Cardiovascular Effects of TestosteroneGraham Jackson, FRCP, FACC, FESC

Corresponding authorGraham Jackson, FRCP, FACC, FESCLondon Bridge Hospital, Suite 301, Emblem House, 27 Tooley Street, London SE1 2PR, United Kingdom. E-mail: gjcardiol@talk21.com

Current Sexual Health Reports 2008, 5:187–189Current Medicine Group LLC ISSN 1548-3584Copyright © 2008 by Current Medicine Group LLC

Several studies have evaluated the relationship between cardiovascular disease (CVD) and low testosterone level. Long-term follow-up data suggest that low testosterone level may increase CVD mortality and be a risk factor for CVD development. Low testosterone level is associated with visceral obesity, increased infl ammatory markers, insulin resistance, the metabolic syndrome, hyperlipid-emia, and impaired endothelial function. Testosterone replacement as a means of modifying CVD risk and reducing CVD morbidity and mortality is an attractive concept; however, evidence of benefi t is not yet avail-able. With the particularly strong association between the potential benefi cial impact of testosterone therapy and obesity, the metabolic syndrome, and CVD, clinical end-point studies are clearly needed to elucidate the role of testosterone replacement in CVD prevention.

IntroductionDebate related to the subject of “hormones and the heart” is invariably driven by the lack of clinical end-point data indicating that testosterone replacement confers benefi t. Hormone replacement therapy (HRT) in women was ini-tially advocated to reduce cardiovascular disease (CVD); however, HRT for CVD was subsequently contraindi-cated before a noncardiovascular role was ultimately clarifi ed [1]. HRT is not recommended to prevent or treat CVD in women [2].

In men, increasing evidence suggests that low andro-gen levels are associated with all-cause death and, in particular, CVD death [3••]. Could this be cause and effect or just coincidence, with testosterone functioning as a sideshow to established risk factors? If testosterone is causative, could replacement be benefi cial and, in turn, safe over time? Because developed and developing countries have aging populations, age-related decline in androgens has important clinical implications for CVD management.

Testosterone and CVD Risk FactorsA low testosterone level is associated with several CVD risk factors [4,5•]. Studies of body fat have identifi ed a signifi cant inverse relationship with visceral fat accumulation. In turn, testosterone replacement in hypogonadal men decreases adiposity. As fat mass (obesity) independently predicts car-diovascular risk, the possibility that testosterone replacement can reduce risk is clearly attractive [6,7].

Testosterone also infl uences carbohydrate metabo-lism. Low testosterone levels are associated with glucose intolerance and type 2 diabetes independently of adi-posity. The association with the metabolic syndrome in middle-aged men is now well established [8]. Therefore, it is possible that, in men with low testosterone levels, testosterone replacement may prevent the development of type 2 diabetes and reduce the CVD risk associated with the metabolic syndrome [9,10].

CVD risk is also associated with abnormalities of coagulation, infl ammatory cytokines, and dyslipidemia [4,11]. A reported inverse relationship with fi brinolysis and increased activity of plasminogen activator inhibitor 1 (PAI-1) and factor VII could predispose to thrombotic events, such as atherothrombosis. Some evidence sug-gests that testosterone replacement decreases fi brinogen levels, augments the fi brinolytic system, decreases platelet aggregation, and reduces PAI-1 activity. Again, because of the lack of randomized trials, we cannot translate these actions into a reduction of CVD events.

Infl ammation plays a signifi cant role in CVD events, especially in acute coronary syndromes [12]. An inverse rela-tionship between testosterone and interleukin-6 (a stimulator of infl ammation) and C-reactive protein (CRP) suggests a role for replacement, modifying the infl ammatory response to CRP and cytokines. Once more, the theory needs to be supported by randomized trials.

Hyperlipidemia is a major risk factor for CVD and its modifi cation by statin therapy is an established means of risk reduction [12]. Studies of testosterone are confl icting regarding the lipid profi le and nonexistent regarding clini-cal end points. Overall, studies of testosterone treatment have identifi ed a 10% decrease in total and low-density lipoprotein (LDL) cholesterol. This reduction would be benefi cial if not accompanied by an adverse lowering of high-density lipoprotein (HDL) cholesterol by 10%. The decline in HDL cholesterol, however, appears to be less pronounced in older men and after prolonged therapy. Testosterone use in hypogonadal men is different from

188 Androgen Defi ciency and Disorders of Ejaculation

its use in healthy men. In one study of healthy men, high doses of testosterone enanthate decreased HDL cholesterol by 26% and increased total cholesterol by 12%, with no effect on LDL cholesterol or triglycerides [13]. Formula-tions may be important. A randomized controlled trial of transdermal testosterone versus placebo, again in healthy men, demonstrated no signifi cant change in total or LDL cholesterol [14]. By contrast, in a study of intramuscular testosterone enanthate given for 3 months to hypogonadal men, total cholesterol and LDL cholesterol were signifi -cantly reduced by 11% to 12% and HDL cholesterol was unchanged [15]. Currently, no convincing message on lipid profi les exists, either positive or negative, regarding testosterone replacement in hypogonadal men. Further, data from randomized trials are insuffi cient to convinc-ingly identify variations in delivery method [16••].

Vascular effectsTestosterone has a direct effect on vascular smooth muscle by an action on calcium or potassium channels [17]. In animal models using isolated coronary, pulmo-nary, and femoral arteries, a dose-dependent vasodilatory effect exists that is independent of the endothelium [18]. The effect is not reduced by fl utamide, a nuclear andro-gen receptor blocker. In the murine model, in which the nuclear androgen receptor is absent, testosterone still causes femoral artery vasodilatation [19]. Experimental studies in animals have demonstrated coronary artery dilatation after acute testosterone administration.

In men, testosterone leads to dose-dependent vasodilata-tion in vitro and in vivo. When testosterone is administered to the left coronary artery, vasodilatation follows, and fl ow increases [20]. A 3-month clinical trial using transdermal testosterone in stable angina patients resulted in improved exercise-induced ischemia during exercise electrocardi-ography and an improved angina threshold [21].

Testosterone therapy has not been shown to affect sys-tolic or diastolic blood pressure in placebo-controlled trials [9]. Of interest, low testosterone levels have been associated with increased atherosclerosis and arterial stiffening [22]. Once more, an attractive argument needs evaluation.

Testosterone and Cardiovascular OutcomeSeveral studies evaluated the link between testoster-one levels and CVD. The most recently reported is the EPIC-Norfolk (European Prospective Investigation into Cancer in Norfolk) study [23••]. This is a nested case-control study designed to determine any association with testosterone levels and all-cause CVD and death from cancer. The study compared 825 men with no CVD at baseline who died and 1489 men who lived from entry between 1993 and 1997 through follow-up in 2003. The cases and controls were matched for age and date of baseline visit. Endogenous testosterone concentrations at baseline were found to be inversely related to all-cause

mortality (n = 825), CVD deaths (n = 369), and deaths from cancer (n = 304). After adjusting for confounding variables, an increase of 6 nmol/L (1.73 mg/mL) serum testosterone was associated with a 14% decrease in death rate, regardless of age. Those in the highest testosterone quartile had a 30% lower risk of death compared with those in the lowest. The study only included a single tes-tosterone sample (not free testosterone) that may have led to measurement error and time of sample variation, but single measures are believed to be accurate for population studies [24]. Occult illness at entry may have distorted the low testosterone group, but after excluding all those who died in the fi rst 2 years, the fi ndings were unchanged. The authors’ conclusion that low testosterone levels may be a marker for those at high risk of CVD is balanced by their view that “defi nitive assessment of the long-term effects of testosterone replacement therapy on health will require large-scale controlled trials.”

The Rancho-Bernardo area study prospectively fol-lowed up 794 men 50 to 91 years old evaluating the link between testosterone levels and all-cause mortality over a 20-year period [25••]. Men in the lowest quartile for testosterone levels were 40% more likely to die than those in the highest quartile (mainly from CVD and respiratory disease). These fi ndings were independent of age, obesity, dyslipidemia, and lifestyle. Another long-term, albeit retrospective, study in men older than age 40 without prostate cancer reported an increased mortality of 12% in the 20% with a low testosterone level [26].

Although several cross-sectional, prospective stud-ies found no relationship between testosterone level and CVD, the overall evidence points to testosterone having a pathogenic role in CVD. It appears not to be simply another marker but, as in erectile dysfunction, an independent factor.

Testosterone replacement and CVDBecause no current evidence indicates that testosterone replacement reduces CVD, a long-term study is required. Testosterone replacement at present should be reserved for those who are symptomatic (eg, decreased libido). How-ever, chronic illness is associated with low testosterone. Therefore, testosterone levels should be screened in those with diabetes and chronic CVD (eg, heart failure).

ConclusionsWe need to defi ne and standardize normality (3–10 mg/mL; 10.4–34.6 nmol/L) across all future studies [16]. Although the data are reassuring, a defi nitive assessment of the long-term effects of testosterone replacement on cardiovascular health requires prospective, large-scale, placebo-controlled studies. For now, because there is no evidence of increased CVD risk, testosterone replace-ment can be advocated on conventional established clinical grounds.

Cardiovascular Effects of Testosterone Jackson 189

DisclosureNo potential confl ict of interest relevant to this article was reported.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

1. Stevenson JC: Cardiovascular disease in women. Menopause Int 2008, 14:5.

2. Jackson G. Gender differences in cardiovascular disease prevention. Menopause Int 2008, 14:13–17.

3.•• Basaria S, Dobs AS: Testosterone making an entry into the cardiometabolic world. Circulation 2007, 116:2658–2661.

An excellent editorial overview.4. Alexandersen P, Christiansen C: The aging male: testosterone

defi ciency and testosterone replacement. An update. Athero-sclerosis 2004, 173:157–169.

5.• Allan CA, Strauss BJG, McLachlan RI: Body composition, metabolic syndrome and testosterone in ageing men. Int J Impot Res 2007, 191:448–457.

An excellent review with 98 references.6. Kapelman PG: Obesity as a medical problem. Nature 2000,

404:635–643.7. Jackson G: The importance of risk factor reduction in

erectile dysfunction. Curr Urol Rep 2007, 8:463–466.8. Makhsida N, Shah J, Yan G, et al.: Hypogonadism and

metabolic syndrome: implications for testosterone therapy. J Urol 2005, 174:827–834.

9. Shabsigh R, Arver S, Channer KD, et al.: The trial of erectile dysfunction, hypogonadism and the metabolic syndrome. Int J Clin Pract 2008, 62:672–674.

10. Kirby M: A new look at the hormonal and metabolic changes in the ageing male. Int J Clin Pract 2008, 62:672–674.

11. Grundy SM: Obesity, metabolic syndrome and cardiovascular disease. J Clin Endocrinol Metab 2004, 89:2595–2600.

12. Cannon CP, Steinberg BA, Murphy SA, et al.: Meta-analysis of cardiovascular outcome trials comparing intensive versus moderate statin therapy. J Am Coll Cardio 2006, 48:438–445.

13. Bagatell CJ, Knopp RH, Vale WW, et al.: Physiologic testosterone levels in normal men suppresses high-density lipoprotein cholesterol levels. Ann Intern Med 1992, 116:967–973.

14. Snyder PJ, Peachey H, Berlin JA, et al.: Effect of transdermal testosterone on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med 2001, 111:255–260.

15. Tenover JS: Efforts of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992, 25:1092–1098.

16.•• Buvat J, Shabsigh R, Guay A, et al.: Hormone, metabolism, aging and men’s health. In Standard Practice in Sexual Medicine. Edited by Porst H, Buvat J. Oxford, UK: Blackwell; 2006:225–286

A defi nitive review with 422 references. 17. Channer KS, Jones TH: Cardiovascular effects of testosterone:

implications of the “male menopause”? Heart 2003, 89:121–122.

18. English KM, Jones RD, Jones TG, et al.: Gender differences in the vasodilator effects of different steroid hormones in rat pulmonary and cardiovascular arteries. Horm Metab Res 2001, 33:645–652.

19. Jones RD, Pugh PJ, English KM, et al.: Isolated arteries from testicular feminised mice have maintained dilator response to testosterone but reduced vascular reactivity to acetylcholine. Br J Pharmacol 2001, 135:P129.

20. Rosano GMC, Leonardo F, Pagnotta P, et al.: Acute anti-ischemic effect of testosterone in men with coronary artery disease. Am J Cardiol 1999, 83:437–439.

21. English KM, Steeds RP, Diver MJ, et al.: Low dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. Circulation 2000, 102:1906–1911.

22. Muller M, Van den Beld AW, Bots ML, et al.: Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 2004, 109:2074–2079.

23.•• Khaw K-T, Dowsett M, Folkerd E, et al.: Endogenous testoster-one and mortality due to all causes, cardiovascular disease, and cancer in men. Circulation 2007, 116:2694–2701.

An important prospective study.24. Liu PY, Death AK, Handelsman DJ: Androgens and cardio-

vascular disease. Endocr Rev 2003, 24:313–340.25.•• Laughlin GA, Barrett-Connor E, Bergstrom J: Low testos-

terone and mortality in older men. J Clin Endocrinol Metab 2008, 93:68–75.

This study supports reference 23 and adds to the evidence regarding low testosterone and increased CVD.26. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR:

Low serum testosterone and mortality in male veterans. Arch Intern Med 2006, 166:1660–1665.