Testosterone Increases Human Platelet Thromboxane A 2 Receptor Density and Aggregation Responses

Abstract

Background The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women. Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acute myocardial infarctions and strokes in young male athletes who abuse anabolic steroids. Thromboxane A 2 (TXA 2 ) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease. We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA 2 receptors. Methods and Results In a double-blind, placebo-controlled, randomized, parallel-group study, we determined the effects of testosterone cypionate 200 mg IM given twice, 2 weeks apart, or saline placebo in 16 healthy men. Platelet TXA 2 receptor density (B max ) and dissociation constant ( K d ) were measured by use of the TXA 2 mimetic 125 I-BOP. Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before treatment (pretreatment phase), at 2 and 4 weeks (active phase), and again at 8 weeks (recovery phase). Treatment with testosterone was associated with an increase in the B max value from 0.95±0.13 to 2.10±0.4 pmol/mg protein (n=9), with a peak effect at 4 weeks ( P =.001), returning to baseline by 8 weeks. There was no significant change in B max values in the saline-treated group. The K d values were unchanged. Testosterone treatment was associated with a significant increase in the maximum platelet aggregation response to I-BOP ( P <.001) at 4 weeks and returned to baseline at 8 weeks. The EC 50 values were not significantly changed. Platelet TXA 2 receptor density was positively correlated ( r =.56, P <.001, n=32 measurements) with pretreatment (endogenous) plasma testosterone levels (range, 215 to 883 ng/dL) but not K d . Conclusions Testosterone regulates the expression of platelet TXA 2 receptors in humans. This may contribute to the thrombogenicity of androgenic steroids.