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Testosterone and the cardiovascular system

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The predominant androgen in men, testosterone, has shown to substantially decline throughout the aging process.[1][2] The decline in both serum and total testosterone with age have been linked to several disease states in men.[1][3][4] In particular, cardiac failure and ischemic heart disease have been linked to this natural biochemical decline in testosterone.[5][6][7] 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.[5] 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.[1]

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.[5][8][9] Some research has identified testosterone as a vasodilator and an endothelium-repairing hormone within many regions in the body, including the coronary arteries.[10][11] 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.[10][12] 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.[12][13]

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.[10][14] Fatty deposition within the aorta associated with low endogenous testosterone has been determined to be independent of the androgen receptor.[10] 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.[10]

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.[5] 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.[5]

Testosterone replacement therapy

Physiological testosterone is crucial for normal functionality in men. Long-term administration of physiological testosterone in mouse models has shown to be atheroprotective by increasing the HDL portion of cholesterol (the anti-atherosclerotic cholesterol).[10][15] The beneficial action of testosterone in elevating the HDL fraction can be attributed to its conversion via aromatase activity in adipose tissue into 17-beta estradiol and its subsequent activation of estrogen alpha-receptors; thus, more testosterone leads to greater conversion into estrogen and thus a healthier lipid profile.[10] It should be noted that this understanding has been determined in several studies, although results of these studies are contradictory.[10][16][17]

Testosterone replacement therapy in men diagnosed with pre-existing heart disease has been related to an increased risk of myocardial infarction.[18] Furthermore, recent research has linked testosterone replacement therapy to an increase in deaths and other cardiovascular occurrences in men whom document a history of coronary artery disease.[19] Further research is required to determine the full extent to which testosterone replacement therapy in aging men plays a role in the risk and/or advantage of cardiovascular occurrences.[20]

References

  1. ^ a b c Stanworth, Roger D; Jones, T Hugh (2008). "Testosterone for the aging male; current evidence and recommended practice". Clinical Interventions in Aging. 3 (1): 25–44. PMC 2544367. PMID 18488876.
  2. ^ Oskui, P. M.; French, W. J.; Herring, M. J.; Mayeda, G. S.; Burstein, S.; Kloner, R. A. (2013). "Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Literature". Journal of the American Heart Association. 2 (6): e000272. doi:10.1161/JAHA.113.000272. PMC 3886770. PMID 24242682.
  3. ^ Harman, S. Mitchell; Metter, E. Jeffrey; Tobin, Jordan D.; Pearson, Jay; Blackman, Marc R. (2001). "Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men". The Journal of Clinical Endocrinology & Metabolism. 86 (2): 724–31. doi:10.1210/jcem.86.2.7219. PMID 11158037.
  4. ^ Feldman, Henry A.; Longcope, Christopher; Derby, Carol A.; Johannes, Catherine B.; Araujo, Andre B.; Coviello, Andrea D.; Bremner, William J.; McKinlay, John B. (2002). "Age Trends in the Level of Serum Testosterone and Other Hormones in Middle-Aged Men: Longitudinal Results from the Massachusetts Male Aging Study". The Journal of Clinical Endocrinology & Metabolism. 87 (2): 589–98. doi:10.1210/jcem.87.2.8201. PMID 11836290.
  5. ^ a b c d e Tirabassi, Giacomo; Gioia, Angelo; Giovannini, Lara; Boscaro, Marco; Corona, Giovanni; Carpi, Angelo; Maggi, Mario; Balercia, Giancarlo (2013). "Testosterone and cardiovascular risk". Internal and Emergency Medicine. 8 (Suppl 1): S65–9. doi:10.1007/s11739-013-0914-1. PMID 23475207.
  6. ^ Kontoleon, Panagiotis E; Anastasiou-Nana, Maria I; Papapetrou, Petros D; Alexopoulos, George; Ktenas, Vasiliki; Rapti, Ageliki C; Tsagalou, Eleftheria P; Nanas, John N (2003). "Hormonal profile in patients with congestive heart failure". International Journal of Cardiology. 87 (2–3): 179–83. doi:10.1016/S0167-5273(02)00212-7. PMID 12559538.
  7. ^ Barrett-Connor, E.; Khaw, K. T. (1988). "Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study". Circulation. 78 (3): 539–45. doi:10.1161/01.CIR.78.3.539. PMID 3409497.
  8. ^ Nettleship, J. E.; Jones, T. H.; Channer, K. S.; Jones, R. D. (2007). "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 (21): 2427–34. doi:10.1161/CIRCULATIONAHA.107.708768. PMID 17984376.
  9. ^ http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM413736.pdf[full citation needed]
  10. ^ a b c d e f g h Corona, Giovanni; Monami, Matteo; Rastrelli, Giulia; Aversa, Antonio; Tishova, Yuliya; Saad, Farid; Lenzi, Andrea; Forti, Gianni; Mannucci, Edoardo; Maggi, Mario (2011). "Testosterone and Metabolic Syndrome: A Meta‐Analysis Study". The Journal of Sexual Medicine. 8 (1): 272–83. doi:10.1111/j.1743-6109.2010.01991.x. PMID 20807333.
  11. ^ Webb, Carolyn M.; McNeill, John G.; Hayward, Christopher S.; de Zeigler, Dominique; Collins, Peter (1999). "Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease". Circulation. 100 (16): 1690–6. doi:10.1161/01.cir.100.16.1690. PMID 10525487.
  12. ^ a b Corrales, JJ; Almeida, M; Burgo, R; Mories, MT; Miralles, JM; Orfao, A (2006). "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". The Journal of Endocrinology. 189 (3): 595–604. doi:10.1677/joe.1.06779. PMID 16731790.
  13. ^ Malkin, CJ; Pugh, PJ; Jones, RD; Jones, TH; Channer, KS (2003). "Testosterone as a protective factor against atherosclerosis--immunomodulation and influence upon plaque development and stability". The Journal of Endocrinology. 178 (3): 373–80. doi:10.1677/joe.0.1780373. PMID 12967330.
  14. ^ Nathan, Lauren; Shi, Weibin; Dinh, Hillary; Mukherjee, Tapan K.; Wang, Xuping; Lusis, Aldons J.; Chaudhuri, Gautam (2001). "Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase". Proceedings of the National Academy of Sciences. 98 (6): 3589–93. Bibcode:2001PNAS...98.3589N. doi:10.1073/pnas.051003698. JSTOR 3055279. PMC 30697. PMID 11248122.
  15. ^ Vigna, GB; Bergami, E (2005). "Testosterone replacement, cardiovascular system and risk factors in the aging male". Journal of Endocrinological Investigation. 28 (11 Suppl Proceedings): 69–74. PMID 16760629.
  16. ^ Shono, N; Kumagai, S; Higaki, Y; Nishizumi, M; Sasaki, H (1996). "The relationships of testosterone, estradiol, dehydroepiandrosterone-sulfate and sex hormone-binding globulin to lipid and glucose metabolism in healthy men". Journal of Atherosclerosis and Thrombosis. 3 (1): 45–51. doi:10.5551/jat1994.3.45. PMID 9225239.
  17. ^ Dai, WS; Gutai, JP; Kuller, LH; Laporte, RE; Falvo-Gerard, L; Caggiula, A (1984). "Relation between plasma high-density lipoprotein cholesterol and sex hormone concentrations in men". The American Journal of Cardiology. 53 (9): 1259–63. doi:10.1016/0002-9149(84)90075-4. PMID 6711424.
  18. ^ Gong, Yan; Finkle, William D.; Greenland, Sander; Ridgeway, Gregory K.; Adams, John L.; Frasco, Melissa A.; Cook, Michael B.; Fraumeni, Joseph F.; Hoover, Robert N. (2014). "Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men". PLoS ONE. 9 (1): e85805. Bibcode:2014PLoSO...985805F. doi:10.1371/journal.pone.0085805. PMC 3905977. PMID 24489673.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Vigen, Rebecca; O'Donnell, Colin I.; Barón, Anna E.; Grunwald, Gary K.; Maddox, Thomas M.; Bradley, Steven M.; Barqawi, Al; Woning, Glenn; Wierman, Margaret E.; Plomondon, Mary E.; Rumsfeld, John S.; Ho, P. Michael (2013). "Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels". JAMA. 310 (17): 1829–36. doi:10.1001/jama.2013.280386. PMID 24193080.
  20. ^ "The risk of Cardiovascular Events in Men Receiving Testosterone Therapy: An Endocrine Society Statement" (PDF). Endocrine Society. February 7, 2014.
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