Relationship between serum testosterone concentration and microvascular endothelial function in Japanese men
1Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, 305-8574 Ibaraki, Japan
2Institute of Health and Sports Science & Medicine, Juntendo University, Inzai, 270-1695 Chiba, Japan
3Faculty of Health & Sport Sciences, Ryutsu Keizai University, Ryugasaki, 301-8555 Ibaraki, Japan
4Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8574 Ibaraki , Japan
5Humanome Lab., Inc., Chuo-ku, 104-0045 Tokyo, Japan
6Department of Health and Sports Sciences, Kyoto Pharmaceutical University, Yamashina-ku, 607-8414 Kyoto, Japan
DOI: 10.31083/jomh.2021.013 Vol.17,Issue 2,April 2021 pp.64-69
Published: 08 April 2021
Background: Both endothelial dysfunction and low circulating androgen levels predict cardiovascular disease in men. Endothelial function evaluation is commonly performed by measuring ﬂow-mediated vasodilatation of the brachial artery. However, studies have suggested that compared with evaluation of large arteries, microvascular function evaluation of peripheral arteries is a better predictor of increased cardiovascular disease risks. Although circulating levels of androgens, such as testosterone and dehydroepiandrosterone sulfate (DHEA-S), positively correlate with cardiovascular function, the association between circulating androgen levels and microvascular function is unknown. In this study, we investigated whether serum androgen levels correlate with microvascular endothelial function in men.
Methods: The study included 105 Japanese men (age 59 ± 1 years) in whom we measured serum testosterone and DHEA-S levels. The reactive hyperemia index (RHI) determined by the Endo-PAT system (ﬁnger plethysmography) was used to evaluate microvascular endothelial function.
Results: Serum testosterone levels were signiﬁcantly correlated with the RHI (r = 0.32, P < 0.01). The association between serum testosterone levels and the RHI remained signiﬁcant even after adjustment for confounders, including age and body mass index (β = 0.31, P < 0.01). Notably, serum DHEA-S levels were not associated with the RHI (r = 0.01, n.s.).
Conclusion: This study showed that serum testosterone levels were positively correlated with microvascular endothelial function in men. These results suggest that endogenous testosterone level is one of the determinants of microvascular endothelial function and may become a biomarker reﬂecting lifestyle modiﬁcations-induced improvement in cardiovascular function in men.
Testosterone; Microvascular endothelial function; Dehydroepiandrosterone; Arterial stiffness; Endo-PAT system; Finger plethysmography
Hiroshi Kumagai,Asako Zempo-Miyaki,Toru Yoshikawa,Kanae Myoenzono,Koichiro Tanahashi,TNobuhiko Akazawa,Seiji Maeda. Relationship between serum testosterone concentration and microvascular endothelial function in Japanese men. Journal of Men's Health. 2021. 17(2);64-69.
 World Health Organization. Cardiovascular diseases (CVDs). Fact sheets. 2017. Available at: https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (Accessed: 2 November, 2020).
 Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis. 2010; 210: 232-236.
 Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. Aging Male. 2019; 23: 81-92.
 Yu J, Akishita M, Eto M, Ogawa S, Son B, Kato S, et al. Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/Akt pathway. Endocrinology. 2010; 151: 1822-1828.
 Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertension Research. 2007; 30: 1029-1034.
 Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Association of plasma dehydroepiandrosterone-sulfate levels with endothelial function in postmenopausal women with coronary risk factors. Hypertension Research. 2008; 31: 69-74.
 Kumagai H, Miyaki A, Higashino R, Akazawa N, Choi Y, Ra S, et al. Lifestyle modification-induced increase in serum testosterone and SHBG decreases arterial stiffness in overweight and obese men. Artery Research. 2014; 8: 80-87.
 Kumagai H, Zempo-Miyaki A, Yoshikawa T, Tsujimoto T, Tanaka K, Maeda S. Lifestyle modification increases serum testosterone level and decrease central blood pressure in overweight and obese men. Endocrine Journal. 2015; 62: 423-430.
 Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Circulation. 2003; 107: 139-146.
 Mitchell GF, Parise H, Vita JA, Larson MG, Warner E, Keaney JF, et al. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension. 2004; 44: 134-139.
 Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. Journal of the American College of Cardiology. 2003; 42: 1149-1160.
 Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. Journal of the American College of Cardiology. 2004; 44: 2137-2141.
 Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012; 126: 753-767.
 Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, et al. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. American Heart Journal. 2003; 146: 168-174.
 Matsuzawa Y, Sugiyama S, Sumida H, Sugamura K, Nozaki T, Ohba K, et al. Peripheral endothelial function and cardiovascular events in high-risk patients. Journal of the American Heart Association. 2013; 2: e000426.
 Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder? European Urology. 2003; 44: 352-354.
 Montorsi P, Ravagnani PM, Galli S, Rotatori F, Briganti A, Salonia A, et al. The artery size hypothesis: a macrovascular link between erectile dysfunction and coronary artery disease. American Journal of Cardiology. 2005; 96: 19M-23M.
 Celermajer DS. Reliable endothelial function testing. Circulation. 2008; 117: 2428-2430.
 Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. European Journal of Cardiovascular Prevention & Rehabilitation. 2011; 18: 775-789.
 Francomano D, Fattorini G, Gianfrilli D, Paoli D, Sgrò P, Radicioni A, et al. Acute endothelial response to testosterone gel administration in men with severe hypogonadism and its relationship to androgen receptor polymorphism: a pilot study. Journal of Endocrinological Investigation. 2016; 39: 265-271.
 Kumagai H, Yoshikawa T, Myoenzono K, Kosaki K, Akazawa N, Asako Z, et al. Sexual function is an indicator of central arterial stiffness and arterial stiffness gradient in Japanese adult men. Journal of the American Heart Association. 2018; 7: e007964
 Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. Journal of Hypertension. 2012; 30: 445-448.
 Costarella CE, Stallone JN, Rutecki GW, Whittier FC. Testosterone causes direct relaxation of rat thoracic aorta. Journal of Pharmacology and Experimental Therapeutics. 1996; 277: 34-39.
 Kelm M, Schrader J. Control of coronary vascular tone by nitric oxide. Circulation Research. 1990; 66: 1561-1575.
 Sugawara J, Komine H, Hayashi K, Yoshizawa M, Yokoi T, Otsuki T, et al. Effect of systemic nitric oxide synthase inhibition on arterial stiffness in humans. Hypertension Research. 2007; 30: 411-415.
 Wilkinson IB, Franklin SS, Cockcroft JR. Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology. Hypertension. 2004; 44: 112-116.
 Vlachopoulos C, Ioakeimidis N, Miner M, Aggelis A, Pietri P, Terentes-Printzios D, et al. Testosterone deficiency: a determinant of aortic stiffness in men. Atherosclerosis. 2014; 233: 278-283.
 Hodes RJ, Lakatta EG, McNeil CT. Another modifiable risk factor for cardiovascular disease? Some evidence points to arterial stiffness. Journal of the American Geriatrics Society. 1995; 43: 581-582.
 Pinsky JL, Branch LG, Jette AM, Haynes SG, Feinleib M, Cornoni-Huntley JC, et al. Framingham Disability Study: relationship of dis-ability to cardiovascular risk factors among persons free of diagnosed cardiovascular disease. American Journal of Epidemiology. 1985; 122: 644-656.
 Safar ME, London GM. Therapeutic studies and arterial stiffness in hypertension: recommendations of the european society of hyper-tension. The clinical committee of arterial structure and function. Working group on vascular structure and function of the european society of hypertension. Journal of Hypertension. 2000; 18: 1527-1535.
 Tsai HK, D’Amico AV, Sadetsky N, Chen M, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. Journal of the National Cancer Institute. 2007; 99: 1516-1524.
 Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. International Journal of Clinical Practice. 2014; 68: 314-329.
 Yaron M, Greenman Y, Rosenfeld JB, Izkhakov E, Limor R, Osher E, et al. Effect of testosterone replacement therapy on arterial stiffness in older hypogonadal men. European Journal of Endocrinology. 2009; 160: 839-846.
Science Citation Index Expanded Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.
Social Sciences Citation Index Social Sciences Citation Index contains over 3,400 journals across 58 social sciences disciplines, as well as selected items from 3,500 of the world’s leading scientific and technical journals. More than 9.37 million records and 122 million cited references date back from 1900 to present.
Current Contents - Social & Behavioral Sciences Current Contents - Social & Behavioral Sciences provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in the social and behavioral sciences.
Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.
SCOPUS Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.
DOAJ DOAJ is a community-curated online directory that indexes and provides access to high quality, open access, peer-reviewed journals.
CrossRef Crossref makes research outputs easy to find, cite, link, assess, and reuse. Crossref committed to open scholarly infrastructure and collaboration, this is now announcing a very deliberate path.
Portico Portico is a community-supported preservation archive that safeguards access to e-journals, e-books, and digital collections. Our unique, trusted process ensures that the content we preserve will remain accessible and usable for researchers, scholars, and students in the future.