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Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Review Article

Testosterone and Peripheral Arterial Disease

Author(s): Aleš Blinc*, Gerit Holger Schernthaner, Pavel Poredoš, Panagiotis Anagnostis, Mojca Jensterle, Katica Bajuk Studen, Pier Luigi Antignani, Dimitri P. Mikhailidis and Mišo Šabović

Volume 21, Issue 5, 2023

Published on: 27 September, 2023

Page: [297 - 303] Pages: 7

DOI: 10.2174/1570161121666230809143023

Price: $65

Abstract

Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidaemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycaemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the haematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.

Graphical Abstract

[1]
Reckelhoff JF. Sex steroids, cardiovascular disease, and hypertension: Unanswered questions and some speculations. Hypertension 2005; 45(2): 170-4.
[http://dx.doi.org/10.1161/01.HYP.0000151825.36598.36] [PMID: 15583070]
[2]
Lopes RAM, Neves KB, Carneiro FS, Tostes RC. Testosterone and vascular function in aging. Front Physiol 2012; 3: 89.
[http://dx.doi.org/10.3389/fphys.2012.00089] [PMID: 22514541]
[3]
Akerman J, Kovac JR, Lipshultz LI. Testosterone therapy improves well being and psychological health. Curr Opin Urol 2017; 27(6): 519-24.
[http://dx.doi.org/10.1097/MOU.0000000000000440] [PMID: 28795962]
[4]
Poredoš P, Schernthaner GH, Blinc A, et al. Endocrine disorders and peripheral arterial disease - a series of reviews, 1 - Introduction. Curr Vasc Pharmacol 2023; 21(3): 147-8.
[http://dx.doi.org/10.2174/1570161121666230516141319] [PMID: 37194233]
[5]
Negro-Vilar A. Selective androgen receptor modulators (SARMs): A novel approach to androgen therapy for the new millennium. J Clin Endocrinol Metab 1999; 84(10): 3459-62.
[http://dx.doi.org/10.1210/jcem.84.10.6122] [PMID: 10522980]
[6]
Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 1995; 91(4): 1154-60.
[http://dx.doi.org/10.1161/01.CIR.91.4.1154] [PMID: 7850954]
[7]
Miller V, Mulvagh S. Sex steroids and endothelial function: Translating basic science to clinical practice. Trends Pharmacol Sci 2007; 28(6): 263-70.
[http://dx.doi.org/10.1016/j.tips.2007.04.004] [PMID: 17466385]
[8]
Vlachopoulos C, Ioakeimidis N, Miner M, et al. Testosterone deficiency: A determinant of aortic stiffness in men. Atherosclerosis 2014; 233(1): 278-83.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.010] [PMID: 24529157]
[9]
Corrigan FE III, Al Mheid I, Eapen DJ, et al. Low testosterone in men predicts impaired arterial elasticity and microvascular function. Int J Cardiol 2015; 194: 94-9.
[http://dx.doi.org/10.1016/j.ijcard.2015.05.065] [PMID: 26022684]
[10]
Empen K, Lorbeer R, Dörr M, et al. Association of testosterone levels with endothelial function in men: results from a population-based study. Arterioscler Thromb Vasc Biol 2012; 32(2): 481-6.
[http://dx.doi.org/10.1161/ATVBAHA.111.232876] [PMID: 22095984]
[11]
Antonopoulos AS, Antoniades C. Mechanisms of testosterone deficiency-related endothelial dysfunction. Hellenic J Cardiol 2018; 59(4): 207-8.
[http://dx.doi.org/10.1016/j.hjc.2018.06.001] [PMID: 29890281]
[12]
Tsikas D, Kinzel M. Associations between asymmetric dimethylarginine (ADMA), nitrite-dependent renal carbonic anhydrase activity, and plasma testosterone levels in hypogonadal men. Hellenic J Cardiol 2018; 59(4): 201-6.
[http://dx.doi.org/10.1016/j.hjc.2017.10.004] [PMID: 29128547]
[13]
Sansone A, Rastrelli G, Cignarelli A, et al. Effect of treatment with testosterone on endothelial function in hypogonadal men: a systematic review and meta-analysis. Int J Impot Res 2020; 32(4): 379-86.
[http://dx.doi.org/10.1038/s41443-019-0163-6] [PMID: 31235898]
[14]
Ajayi AAL, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995; 91(11): 2742-7.
[http://dx.doi.org/10.1161/01.CIR.91.11.2742] [PMID: 7758179]
[15]
Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: A systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95(6): 2560-75.
[http://dx.doi.org/10.1210/jc.2009-2575] [PMID: 20525906]
[16]
Walker RF, Zakai NA, MacLehose RF, et al. Association of testosterone therapy with rRisk of venous thromboembolism among men with and without hypogonadism. JAMA Intern Med 2020; 180(2): 190-7.
[http://dx.doi.org/10.1001/jamainternmed.2019.5135] [PMID: 31710339]
[17]
Huhtaniemi IT, Wu FCW. Ageing male (part I): Pathophysiology and diagnosis of functional hypogonadism. Best Pract Res Clin Endocrinol Metab 2022; 36(4): 101622.
[http://dx.doi.org/10.1016/j.beem.2022.101622] [PMID: 35210191]
[18]
Khaw KT, Barrett-Connor E. Lower endogenous androgens predict central adiposity in men. Ann Epidemiol 1992; 2(5): 675-82.
[http://dx.doi.org/10.1016/1047-2797(92)90012-F] [PMID: 1342319]
[19]
Haring R, Völzke H, Felix SB, et al. Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes 2009; 58(9): 2027-31.
[http://dx.doi.org/10.2337/db09-0031] [PMID: 19581420]
[20]
Vikan T, Schirmer H, Njølstad I, Svartberg J. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur J Endocrinol 2010; 162(4): 747-54.
[http://dx.doi.org/10.1530/EJE-09-0943] [PMID: 20061333]
[21]
Haring R, Baumeister SE, Völzke 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(1): 86-96.
[http://dx.doi.org/10.1097/HJR.0b013e32833c1a8d] [PMID: 20562628]
[22]
Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev 2003; 24(3): 313-40.
[http://dx.doi.org/10.1210/er.2003-0005] [PMID: 12788802]
[23]
Grossmann M, Matsumoto AM. A perspective on middle-aged and older men with functional hypogonadism: Focus on holistic management. J Clin Endocrinol Metab 2017; 102(3): 1067-75.
[http://dx.doi.org/10.1210/jc.2016-3580] [PMID: 28359097]
[24]
Calderón B, Gómez-Martín JM, Vega-Piñero B, et al. Prevalence of male secondary hypogonadism in moderate to severe obesity and its relationship with insulin resistance and excess body weight. Andrology 2016; 4(1): 62-7.
[http://dx.doi.org/10.1111/andr.12135] [PMID: 26663756]
[25]
Haring R, Völzke H, Steveling A, et al. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J 2010; 31(12): 1494-501.
[http://dx.doi.org/10.1093/eurheartj/ehq009] [PMID: 20164245]
[26]
Muraleedharan V, Hugh Jones T. Testosterone and mortality. Clin Endocrinol 2014; 81(4): 477-87.
[http://dx.doi.org/10.1111/cen.12503] [PMID: 25041142]
[27]
Kaur H, Werstuck GH. The Effect of testosterone on cardiovascular disease and cardiovascular risk factors in men: A review of clinical and preclinical data. CJC Open 2021; 3(10): 1238-48.
[http://dx.doi.org/10.1016/j.cjco.2021.05.007] [PMID: 34888506]
[28]
Price JF, Lee AJ, Fowkes FGR. Steroid sex hormones and peripheral arterial disease in the Edinburgh Artery Study. Steroids 1997; 62(12): 789-94.
[http://dx.doi.org/10.1016/S0039-128X(97)00103-7] [PMID: 9434345]
[29]
Haring R, Travison TG, Bhasin S, et al. Relation between sex hormone concentrations, peripheral arterial disease, and change in ankle-brachial index: Findings from the Framingham Heart Study. J Clin Endocrinol Metab 2011; 96(12): 3724-32.
[http://dx.doi.org/10.1210/jc.2011-1068] [PMID: 21937625]
[30]
Tivesten Å, Mellström D, Jutberger H, et al. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arte-rial disease in elderly men. The MrOS Study in Sweden. J Am Coll Cardiol 2007; 50(11): 1070-6.
[http://dx.doi.org/10.1016/j.jacc.2007.04.088] [PMID: 17825717]
[31]
Collet TH, Ewing SK, Ensrud KE, et al. Endogenous testosterone levels and the risk of incident cardiovascular events in elderly men: The MrOS prospective study. J Endocr Soc 2020; 4(5): bvaa038.
[http://dx.doi.org/10.1210/jendso/bvaa038]
[32]
Maggio M, Cattabiani C, Lauretani F, et al. The relationship between sex hormones, sex hormone binding globulin and peripheral artery disease in older persons. Atherosclerosis 2012; 225(2): 469-74.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.09.014] [PMID: 23102785]
[33]
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): e109-18.
[http://dx.doi.org/10.1016/S2666-7568(22)00001-0] [PMID: 35252940]
[34]
Hernández-Mijares A, García-Malpartida K, Solá-Izquierdo E, et al. Testosterone levels in males with type 2 diabetes and their relationship with cardiovascular risk factors and cardiovascular disease. J Sex Med 2010; 7(1): 954-64.
[http://dx.doi.org/10.1111/j.1743-6109.2010.01705.x]
[35]
Yeap BB, Hyde Z, Norman PE, Chubb SAP, Golledge J. Associations of total testosterone, sex hormone-binding globulin, calculated free testosterone, and luteinizing hormone with prevalence of abdominal aortic aneurysm in older men. J Clin Endocrinol Metab 2010; 95(3): 1123-30.
[http://dx.doi.org/10.1210/jc.2009-1696] [PMID: 20061425]
[36]
Brooks RV. 1 Androgens. Clin Endocrinol Metab 1975; 4(3): 503-20.
[http://dx.doi.org/10.1016/S0300-595X(75)80045-4] [PMID: 58744]
[37]
Mayo Clinic Laboratories Testosterone, total, bioavailable, and free serum Available from: https://www.mayocliniclabs.com/test-catalog/overview/83686#Clinical-and-Interpretive
[38]
Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. A reappraisal of testosterone’s binding in circulation: Physiological and clinical implications. Endocr Rev 2017; 38(4): 302-24.
[http://dx.doi.org/10.1210/er.2017-00025] [PMID: 28673039]
[39]
Hudson J, Cruickshank M, Quinton R, et al. Adverse cardiovascular events and mortality in men during testosterone treatment: An individual patient and aggregate data meta-analysis. Lancet Healthy Longev 2022; 3(6): e381-93.
[http://dx.doi.org/10.1016/S2666-7568(22)00096-4] [PMID: 35711614]
[40]
Groti K, Žuran I, Antonič B, Foršnarič L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. Aging Male 2018; 21(3): 158-69.
[http://dx.doi.org/10.1080/13685538.2018.1468429] [PMID: 29708829]
[41]
Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons from the testosterone trials. Endocr Rev 2018; 39(3): 369-86.
[http://dx.doi.org/10.1210/er.2017-00234] [PMID: 29522088]
[42]
Price J, Leng GC. Steroid sex hormones for lower limb atherosclerosis. Cochrane Libr 2012; 10(10): CD000188.
[http://dx.doi.org/10.1002/14651858.CD000188.pub2] [PMID: 23076884]
[43]
US Food and Drug Administration. Drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communicationfda- cautions-about-using-testosterone-products-low-testosterone-due
[44]
European Medicines Agency No consistent evidence of an increased risk of heart problems with testosterone medicines Available from : https://www.ema.europa.eu/en/news/no-consistent-evidence-increased-risk-heart-problems-testosterone-medicines
[45]
Bhasin S, Lincoff AM, Basaria S, et al. Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study. Am Heart J 2022; 245: 41-50.
[http://dx.doi.org/10.1016/j.ahj.2021.11.016] [PMID: 34871580]
[46]
Fink J, Horie S. Novel methods for the treatment of low testosterone. Expert Rev Endocrinol Metab 2023; 18(3): 221-9.
[http://dx.doi.org/10.1080/17446651.2023.2197059] [PMID: 37010438]
[47]
Boland J, Choi W, Lee M, Lin J. Cardiovascular toxicity of androgen deprivation therapy. Curr Cardiol Rep 2021; 23(8): 109.
[http://dx.doi.org/10.1007/s11886-021-01561-9] [PMID: 34216282]
[48]
Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006; 24(27): 4448-56.
[http://dx.doi.org/10.1200/JCO.2006.06.2497] [PMID: 16983113]
[49]
Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK, Nilsson J. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 2014; 65(3): 565-73.
[http://dx.doi.org/10.1016/j.eururo.2013.10.032] [PMID: 24210090]
[50]
Gheorghe GS, Hodorogea AS, Ciobanu A, Nanea IT, Gheorghe ACD. Androgen deprivation therapy, hypogonadism and cardiovascular toxicity in men with advanced prostate cancer. Curr Oncol 2021; 28(5): 3331-46.
[http://dx.doi.org/10.3390/curroncol28050289] [PMID: 34590590]
[51]
Lopes RD, Higano CS, Slovin SF, et al. Cardiovascular safety of degarelix versus leuprolide in patients with prostate cancer: The primary results of the PRONOUNCE randomized trial. Circulation 2021; 144(16): 1295-307.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056810] [PMID: 34459214]
[52]
Pope HG, Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S. Adverse health consequences of performance-enhancing drugs: An Endocrine Society scientific statement. Endocr Rev 2014; 35(3): 341-75.
[http://dx.doi.org/10.1210/er.2013-1058]
[53]
Saetereng T, Vanberg P, Steine K, Atar D, Halvorsen S. Cardiovascular risk associated with long-term anabolic-androgenic steroid abuse: An observational study from Norway. Eur Heart J 2021. 2021(S1):ehab724.2772.
[http://dx.doi.org/10.1093/eurheartj/ehab724.2772]
[54]
Irwig MS. Cardiovascular health in transgender people. Rev Endocr Metab Disord 2018; 19(3): 243-51.
[http://dx.doi.org/10.1007/s11154-018-9454-3] [PMID: 30073551]
[55]
Streed CG Jr, Harfouch O, Marvel F, Blumenthal RS, Martin SS, Mukherjee M. Cardiovascular disease among transgender adults receiving hormone therapy: A narrative review. Ann Intern Med 2017; 167(4): 256-67.
[http://dx.doi.org/10.7326/M17-0577] [PMID: 28738421]
[56]
Connelly PJ, Marie Freel E, Perry C, et al. Gender-affirming hormone therapy, vascular health and cardiovascular disease in transgender adults. Hypertension 2019; 74(6): 1266-74.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13080] [PMID: 31656099]

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