Prior to going through menopause, women have fewer heart attacks and other types of heart-related events than men. This is almost certainly due to the protective effects of estrogen on the cardiovascular system (Kolovou G, et al., Curr Vasc Pharmacol. 2011;9(2):244-57). However, once women experience a heart attack, they actually fare more poorly than men (Vaccarino V, et al., Arch Intern Med 2009;169:1767-74 and Daly C, et al., Circulation 2006;113:490-8). This reason for this seems to due to the male sex hormone testosterone.
Several studies provide evidence of the pro-blood vessel-making effects of the hormone testosterone. First of all, several large clinical studies have shown that men with low testosterone levels have an increased risk of cardiovascular diseases and mortality (Shores MM, et al., Arch Intern Med 2006;116(15):1660-5;Khaw KT, et al., Circulation 2007;116:2694-2701; Laughlin GA, et al., J. Clin Endocrinol Metab 2008;93:68-75). Secondly, a meta-analysis of these data has also supported the role of testosterone in supporting male cardiovascular health (Kintzel PE, et al., Pharmacotherapy 2008;28:1511-22). Finally, males show higher levels of collateral circulation in their hearts after a heart attack than women who have suffered a heart attack, which also supports a role for testosterone in the induction of new blood vessels formation in the heart (Abaci A, et al., Circulation 1999;99:2239-42).
Given these data, a Chinese research group has used a rat model to examine the ability of testosterone to induce new blood vessels growth after a heart attack. Yeping Chen and Lu Fu and their co-workers from the Harbin Medical University in Harbin, China have published a paper in the European Journal of Pharmacology that addressed this issue. Their results are fascinating and might bring new implications for post-heart attack cardiac therapy in men.
In the experiment, Chen and Fu and colleagues used rats as a model system. They took 100 male laboratory rats and broke them into two groups. Rats in the first group were surgically castrated, and rats in the second group underwent the castration surgery but without actual castration (known as a sham castration procedure). Then the rats were broken into four groups. The first group was sham castrated rats, the second was castrated rats that had been given placebos, the third was castrated rats that received testosterone supplementation (2 mg / kg body weight), and the fourth group consisted of castrated rats that received testosterone and an anti-testosterone drug called flutamide. All drug treatments commenced on the same day as the castration procedure.
One to three days after the castration procedure, peripheral blood samples were taken from all rats to measure the levels of CD34+ stem cells. CD34+ stem cells make blood vessels, and the levels of these stem cells in circulating blood are an indication of how well these animals make new blood vessels.
All rats were given two weeks to recover from the castration surgery and then were given heart attacks. Four weeks later, all rats were subjected to electrocardiograms and then some were sacrificed and their heart tissues were examined microscopically.
The results of these experiments were quite telling. Groups 1 and 3 rats (the sham castrated rats and castrated rats that had received testosterone supplementation) and group 4 rats (castrated rats that had received testosterone and flutamide) had significantly more circulating CD34+stem cells than group 2 rats (castrated rats that received no testosterone supplementation). Testosterone raised the level of circulating CD34+ stem cells and flutamide did not reverse this effect. Flutamide (Eulexin, Flutamin) works by competing with testosterone and its active metabolite dihydrotestosterone for the androgen receptor in prostate gland cells. For this reason, flutamide is categorized as an “anti-androgen” drug. It is given orally for prostate cancer in males and is also used to treat polycystic ovary syndrome in females, since it can reduce androgen levels in women.
The increase in CD34+ stem cells was due to testosterone-induced increases in the expression of several pro-blood vessel-inducing molecules. These molecules that induce new blood vessels are called “angiogenic factors.” The angiogenic factors induced by testosterone in group 1, 3, and 4 rats, but not in group 2 rats, include HIF1a (hypoxia-induced factor-1a), SDF-1 (stromal cell derived factor-1), and VEGF (vascular endothelial growth factor). The expression of these angiogenic factors is significantly increased in group 1, 3, & 4 rats, but not group 2. Furthermore, tissue examinations of hearts from all four groups show that hearts from groups 1, 3, & 4 have significantly greater quantities of CD34+ stem cells infiltrating them than those from group 2.
Echocardiograms of hearts from rats from all four groups show that groups 1, 3, and 4 had significantly smaller areas of cell death than hearts from rats in group 2. Cell death assays showed similar results as well.
Functional aspects of the heart also showed that hearts from rats in groups 1, 3, & 4 functioned more efficiently than hearts from rats from group 3.
These results suggest that testosterone could improve the blood vessel production in the heart of males after a heart attack. These data also suggest that this mechanism by which testosterone does this is independent of the androgen receptor found in the prostate gland. Therefore, if patients have a family risk of prostate cancer, a drug like flutamide can be given with the testosterone to improve the circulation in the damaged heart without increasing the risk of the patient for prostate cancer. Perhaps a clinical trial should be proposed to examine the effects of testosterone in human heart attack patients.