The Gordon Wilson Lecture. Regulation of thromboxane A2 receptors by testosterone: implications for steroid abuse and cardiovascular disease.

Thromboxane A2 (TXA2), a platelet aggregator and vasoconstrictor, has been implicated as a potential pathophysiologic mediator of a wide variety of cardiovascular diseases. It is well established that men are at greater risk for cardiovascular disease compared to premenopausal females. Abuse of androgenic/anabolic steroids has been associated with thrombotic cardiovascular diseases in young male athletes. These observations along with several others have led to the hypothesis that testosterone may regulate the expression of TXA2 receptors. Rat aortic smooth muscle cells (RASMC) and human erythroleukemia cells (HEL), a megakaryocyte-like cell, were incubated with testosterone. TXA2 receptor affinity (Kd) and density (Bmax) were determined via equilibrium binding experiments using the radiolabeled TXA2 mimetic [125I]-BOP. Testosterone significantly increased the Bmax without any significant change in Kd. Hydroxyflutamide (1 microM), an androgen receptor antagonist, completely blocked the effect of testosterone. Dihydrotestosterone, the active metabolite of testosterone also increased Bmax in a concentration-dependent manner and was more potent than testosterone. These observations along with several others are consistent with the notion that androgenic steroids may regulate the expression of functional TXA2 receptors in HEL and RASMC. These results raise the possibility that the increase in TXA2 receptor density induced by testosterone may contribute to its thrombotic potential in cardiovascular diseases.