Impact of long-term testosterone treatment on plasma levels of free TFPI and TF-induced thrombin generation ex vivo in elderly men with low testosterone levels

 

 Buy Article Permissions and Reprints

Summary

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 (≤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.

• References

• 1 Smith EB. Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. Clin Haematol 1986; 15: 355-370.
  PubMedGoogle Scholar
• 2 Niewiarowski S, Rao AK. Contribution of thrombogenic factors to the pathogenesis of atherosclerosis. Prog Cardiovasc Dis 1983; 26: 197-222.
  CrossrefPubMedGoogle Scholar
• 3 Tremoli E, Camera M, Toschi V. et al. Tissue factor in atherosclerosis. Atherosclerosis 1999; 144: 273-283.
  CrossrefPubMedGoogle Scholar
• 4 Liu PY, Death AK, Handelsman DJ. et al. Androgens and cardiovascular disease. Endocr Rev 2003; 24: 313-340.
  CrossrefPubMedGoogle Scholar
• 5 Svartberg J, von Muhlen D, Sundsfjord J. et al. Waist circumference and testosterone levels in community dwelling men. The Tromso study. Eur J Epidemiol 2004; 19: 657-663.
  PubMedGoogle Scholar
• 6 Svartberg J, von Muhlen D, Schirmer H. et al. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. Eur J Endocrinol 2004; 150: 65-71.
  CrossrefPubMedGoogle Scholar
• 7 Agledahl I, Skjaerpe PA, Hansen JB. et al. Low serum testosterone in men is inversely associated with non-fasting serum triglycerides: the Tromso study. Nutr Metab Cardiovasc Dis 2008; 18: 256-262.
  CrossrefPubMedGoogle Scholar
• 8 Khaw KT, Dowsett M, Folkerd E. et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007; 116: 2694-2701.
  CrossrefPubMedGoogle Scholar
• 9 Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68-75.
  CrossrefPubMedGoogle Scholar
• 10 Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA 1977; 74: 5260-5264.
  CrossrefPubMedGoogle Scholar
• 11 Broze Jr. GJ, Miletich JP. Characterization of the inhibition of tissue factor in serum. Blood 1987; 69: 150-155.
  PubMedGoogle Scholar
• 12 Sandset PM, Warn-Cramer BJ, Rao LV. et al. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991; 88: 708-712.
  CrossrefPubMedGoogle Scholar
• 13 Grabowski EF, Zuckerman DB, Nemerson Y. The functional expression of tissue factor by fibroblasts and endothelial cells under flow conditions. Blood 1993; 81: 3265-3270.
  PubMedGoogle Scholar
• 14 Van Dreden P, Grosley M, Cost H. Total and free levels of tissue factor pathway inhibitor: a risk factor in patients with factor V Leiden?. Blood Coagul Fibrinolysis 1999; 10: 115-116.
  CrossrefPubMedGoogle Scholar
• 15 Dahm A, van Hylckama V, Bendz B. et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392.
  CrossrefPubMedGoogle Scholar
• 16 Saigo M, Abe S, Ogawa M. et al. Imbalance of plasminogen activator inhibitor-I/ tissue plasminogen activator and tissue factor/tissue factor pathway inhibitor in young Japanese men with myocardial infarction. Thromb Haemost 2001; 86: 1197-1203.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Mannhalter C, Quehenberger P. Laboratory methods in the haemostatic laboratory. Thromb Haemost 2006; 96: 545-546.
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Veer C, Mann KG. Regulation of tissue factor initiated thrombin generation by the stoichiometric inhibitors tissue factor pathway inhibitor, antithrombin- III, and heparin cofactor-II. J Biol Chem 1997; 272: 4367-4377.
  CrossrefPubMedGoogle Scholar
• 19 Brodin E, Appelbom H, Osterud B. et al. Regulation of thrombin generation by TFPI in plasma without and with heparin. Transl Res 2009; 153: 124-131.
  CrossrefPubMedGoogle Scholar
• 20 Rosano GM, Leonardo F, Pagnotta P. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999; 99: 1666-1670.
  CrossrefPubMedGoogle Scholar
• 21 Webb CM, Adamson DL, de Zeigler D. et al. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 1999; 83: 437-439 A9.
  CrossrefPubMedGoogle Scholar
• 22 Smith AM, English KM, Malkin CJ. et al. Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina. Eur J Endocrinol 2005; 152: 285-291.
  CrossrefPubMedGoogle Scholar
• 23 Haidar A, Yassin A, Saad F. et al. Effects of androgen deprivation on glycaemic control and on cardiovascular biochemical risk factors in men with advanced prostate cancer with diabetes. Aging Male 2007; 10: 189-196.
  CrossrefPubMedGoogle Scholar
• 24 Fearnley GR, Chakrabarti R. Increase of blood fibrinolytic activity by testosterone. Lancet 1962; 02: 128-132.
  PubMedGoogle Scholar
• 25 Anderson RA, Ludlam CA, Wu FC. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost 1995; 74: 693-697.
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Jin H, Lin J, Fu L. et al. Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells. Biochem Cell Biol 2007; 85: 246-251.
  CrossrefPubMedGoogle Scholar
• 27 Agledahl I, Brodin E, Svartberg J. et al. Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels. Thromb Haemost 2009; 101: 471-477.
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Svartberg J, Agledahl I, Figenschau Y. et al. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res 2008; 20: 378-387.
  CrossrefPubMedGoogle Scholar
• 29 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666-3672.
  CrossrefPubMedGoogle Scholar
• 30 Hemker HC, Giesen P, Al RDieri. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
  CrossrefPubMedGoogle Scholar
• 31 Morrissey JH, Macik BG, Neuenschwander PF. et al. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744.
  PubMedGoogle Scholar
• 32 Hansen JB, Olsen R, Webster P. Association of tissue factor pathway inhibitor with human umbilical vein endothelial cells. Blood 1997; 90: 3568-3578.
  PubMedGoogle Scholar
• 33 Ott I, Miyagi Y, Miyazaki K. et al. Reversible regulation of tissue factor-induced coagulation by glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2000; 20: 874-882.
  CrossrefPubMedGoogle Scholar
• 34 Jin H, Lin J, Fu L. et al. Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells. Biochem Cell Biol 2007; 85: 246-251.
  CrossrefPubMedGoogle Scholar
• 35 Mannhalter C, Quehenberger P. Laboratory methods in the haemostatic laboratory. Thromb Haemost 2006; 96: 545-546.
  Article in Thieme ConnectPubMedGoogle Scholar
• 36 Hanke H, Lenz C, Hess B. et al. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 2001; 103: 1382-1385.
  CrossrefPubMedGoogle Scholar
• 37 Rao LV, Pendurthi UR. Regulation of tissue factorfactor VIIa expression on cell surfaces: a role for tissue factor-factor VIIa endocytosis. Mol Cell Biochem 2003; 253: 131-140.
  CrossrefPubMedGoogle Scholar