Natural Androgens Inhibit Male Atherosclerosis

Abstract

The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308+/-39) and lowest in the TE group (61+/-12), but was intermediate in the DHEA (155+/-30), TU (191+/-43), and sham operation (162+/-29) groups (ANOVA, P<0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect.

Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men

“…In follow-up studies, those patients with a low testosterone blood level had bigger changes in CIMT over time, representing increased atheroma progression (19,20). Prospective animal studies are consistent with this and have shown that physiological androgen replacement inhibits atheroma progression (11,(21)(22)(23). There are currently no in vivo human data on the effects of androgen therapy on atheroma.…”

“…Numerous animal models have demonstrated that physiological testosterone replacement therapy prevents progression of established atheroma and development of nascent atheroma (11,21). This outcome has never been reported in prospective randomised clinical trials of testosterone in humans.…”

“…Importantly, no adverse effects of testosterone replacement therapy on coagulation have been demonstrated in men with chronic stable angina (10). Furthermore, animal studies have shown that testosterone replacement inhibits the development and progression of atheroma (11). Finally, testosterone has direct effects on vascular tone causing vasodilatation, an increase in coronary blood flow (12,13) and an increase in the ischaemic threshold in patients with symptoms of stable angina (14,15).…”

Hormonal effects on blood vessels

“…[89][90][91] Effects of testosterone on animal models of atherosclerosis and neointima formation It has been demonstrated that the administration of testosterone in castrated male rabbits that were fed a high-cholesterol diet reduced aortic atherosclerosis, largely independent of plasma lipids. 92,93 In addition, neointima formation after coronary balloon injury in swine was increased by castration and was reversed by testosterone replacement. 94 Regarding the role of AR, conflicting findings have been reported.…”

Effect of testosterone replacement therapy on arterial stiffness in older hypogonadal men

“…In the experimental setting, testosterone may retard atherogenesis through both aromatization to estradiol and activation of nonclassical androgen receptors (17). Just as estradiol, testosterone was shown to exert antiatherogenic effects in the cholesterol-fed rabbit (18). Finally, pharmacological suppression of circulating testosterone in men with prostate cancer can result in increased arterial stiffness (19,20), thus indirectly suggesting the induction of structural changes.…”