The authors are to be congratulated on an elegant and powerful study. If possible, the study should be extended to examine the effect of concomitant primary preventative aspirin, adjunctive aromatase inhibitor therapy, and daily use of tadalafil. Each of these drugs could substantially alter the effect of testosterone on cardiovascular events. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses (1). The latter effect would likely be attenuated by aspirin's suppression of thromboxane A2 formation. Hence, the reported results may overstate the adverse effects of testosterone for those taking aspirin while understating it for those not taking aspirin. Similarly, patients taking adjunctive aromatase inhibitors may experience a lesser effect on cardiovascular events due to decreased metabolism of exogenous testosterone to estradiol, which has been positively correlated with cardiovascular disease (2). Finally, there is evidence that daily tadalafil may block some potentially deleterious vascular effects of testosterone's metabolite, dihydrotestosterone (DHT). DHT promotes endothelial vascular cell adhesion molecule-1 (VCAM) expression and increases human monocyte adhesion to the vascular endothelium (3,4) whereas daily tadalafil causes a robust and sustained decline in VCAM, endothelin-1, and CRP.(5) With mounting evidence of increased cardiovascular risk with exogenous testosterone administration alone, it is time to look at the effects of these combined regimins - particularly those that are already in common use.

-Woodrow Gandy, MD

(1) Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation. 1995 Jun 1;91(11):2742-7.

(2) Coronal G, Giulia R, Matteo M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol November 1, 2011 165 687-701.

(3) Death AK, McGrath KC, Sader MA, et al. Dihydrotestosterone promotes vascular cell adhesion molecule-1 expression in male human endothelial cells via a nuclear factor-kappaB dependent pathway. Endocrinology.2004;145(4):1889-1897.

(4) McCrohon JA, JessupW, Handelsman DJ, Celermajer DS. Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1. Circulation.
1999;99(17):2317-2322.

(5) Aversa A, Greco E, Bruzziches R, et al. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res. 2007 Mar-Apr;19(2):200-7. Epub 2006 Aug 31.