Abstract
For decades, it has been recognized that men have a higher age-adjusted risk of ischemic cardiovascular (CVD) events compared to women, thus generating hypotheses that sex steroids contribute to CVD risk. Potential mechanisms include genomic and non-genomic effects of sex steroids as well as mediation through classic CVD risk factors and obesity. However, results from randomized studies suggest that sex steroid supplementation in men and women do not result in improved CVD outcomes and may increase CVD risk. In contrast, prospective observations from endogenous sex steroid studies, i.e. among participants not using sex steroids, have suggested the opposite relationship. We reviewed the findings of prospective observational studies in men (17 studies) and women (8 studies) that examined endogenous sex steroids and CVD risk. These studies suggested a lack of association or that lower levels of testosterone or dihydrotestosterone are associated with higher CVD risk in both men and women. Higher, rather than lower, estradiol levels were associated with higher CVD risk in women. There were several significant gaps in the literature. First, it is unclear whether more sensitive measures of sex steroid levels might detect significant differences. Second, there are few prospective studies in women. Similarly, no studies report outcomes for high-risk groups such as African-Americans and Hispanics. Finally, few studies report upon ischemic coronary disease as opposed to ischemic stroke separately, although relationships between sex steroids and CVD may vary by vascular bed. Future investigations need to examine high risk groups and to distinguish between subtypes of CVD.
Keywords: Coronary disease, epidemiology, estradiol, ischemia, stroke, testosterone.
Graphical Abstract
[1]
Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemiology: a systematic review. Stroke 2009; 40: 1082-90.
[2]
Barrett-Connor E. Why women have less heart disease than men and how diabetes modifies women’s usual cardiac protection. Glob Heart 2013; 8: 95-104.
[3]
Go A, Mozaffarian D, Roger V, et al. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014; 129: 399-410.
[4]
Bushnell C, McCullough L, Awad I, et al. Guidelines for the prevention of stroke in women: a statement from healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45: 1545-88.
[5]
Shores M, Arnold A, Biggs M, et al. Testosterone and dihydrotestosterone and incident ischemic stroke in men in the Cardiovascular Health Study (CHS). Clin Endocrinol(Oxf) 2014; 81(5): 746-53.
[6]
Shores M, Biggs M, Arnold A, et al. Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the Cardiovascular Health Study. J Clin Endocrinol Metab 2014; 99(6): 2061-8.
[7]
Laughlin G, 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: 740-7.
[8]
Vigen R, O’Donnell C, Baron A, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: 1829-36.
[9]
Xu L, Freeman G, Cowling B, Schooling C. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013; 11: 108.
[10]
Crandall C, Barrett-Connor E. Endogenous sex steroid levels and cardiovascular disease in relation to the menopause: a systematic review. Endocrinol Metab Clin North Am 2013; 42: 227-53.
[11]
Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2012; 7CD004143
[12]
Golden S, 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: 437-45.
[13]
El Khoudary S, Wildman R, Matthews K, Thurston R, Bromberger J, Sutton-Tyrrell K. Endogenous sex hormones impact the progression of subclinical atherosclerosis in women during the menopausal transition. Atherosclerosis 2012; 225: 180-6.
[14]
Thurston R. Getting to the heart of things: is endogenous estradiol associated with coronary artery calcification? Menopause 2010; 17: 887-8.
[15]
Ouyang P, Vaidya D, Dobs A, et al. Sex hormone levels and subclinical atherosclerosis in postmenopausal women: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2009; 204: 255-61.
[16]
Ohlsson C, Barrett-Connor E, Bhasin S, 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.
[17]
Scarabin-Carre V, Canonico M, Brailly-Tabard S, et al. High level of plasma estradiol as a new predictor of ischemic arterial disease in older postmenopausal women: the 3-city cohort study. J Am Heart Assoc 2012; 1e001388
[18]
Jimenez M, Sun Q, Schurks M, et al. Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women. Stroke 2013; 44: 1784-9.
[19]
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: 699-708.
[20]
Bui H, Sluss P, Blincko S, Knol D, Blankenstein M, Heijboer A. Dynamics of serum testosterone during the menstrual cycle evaluated by daily measurements with an ID-LC-MS/MS method and a 2nd generation automated immunoassay. Fertil Steril 2012; 78: 96-101.
[21]
Soisson V, Brailly-Tabard S, Helmer C, et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: The French 3C cohort study. Maturitas 2013; 75: 282-8.
[22]
Rexrode K, Manson J, Lee I, et al. Sex hormone levels and risk of cardiovascular events in postmenopausal women. Circulation 2003; 108: 1688-93.
[23]
Lee J, Yaffe K, Lui L, et al. Prospective study of endogenous circulating estradiol and risk of stroke in older women. Arch Neurol 2010; 67: 195-201.
[24]
Chen Y, Zeleniuch-Jacquotte A, Arslan A, et al. Endogenous hormones and coronary heart disease in postmenopausal women. Atherosclerosis 2011; 216: 414-9.
[25]
Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis 2009; 210: 232-6.
[26]
Ruige J, Mahmoud A, De Bacquer D, Kaufman J. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 2011; 97: 870-5.
[27]
Arnlov J, Pencina M, Amin S, et al. Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 2006; 145: 176-84.
[28]
Haring R, Teng Z, Xanthakis V, 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 2013; 78: 629-34.
[29]
Yeap B, Hyde Z, Almeida O, et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab 2009; 94: 2353-9.
[30]
Abbott R, Launer L, Rodriguez B, et al. Serum estradiol and risk of stroke in elderly men. Neurology 2007; 68: 563-8.
[31]
Cauley J, Gutai J, Kuller L, Dai W. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Cardiol 1987; 60: 771-7.
[32]
Barrett-Connor E, Khaw K. Endogenous sex hormones and cardiovascular disease in men. a prospective population-based study. Circulation 1988; 78: 539-45.
[33]
Phillips G, Yano K, Stemmermann G. Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program. Pitfalls in prospective studies on sex hormones. J Clin Epidemiol 1988; 41: 1151-6.
[34]
Yarnell J, Beswick A, Sweetnam P, Riad-Fahmy D. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arterioscler Thromb 1993; 13: 517-20.
[35]
Hautanen A, Manttari M, Manninen V, Huttunen J, Frick M, Adlercreutz H. Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study. Atherosclerosis 1994; 105: 191-200.
[36]
Mikulec K, Holloway L, Krasnow R, et al. Relationship of endogenous sex hormones to coronary heart disease: a twin study. J Clin Endocrinol Metab 2004; 89: 1240-5.
[37]
Nilsson S, Fransson E, Brismar K. Relationship between serum progesterone concentrations and cardiovascular disease, diabetes, and mortality in elderly Swedish men and women: an 8-year prospective study. Gend Med 2009; 6: 433-43.
[38]
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 2009; 161: 435-42.
[39]
Vandenplas G, DeBacquer D, Calders P, et al. Endogenous oestradiol and cardiovascular disease in healthy men: a systematic review and meta-analysis of prospective studies. Heart 2012; 98: 1478-82.
[40]
Labrie F, Belanger A, Belanger P, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006; 99: 182-8.
[41]
Davis S, Panjari M, Stanczyk F. DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011; 96: 1642-53.
[42]
Roy-O’Reilly MLD. Sex differences in stroke: the contribution of coagulation. Exp Neurol 2014; •••: S0014-4886.
[43]
Gonzales R. Androgens and the cerebrovasculature: modulation of vascular function during normal and pathophysiological conditions. Eur J Phys 2013; 265: 627-42.
[44]
Gilliver S. Sex steroids as inflammatory regulators. Journal of
Steroid Biochemistry and Mol Biol 2010; 120: 105-15.
[45]
Oskui P, French W, Herring M, Mayeda G, Burstein S, Kloner R. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc 2013; 2e000272
[46]
Quillinan N, Deng G, Grewal H, Herson P. Androgens and stroke: good, bad or indifferent? Exp Neurol 2014; 259: 10-5.
[47]
Sowers M, Matthews K, Jannausch M, et al. Hemostatic factors and estrogen during the menopausal transition. J Clin Endocrinol Metab 2005; 90: 5942-8.
[48]
Dieudonne M, Leneveu M, Giudicelli Y, Pecquery R. Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol 2004; 286: c655-61.
[49]
Dieudonne M, Pecquery R, Boumediene A, Leneveu M, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids. Am J Physiol 1998; 274: C1645-52.
[50]
Dieudonne M, Pecquery R, Leneveau M, Giudicelli Y. Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: evidence for sex and site-relates specificities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor gamma 2. Endocrinology 2000; 141: 649-56.
[51]
Kim C, Halter J. Endogenous sex hormones, metabolic syndrome, and diabetes in men and women. Curr Cardiol Rep 2014; 16: 467.
[52]
Torkler S, Wallaschofski H, Baumeister S, et al. Inverse association between total testosterone concentrations, incident hypertension, and blood pressure. Aging Male 2011; 14: 176-82.
[53]
Haring R, Baumeister S, Volzke H, et al. Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. Eur J Cardiovasc Prev Rehabil 2011; 18: 86-96.
[54]
Wang L, Szklo M, Folsom A, Cook N, Gapstur S, Ouyang P. Endogenous sex hormones, blood pressure change, and risk of hypertension in postmenopausal women: The Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2012; 224: 228-34.
[55]
Ziemens B, Wallaschofski H, Volzke H, et al. Positive association between testosterone, blood pressure, and hypertension in women: longitudinal findings from the Study of Health in Pomerania. J Hypertens 2013; 31: 1106-13.
[56]
Sutton-Tyrrell K, Wildman R, Matthews K, et al. Sex-hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN). Circulation 2005; 111: 1242-9.
[57]
Santilli F, Vazzana N, Liani R, Guagnano M, Davi G. Platelet activiation in obesity and metabolic syndrome. Obes Rev 2012; 13: 27-42.
[58]
Nguyen P, Je Y, Schutz F, et al. Association of androgen depviration therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011; 306: 2359-66.
[59]
Manson J, Chlebowski R, Stefanick M, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013; 310: 1353-68.
[60]
Wassertheil-Smoller S, Hendrix S, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003; 289: 2673-84.
[61]
Anderson G, Limacher M, Assaf A, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiatve randomized controlled trial. JAMA 2004; 291: 1701-12.
[62]
Hendrix S, Wassertheil-Smoller S, Johnson K, et al. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation 2006; 113: 2425-34.
[63]
Viscoli C, Brass L, Kernan W, Sarrel P, Suissa S, Horwitz R. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345: 1243-9.
[64]
Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS). JAMA 2002; 288: 49-57.
[66]
Nachitgall L, Raju U, Banerjee S, Wan L, Levitz M. Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels. Menopause 2000; 7: 243-50.
[67]
Flaumenhaft R, Nachitgall M, Lowenstein J, Nachitgall L, Nachtigall R, Nachtigall L. Association of oral but not transdermal estrogen therapy with enhanced platelet reactivity in a subset of postmenopausal women. Menopause 2009; 16: 407-12.
[68]
Shufelt C, Merz C, Prentice R, et al. Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women’s Health Initiative Observational Study. Menopause 2014; 21: 260-6.
[69]
Smith N, Blondon M, Wiggins K, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med 2014; 174: 25-31.
[70]
Cunningham G, Toma S. Clinical review: why is androgen replacement in males controversial? J Clin Endocrinol Metab 2011; 96: 38-52.
[71]
Sowers M, Randolph J Jr, Jannausch M, Lasley B, Jackson E, McConnell D. Levels of sex steroid and cardiovascular disease measures in premenopausal and hormone-treated women at midlife: implications for the “timing hypothesis”. Arch Intern Med 2008; 168: 2146-53.
[72]
Snyder P, Peachey H, Berlin 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 2001; 111: 255-60.
[73]
Spitzer M, Basaria S, Travison T, et al. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med 2012; 157: 681-91.
[74]
Svartberg J, Agledahl I. figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impotence Research 2008; 20: 378-87.
[75]
Legros J, Meuleman E, Elbers J, et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur J Endocrinol 2009; 160: 821-31.
[76]
Kaufman J, Miller M, Garwin J, Fitzpatrick S, McWhirter C, Brennan J. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med 2011; 8: 2079-89.
[77]
Kalinchenko S, Tishova Y, Mskhalaya G, Gooren L, Giltay E, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic sydrome: the double-blinded placebo-controlled Moscow Study. Clin Endocrinol 2010; 73: 602-12.
[78]
Wartofsky L, Handelsman D. Standardization of hormonal assays for the 21st century. J Clin Endocrinol Metab 2010; 95: 5141-3.
[79]
Handelsman D, Wartofsky L. Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J Clin Endocrinol Metab 2013; 98: 3971-3.
[80]
Rosner W, Hankinson S, Sluss P, Vesper H, Wierman M. Challenges to the measurement of estradiol: an endocrine society position statement. J Clin Endocrinol Metab 2013; 98: 1376-87.
[81]
Rosner W, Auchus R, Azziz R, Sluss P, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007; 92: 405-13.
[82]
Vermeulen A, Verdonck L, Kaufman J. A critical calculation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 86: 3666-72.
[83]
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.
[84]
Wang Y, Gay G, Botelho J, Caudill S, Vesper H. Total testosterone quantitative measurement in serum by LC-MS/MS. Clin Chim Acta 2014; 436: 263-7.
[85]
Prevention CfDCa. CDC HoSt-Testosterone Certified Procedures 2014.[cited 2014]. Available from: . http://www.cdc.gov/ labstandards/pdf/hs/CDC_Certified_Testosterone_Procedures.pdf
[86]
Go A, Mozaffarian D, Roger V, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 2013; 127: e6-e245.
[87]
Association AHAAS. African-Americans and cardiovascular disease 2014. [cited 2014]. Available from: . http://www.heart. org/idc/groups/heart-public/@wcm/@sop/@smd/documents/down-loadable/ucm_462015.pdf
[88]
Cruz-Flores S, Rabinstein A, Biller J, et al. Racial-ethnic disparities in stroke care: the American experience. Stroke 2011; 42: 2091-16.
[89]
Safford M, Brown T, Muntner P, et al. Association of race and sex with risk of incident acute coronary heart disease events. JAMA 2012; 308: 1768-74.
[90]
Richard A, Rohrmann S, Zhang L, et al. Racial variation in sex steroid hormone concentration in black and white men: a meta-analysis. Andrology 2014; 2: 428-35.
[91]
Rohrmann S, Nelson W, Rifai 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.
[92]
Orwoll E, Nielson C, Labrie F, et al. Evidence for geographical and racial variation in serum sex steroid levels in older men. J Clin Endocrinol Metab 2010; 95: E151-60.
[93]
Setiawan V, Haiman C, Stanczyk F, Le Marchand L, Henderson B. Racial/ethnic differences in postmenopausal endogenous hormones: the Multiethnic Cohort Study. Cancer Epidemiol Biomarkers Prev 2006; 15: 1849-55.
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