Castration reduces platelet thromboxane A2 receptor density and aggregability

Abstract

Background: Exogenously administered testosterone upregulates platelet thromboxane A2 (TXA2) receptors and increases aggregation response to thromboxane mimetics in healthy male volunteers. However, the biological impact of endogenous testosterone on platelet TXA2 receptor expression, especially in older men at risk of coronary artery disease, is unclear. Aim: To investigate the impact of reduction in circulating testosterone on platelet TXA2 receptor expression in older men. Design: Cross-sectional case-control study. Methods: We studied surgically and/or medically castrated men with prostate cancer (group A, n = 8, aged 71±8 years) and age-matched, uncastrated urology patients (group B, n: 7, aged 67±9 years). Plasma testosterone was measured by radioimmunoassay. Platelet TXA2 receptor expression was assessed by radioligand binding studies using radioactive 125I-BOP. Platelet aggregation responses to TXA2-mimetic I-BOP, and to thrombin, were also studied. Results: Group A had significantly lower plasma testosterone than group B (16±5ng/dl vs. 308±47 ng/dl, p<0.001). Platelet TXA2 receptor density (Bmax) but not affinity (Kd) was lower in group A (0.50±0.12 vs. 1.01±0.17pmol/mg protein, p=0.03). Maximum platelet aggregation response to I-BOP (Emax), but not sensitivity (EC50) was lower in group A (53±2% vs. 63±2%, p=0.003 ANOVA). In vitro, high concentrations of hydroxyflutamide (1001μM) competitively inhibited U46619-induced platelet aggregation in washed platelets, without affecting the binding of 125I-BOP to platelet TXA2 receptors. Discussion: Endogenous testosterone regulates platelet TXA2 receptor Bmax and the Emax aggregation response to thromboxane mimetic I-BOP. Blockade of androgen receptors or inhibition of testosterone production may reduce platelet aggregation responses. Preliminary evidence suggests the presence of functional androgen receptors on human platelets, which may regulate TXA2 receptor expression. © The Author 2005. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved.