Dipti Gupta, MD, MPH: Before we jump into the pathophysiology of metabolic and cardiovascular side effects of ADT, I think it’s important to sort of recapitulate some of the important things that Dr. Slovin has shared with us thus far. About 40% to 50% of patients with prostate cancer will, at some point in their therapy, receive androgen deprivation therapy. The idea is to drop down testosterone levels to castrate levels. Despite the inconsistencies in the data, there is a clear signal that cardiovascular toxicity is associated with these agents. That said, GnRH antagonists might be preferable and might have lesser of that signal as compared to GnRH agonists. Last but not least, we are first going to discuss the protective role of androgens in the cardiovascular system before I jump into the metabolic and cardiovascular side effects.

Starting off with coronary vasodilatation: In the 1990s, a lot of studies that were done showed that androgens actually promote direct arterial vasodilatation in the coronary bed. When you inject intracoronary testosterone, it induces coronary vasodilatation. In men with known coronary artery disease, testosterone prolongs the time to ischemic ST segment depression while they are exercising on a treadmill or are taking a stress test. This suggests that the mechanism is increased coronary blood flow.

The other thing that the androgens and testosterone accomplish, which is very favorable for the cardiovascular system, is that they play a direct role within the pathophysiology of atherosclerosis by modulating local inflammatory processes through the monocyte macrophage lineage, which is a key player in keeping these plaques stable. When the testosterone is taken away, these plaques become unstable—meaning they rupture and cause heart attacks. In addition, there is evidence that testosterone inhibits platelet aggregation. Again, this is something that we don’t want because that also promotes the perfect set up for a heart attack. It does so by stimulating endothelial production of nitric oxide. It may also stimulate fibrinolysis and clot degradation by increasing expression of tissue plasminogen activators. So, all in all, it helps to maintain plaque stability in health.

Men are known to have shorter QT intervals than women, and recent evidence has suggested that there are probably hormonal differences that explain this difference. In a study of over 700 men participating in the NHANES (National Health and Nutrition Examination Survey), the higher the testosterone level, the shorter the QT interval. We don’t exactly know the clinical significance, but this may be because of the shortening of action potential by an interplay of calcium potassium currents. One could infer that this probably confers some antiarrhythmic properties. Last but not the least, testosterone affects body composition, and it does so in a very favorable fashion. It helps increase muscle mass and helps increase or promote insulin sensitivity—both things that we like and want. So, this is the protective role of testosterone in the cardiovascular system.

Transcript Edited for Clarity