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Testosterone and cardiovascular system
The predominant androgen in men, testosterone, has shown to substantially decline throughout the aging process.〔Stanworth, R., Jones T., Testosterone for the aging male; current evidence and recommended practice. Clin Inter in Aging. 2008;3(1):24-44〕〔http://jaha.ahajournals.org/content/2/6/e000272.full〕 The decline in both serum and total testosterone with age have been linked to several disease states in men.〔〔Harman S., Metter E., Tobin J., 2001. Longitudinal effects of aging on serum total and free testosterone levels in healthy men – Baltimore Longitudinal Study of Aging. J clin Endocrinol Metab. 2001;86:724-731.〕〔Feldman H., Loongcope C., Derby C. 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. 2002; 87:589-598.〕 In particular, cardiac failure and ischemic heart disease have been linked to this natural biochemical decline in testosterone.〔Tirabassi G., Gioia A., Giovannini L., Boscaro M., Corona G., Carpi A., Maggi M., Balercia G. Testosterone and cardiovascular risk. Intern Emerg Med 2013;8(1):S65-S69.〕〔Kontoleon P., Anastasiou-Nana M., Papapetrou P. Hormonal profile in patients with congestive heart failure. Int J Cardiol, 2003;87:179-183.〕〔Barrett-Connor E., Khaw K. Endogenous sex hormones and cardiovascular disease in men: a prospective population-based study. Circulation.1988;75:539-545.〕 Previously, the higher cardiovascular risk in men has been attributed in part to the negative effects of systemic testosterone, however, more recent research has highlighted the protective nature of testosterone against cardiovascular disease.〔 The magnitude and mechanism of action by which low testosterone in men is influential in the pathogenesis of cardiovascular risk and the potential benefits of testosterone therapy has yet to be fully determined.〔
== Systemic Effects of Testosterone on the Cardiovascular System ==
Low testosterone is associated with an increased risk for coronary artery disease through the promotion of a pro-atherosclerotic environment.〔〔Nettleship J., Jones T., Channer K., Jones R. 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. 2007;116:2427-2434.〕〔http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM413736.pdf〕 Some research has identified testosterone as a vasodilator and an endothelium-repairing hormone within many regions in the body, including the coronary arteries.〔Corona G., Monami M., Rastrelli G., Aversa A., Tishova Y., Saad F., Lenzi A., Forti G., Mannucci E., Maggi M. Testosterone and Metablic Syndrome: A Meta-Analysis Study. J Sex Med 2011; 8:272-283.〕〔Webb C., McNeil J., Haywar C/. de Xeigler D., Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation. 1999;100:1690-1696.〕 Recent research depicts testosterone as important in decreasing the production of inflammatory cytokines such as tumor necrosis factor alpha, interleukin-1beta and interleukin-6, which are influential in atherosclerotic profiles.〔〔Corrales J., Almeida M., Burgo R., Mories M., Miralles J., Orfao A. Androgen-replacement therapy depresses the ex vivo production of inflammatory cytokines by circulating antigen-presenting cells in aging type-2 diabetic men with partial androgen deficiency. J Endocrinol. 2006;189:595-604.〕 Although it is believed that the reduction in inflammatory cytokines is related to a decreased atherosclerotic profile, the full explanation of this mechanism requires further research.〔〔Malkin C., Pugh P., Jones R., Jones T., Channer K. Testosterone as a protective factor against atherosclerosis – immunomodulation and influence upon plaque development and stability. J Endocrinology. 2003; 178:373-380.〕
Testosterone has also shown to be effective as an anti-atherosclerotic through preventing aortic cholesterol deposition in both rabbits fed high cholesterol diets and mice with low-density lipoprotein gene knockout.〔〔Nathan L., Shi W.B., Mukherjee T.K., Wang X.P., Lusis A.J., Chaudhuri G. Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc Natl Acad Sci USA. 2001;98:3589-3593.〕 Fatty deposition within the aorta associated with low endogenous testosterone has been determined to be independent of the androgen receptor.〔 Although the mechanism has yet to be fully determined, aromatase activity and the activation of estrogen receptor alpha is partially responsible for the atherosclerotic profile characteristic of low testosterone.〔
Decreased systemic testosterone in men has also been reported in men with heart failure, whereby the severity of the disease is proportional to the reduction in systemic testosterone levels.〔 Although a direct mechanism of action is not fully understood, some research attribute low testosterone to advancing side effects of heart failure, such as decreased exercise ability, decreased muscle mass, fatigue/dyspnea and cachexia.〔
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