Physiological Testosterone Replacement Therapy Attenuates Fatty Streak Formation and Improves High-Density Lipoprotein Cholesterol in the Tfm Mouse

Abstract

Background-Research supports a beneficial effect of physiological testosterone on cardiovascular disease. The mechanisms by which testosterone produces these effects have yet to be elucidated. The testicular feminized (Tfm) mouse exhibits a nonfunctional androgen receptor and low circulating testosterone concentrations. We used the Tfm mouse to determine whether testosterone modulates atheroma formation via its classic signaling pathway involving the nuclear androgen receptor, conversion to 17␤-estradiol, or an alternative signaling pathway. Methods and Results-Tfm mice (nϭ31) and XY littermates (nϭ8) were separated into 5 experimental groups. Each group received saline (Tfm, nϭ8; XY littermates, nϭ8), physiological testosterone alone (Tfm, nϭ8), physiological testosterone in conjunction with the estrogen receptor ␣ antagonist fulvestrant (Tfm, nϭ8), or physiological testosterone in conjunction with the aromatase inhibitor anastrazole (Tfm, nϭ7). All groups were fed a cholesterol-enriched diet for 28 weeks. Serial sections from the aortic root were examined for fatty streak formation. Blood was collected for measurement of total cholesterol, high-density lipoprotein cholesterol (HDLC), non-HDLC, testosterone, and 17␤-estradiol. Physiological testosterone replacement significantly reduced fatty streak formation in Tfm mice compared with placebo-treated controls (0.37Ϯ0.07% versus 2.86Ϯ0.39%, respectively; PՅ0.0001). HDLC concentrations also were significantly raised in Tfm mice receiving physiological testosterone replacement compared with those receiving placebo (2.81Ϯ0.30 versus 2.08Ϯ0.09 mmol/L, respectively; Pϭ0.05). Cotreatment with either fulvestrant or anastrazole completely abolished the improvement in HDLC. Conclusion-Physiological testosterone replacement inhibited fatty streak formation in the Tfm mouse, an effect that was independent of the androgen receptor. The observed increase in HDLC is consistent with conversion to 17␤-estradiol.

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.…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…There is, however, compelling evidence suggesting that estrogens exert atheroprotective effects in males also under conditions in which E 2 in plasma is not elevated to supraphysiological levels. For instance, anti-atherogenic effects exerted by dehydroepiandrosterone in oophorectomized rabbits or by testosterone in orchidectomized wild-type B6 mice or in testicular feminized mice exhibiting a nonfunctional androgen receptor were reduced by pharmacological inhibitors of aromatasean enzyme that converts testosterone to E 2 (Hayashi et al 2000, Nathan et al 2001, Nettleship et al 2007). More recently, reduction of atherosclerosis under testosterone treatment could be observed in orchidectomized Apoe KO mice lacking androgen receptor (Bourghardt et al 2010).…”

Are declining testosterone levels a major risk factor for ill-health in aging men?

“…66,117,118 Testosterone may also exhibit antiatherogenic effects at the tissue level, whether mediated by classical or nonclassical pathways. 119,127,128 The key question is whether testosterone therapy reduces the risk of cardiovascular disease distinct from any effects on erectile dysfunction. Trials of testosterone therapy generally have not been designed or adequately powered to detect effects on clinically significant cardiovascular events.…”