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Men have a higher incidence of cardiovascular disease (CVD) than women, and adverse thrombotic events increase with age. Recent experimental cross-sectional, and case-control studies have shown that testosterone may affect the hemostatic/fibrinolytic system in men in several ways. It has been hypothesized that physiological doses of testosterone would have a beneficial effect on tissue factor-induced thrombin generation and the development of CVD. The search for eternal youth has created a market for testosterone treatment in aging men during the last few years. However, whether testosterone supplementation could be useful in the treatment of testosterone-deficient elderly men is still controversial. The present review focuses on the coagulation system and CVD from the perspective of testosterone., (© Thieme Medical Publishers.)

Men have a higher incidence of cardiovascular disease (CVD) than women of similar age, and it has been suggested that testosterone may influence the development of CVD. Recently, we demonstrated that elderly men with low testosterone levels had lower plasma levels of free tissue factor pathway inhibitor (TFPI) Ag associated with shortened tissue factor (TF)-induced coagulation initiation in a population based case-control study. Our hypothesis was that one year of testosterone treatment to physiological levels in elderly men would increase the levels of free TFPI Ag in plasma and have a favorable effect on TF-induced coagulation. Twenty-six men with low testosterone levels (< or =11.0 nM) were randomly assigned to treatment with intramuscular testosterone depot injections (testosterone undecanoate 1,000 mg) or placebo in a double-blinded study. Each participant received a total of five injections, at baseline, 6, 16, 28 and 40 weeks, and TF-induced thrombin generation ex vivo and plasma free TFPI Ag were measured after one year. At the end of the study total and free testosterone levels were significantly higher in the testosterone treated group (14.9 +/- 4.5 nM vs. 8.1 +/- 2.4 nM; p < 0.001, and 363.3 +/- 106.6 pM vs. 187.3 +/- 63.2 pM; p < 0.001, respectively). Testosterone treatment for one year did neither cause significant changes in TF-induced thrombin generation ex vivo nor changes in plasma levels of free TFPI Ag. In conclusion, normalising testosterone levels by testosterone treatment for 12 months in elderly men did not affect TF-induced coagulation or plasma TFPI levels. The potential antithrombotic role of testosterone therapy remains to be elucidated.

Low testosterone levels in men have been associated with cardiovascular risk factors, some prothrombotic factors, and lately also an increased risk of both cardiovascular disease and all-cause mortality. Experimental studies have shown increased synthesis and release of tissue factor pathway inhibitor (TFPI) by physiological levels of testosterone in endothelial cells. Our hypothesis was that elderly men with low testosterone levels would have lower plasma levels of plasma free TFPI with subsequent increased thrombin generation. Elderly men with low (n = 37) and normal (n = 41) testosterone levels were recruited from a general population, and tissue factor (TF)-induced thrombin generation ex vivo and plasma free TFPI Ag were measured. Elderly men with low testosterone levels had lower plasma free TFPI Ag (10.9 +/- 2.3 ng/ml vs. 12.3 +/- 3.0 ng/ml, p = 0.027) and shorter initiation phase of TF-induced coagulation assessed by lag-time (5.1 +/- 1.0 min vs. 5.7 +/- 1.3, p = 0.039). The differences between groups remained significant and were strengthened after adjustment for waist circumference and other cardiovascular risk factors. Lag-time increased linearly across quartiles of plasma free TFPI Ag (p<0.001). Multiple regression analysis revealed that total and free testosterone were independent predictors of plasma free TFPI Ag. Our findings suggest that low testosterone levels in elderly men is associated with low plasma free TFPI Ag and subsequent shortened initiation phase of TF-induced coagulation.