686. doi: 10.1210/er.2001-0045.
   PubMed Web of Science ®Google Scholar
• Leiberman EH, Gerhard M, Uehata A, et al. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121:936–941.
   PubMed Web of Science ®Google Scholar
• Vitale C, Mercuro G, Cerquetani E, et al. Time since menopause influences the acute and chronic effect of estrogens on endothelial function. Arterioscler Thromb Vasc Biol. 2008;28(2):348–352. doi: 10.1161/ATVBAHA.107.158634.
   PubMed Web of Science ®Google Scholar
• Montalcini T, Gorgone G, Gazzaruso C, et al. Endogenous testosterone and endothelial function in postmenopausal women. Coron Artery Dis. 2007;18(1):9–13. doi: 10.1097/01.mca.0000236290.79306.d1.
   PubMed Web of Science ®Google Scholar
• Rech CM, Clapauch R, de Souza M, et al. Low testosterone levels are associated with endothelial dysfunction in oophorectomized early postmenopausal women. Eur J Endocrinol. 2016;174(3):297–306. doi: 10.1530/EJE-15-0878.
   PubMed Web of Science ®Google Scholar
• Worboys S, Kotsopoulos D, Teede H, et al. Parental testosterone improves endothelium-dependent and independent vasodilation in postmenopausal women already receiving estrogen. J Clin Endocrinol Metab. 2001;86(1):158–161. doi: 10.1210/jcem.86.1.7103.
   PubMed Web of Science ®Google Scholar
• Campelo AE, Cutini PH, Massheimer VL. Cellular actions of testosterone in vascular cells: mechanism independent of aromatization to estradiol. Steroids. 2012;77(11):1033–1040. doi: 10.1016/j.steroids.2012.05.008.
   PubMed Web of Science ®Google Scholar
• Navarro-Dorado J, Orensanz LM, Recio P, et al. Mechanisms involved in testosterone-induced vasodilatation in pig prostatic small arteries. Life Sci. 2008;83(15–16):569–573. doi: 10.1016/j.lfs.2008.08.009.
   PubMed Web of Science ®Google Scholar
• Wynne FL, Khalil RA. Testosterone and coronary vascular tone: implications in coronary artery disease. J Endocrinol Invest. 2003;26(2):181–186. doi: 10.1007/BF03345150.
   PubMed Web of Science ®Google Scholar
• Davison S, Thipphawong J, Blanchard J, et al. Pharmacokinetics and acute safety of inhaled testosterone in postmenopausal women. J Clin Pharmacol. 2005;45(2):177–184. doi: 10.1177/0091270004269840.
   PubMed Web of Science ®Google Scholar
• Grohe C, Kahlert S, Lobbert K, et al. Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. J Endocrinol. 1998;156(2):R1–R7. doi: 10.1677/joe.0.156r001.
   PubMed Web of Science ®Google Scholar
• van Weerden WM, Bierings HG, van Steenbrugge GJ, et al. Adrenal glands of mouse and rat do not synthesize androgens. Life Sci. 1992;50(12):857–861. doi: 10.1016/0024-3205(92)90204-3.
   PubMed Web of Science ®Google Scholar
• Bell JR, Mellor KM, Wollermann AC, et al. Aromatase deficiency confers paradoxical postischemic cardioprotection. Endocrinology. 2011;152(12):4937–4947. doi: 10.1210/en.2011-1212.
   PubMed Web of Science ®Google Scholar
• Fu L, Liu Y, Wang J, et al. Cardioprotection by low-dose of estrogen and testosterone at the physiological ratio on ovariectomized rats during ischemia/reperfusion injury. J Cardiovasc Pharmacol. 2017;70(2):87–93. doi: 10.1097/FJC.0000000000000497.
   PubMed Web of Science ®Google Scholar
• Bidoggia H, Maciel JP, Capalozza N, et al. Sex differences on the electrocardiographic pattern of cardiac repolarization: possible role of testosterone. Am Heart J. 2000;140(4):678–683. doi: 10.1067/mhj.2000.109918.
   PubMed Web of Science ®Google Scholar
• Dunlay SM, Roger VL. Gender differences in the pathophysiology, clinical presentation, and outcomes of ischemic heart failure. Curr Heart Fail Rep. 2012;9(4):267–276. doi: 10.1007/s11897-012-0107-7.
   PubMedGoogle Scholar
• Curl CL, Delbridge LMD, Canny BJ, et al. Testosterone modulates cardiomyocyte Ca(2+) handling and contractile function. Physiol Res. 2009;58(2):293–297. doi: 10.33549/physiolres.931460.
   PubMed Web of Science ®Google Scholar
• Worsley R, Robinson PJ, Bell RJ, et al. Endogenous estrogen and androgen levels are not independent predictors of lipid levels in postmenopausal women. Menopause. 2013;20(6):640–645. doi: 10.1097/GME.0b013e318279bd4a.
   PubMed Web of Science ®Google Scholar
• Kische H, Gross S, Wallaschofski H, et al. Clinical correlates of sex hormones in women: the study of health in pomerania. Metabolism. 2016;65(9):1286–1296. doi: 10.1016/j.metabol.2016.05.011.
   PubMed Web of Science ®Google Scholar
• Mudali S, Dobs AS, Ding J, et al. Endogenous postmenopausal hormones and serum lipids: the atherosclerosis risk in communities study. J Clin Endocrinol Metab. 2005;90(2):1202–1209. doi: 10.1210/jc.2004-0744.
   PubMed Web of Science ®Google Scholar
• Bell RJ, Davison SL, Papalia MA, et al. Endogenous androgen levels and cardiovascular risk profile in women across the adult life span. Menopause. 2007;14(4):630–638. doi: 10.1097/GME.0b013e31802b6cb1.
   PubMed Web of Science ®Google Scholar
• Janssen I, Powell LH, Kazlauskaite R, et al. Testosterone and visceral fat in midlife women: the Study of Women’s Health across the Nation (SWAN) fat patterning study. Obesity. 2010;18(3):604–610. doi: 10.1038/oby.2009.251.
   PubMed Web of Science ®Google Scholar
• Davis SR, Robinson PJ, Moufarege A, et al. The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. Clin Endocrinol. 2012;77(4):541–547. doi: 10.1111/j.1365-2265.2011.04301.x.
   PubMed Web of Science ®Google Scholar
• Ding EL, Song Y, Manson JE, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361(12):1152–1163. doi: 10.1056/NEJMoa0804381.
   PubMed Web of Science ®Google Scholar
• Muka T, Nano J, Jaspers L, et al. Associations of steroid sex hormones and sex hormone-binding globulin with the risk of type 2 diabetes in women: a population-based cohort study and meta-analysis. Diabetes. 2017;66(3):577–586. doi: 10.2337/db16-0473.
   PubMed Web of Science ®Google Scholar
• Benn M, Voss SS, Holmegard HN, et al. Extreme concentrations of endogenous sex hormones, ischemic heart disease, and death in women. Arterioscler Thromb Vasc Biol. 2015;35(2):471–477. doi: 10.1161/ATVBAHA.114.304821.
   PubMed Web of Science ®Google Scholar
• Laughlin GA, Goodell V, Barrett-Connor E. Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. J Clin Endocrinol Metab. 2010;95(2):740–747. doi: 10.1210/jc.2009-1693.
   PubMed Web of Science ®Google Scholar
• Sievers C, Klotsche J, Pieper L, et al. Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients. Eur J Endocrinol. 2010;163(4):699–708. doi: 10.1530/EJE-10-0307.
   PubMed Web of Science ®Google Scholar
• Schaffrath G, Kische H, Gross S, et al. Association of sex hormones with incident 10-year cardiovascular disease and mortality in women. Maturitas. 2015;82(4):424–430. doi: 10.1016/j.maturitas.2015.08.009.
   PubMed Web of Science ®Google Scholar
• Zhao D, Guallar E, Ouyang P, et al. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. J Am Coll Cardiol. 2018;71(22):2555–2566. doi: 10.1016/j.jacc.2018.01.083.
   PubMed Web of Science ®Google Scholar
• Naessen T, Sjogren U, Bergquist J, et al. Endogenous steroids measured by high-specificity liquid chromatography-tandem mass spectrometry and prevalent cardiovascular disease in 70-year-old men and women. J Clin Endocrinol Metab. 2010;95(4):1889–1897. doi: 10.1210/jc.2009-1722.
   PubMed Web of Science ®Google Scholar
• Debing E, Peeters E, Duquet W, et al. Endogenous sex hormone levels in postmenopausal women undergoing carotid artery endarterectomy. Eur J Endocrinol. 2007;156(6):687–693. doi: 10.1530/EJE-06-0702.
   PubMed Web of Science ®Google Scholar
• Bernini GP, Sgro’ M, Moretti A, et al. Endogenous androgens and carotid intimal-medial thickness in women. J Clin Endocrinol Metab. 1999;84(6):2008–2012. doi: 10.1210/jcem.84.6.5824.
   PubMed Web of Science ®Google Scholar
• Golden SH, Maguire A, Ding J, et al. Endogenous postmenopausal hormones and carotid atherosclerosis: a case-control study of the atherosclerosis risk in communities cohort. Am J Epidemiol. 2002;155(5):437–445. doi: 10.1093/aje/155.5.437.
   PubMed Web of Science ®Google Scholar
• Kwapong YA, Sharma G, Valero-Elizondo J, et al. The association of sex-specific hormones with coronary artery plaque characteristics from Miami Heart (MiHeart) study. Am J Prev Cardiol. 2023;14:100479. doi: 10.1016/j.ajpc.2023.100479.
   PubMedGoogle Scholar
• Schederecker F, Cecil A, Prehn C, et al. Sex hormone-binding globulin, androgens and mortality: the KORA-F4 cohort study. Endocr Connect. 2020;9(4):326–336. doi: 10.1530/EC-20-0080.
   PubMed Web of Science ®Google Scholar
• Meun C, Franco OH, Dhana K, et al. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. J Clin Endocrinol Metab. 2018;103(4):1622–1630. doi: 10.1210/jc.2017-02421.
   PubMed Web of Science ®Google Scholar
• Islam RM, Bell RJ, Handelsman DJ, et al. Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial. Lancet Healthy Longev. 2022;3(2):e109–e18. doi: 10.1016/S2666-7568(22)00001-0.
   PubMedGoogle Scholar
• Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13(6):368–378. doi: 10.1038/nrcardio.2016.25.
   PubMed Web of Science ®Google Scholar
• Chan YK, Tuttle C, Ball J, et al. Current and projected burden of heart failure in the Australian adult population: a substantive but still ill-defined major health issue. BMC Health Serv Res. 2016;16(1):501. doi: 10.1186/s12913-016-1748-0.
   PubMedGoogle Scholar
• Pandey A, Cornwell WK, 3rd, Willis B, et al. Body mass index and cardiorespiratory fitness in mid-life and risk of heart failure hospitalization in older age: findings from the cooper center longitudinal study. JACC Heart Fail. 2017;5(5):367–374. doi: 10.1016/j.jchf.2016.12.021.
   PubMed Web of Science ®Google Scholar
• Beale AL, Meyer P, Marwick TH, et al. Sex differences in cardiovascular pathophysiology: Why women are overrepresented in heart failure with preserved ejection fraction. Circulation. 2018;138(2):198–205. doi: 10.1161/CIRCULATIONAHA.118.034271.
   PubMed Web of Science ®Google Scholar
• Pieske B, Tschope C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297–3317. doi: 10.1093/eurheartj/ehz641.
   PubMed Web of Science ®Google Scholar
• Haykowsky MJ, Tomczak CR, Scott JM, et al. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. J Appl Physiol. 2015;119(6):739–744. doi: 10.1152/japplphysiol.00049.2015.
   PubMed Web of Science ®Google Scholar
• Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a Multiorgan roadmap. Circulation. 2016;134(1):73–90. doi: 10.1161/CIRCULATIONAHA.116.021884.
   PubMed Web of Science ®Google Scholar
• Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27(11):1954–1960. doi: 10.1038/s41591-021-01536-x.
   PubMed Web of Science ®Google Scholar
• Howden EJ, Sarma S, Lawley JS, et al. Reversing the cardiac effects of sedentary aging in middle age – a randomized controlled trial: implications for heart failure prevention. Circulation. 2018;137(15):1549–1560. doi: 10.1161/CIRCULATIONAHA.117.030617.
   PubMed Web of Science ®Google Scholar
• Zhao D, Guallar E, Ballantyne CM, et al. Sex hormones and incident heart failure in men and postmenopausal women: the atherosclerosis risk in communities study. J Clin Endocrinol Metab. 2020;105(10):e3798–e3807.
   PubMed Web of Science ®Google Scholar
• Islam RM, Bell RJ, Green S, et al. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019;7(10):754–766. doi: 10.1016/S2213-8587(19)30189-5.
   PubMed Web of Science ®Google Scholar
• Braunstein GD, Sundwall DA, Katz M, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med. 2005;165(14):1582–1589. doi: 10.1001/archinte.165.14.1582.
   PubMedGoogle Scholar
• Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol. 2005;105(5 Pt 1):944–952. doi: 10.1097/01.AOG.0000158103.27672.0d.
   PubMed Web of Science ®Google Scholar
• Simon J, Braunstein G, Nachtigall L, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab. 2005;90(9):5226–5233. doi: 10.1210/jc.2004-1747.
   PubMed Web of Science ®Google Scholar
• Davis SR, van der Mooren MJ, van Lunsen RHW, et al. The efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause. 2006;13(3):387–396. doi: 10.1097/01.gme.0000179049.08371.c7.
   PubMed Web of Science ®Google Scholar
• Davis SR, Moreau M, Kroll R, et al. Testosterone for low libido in menopausal women not taking estrogen therapy. N Engl J Med. 2008;359(19):2005–2017. doi: 10.1056/NEJMoa0707302.
   PubMed Web of Science ®Google Scholar
• Panay N, Al-Azzawi F, Bouchard C, et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010;13(2):121–131. doi: 10.3109/13697131003675922.
   PubMed Web of Science ®Google Scholar
• Shifren J, Davis SR, Moreau M, et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 study. Menopause. 2006;13(5):770–779. doi: 10.1097/01.gme.0000243567.32828.99.
   PubMed Web of Science ®Google Scholar
• Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010;56(16):1310–1316. doi: 10.1016/j.jacc.2010.03.090.
   PubMed Web of Science ®Google Scholar
• Kontis V, Bennett JE, Mathers CD, et al. Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet. 2017;389(10076):1323–1335. doi: 10.1016/S0140-6736(16)32381-9.
   PubMed Web of Science ®Google Scholar