Testosterone, tissue factor inhibition and vascular aging.

Aging is associated with important changes in the cardiovascular system. A key feature is the development of endothelial dysfunction, with the concomitance of enhanced vascular tone, increased production of reactive oxygen species, a fall in fibrinolytic capacity and a rise in vascular and blood procoagulant activity (1). In parallel, the ability to repair vessel injury is impaired by a decreased number and function of circulating progenitor cells. The decline in sex hormone levels with age in both men and women has been thought to contribute to the increased prevalence of endothelial dysfunction, cardiovascular diseases and cardiac-related mortality with age. More specifically, the higher prevalence of ischaemic heart disease in men compared to pre-menopausal age-matched women has suggested that oestrogens, more than testosterone, may exert cardiovascular protection. However, prospective, cross-sectional, and interventional studies have not confirmed these hypotheses (2–4), and have even fuelled the notion of an “oestrogen-androgen paradox” whereby oestrogens may enhance and testosterone may attenuate athero-thrombotic risk (5). In vivo thrombin generation is largely dependent on tissue factor (TF), a fullyfunctional 45 kDa membrane glycoprotein expressed in vascular smooth muscle cells and adventitial fibroblasts (6). A circulating, often encrypted form can be found on white cells, platelets, and shed microparticles (6). Endothelial cells may express TF upon pro-inflammatory cytokine activation (7). At sites of vessel injury/activation, TF may thus come into contact with blood and interact with FVIIa, initiating coagulation (6). Generated thrombin further induces TF expression on the surface of activated platelets, leading to the propagation of coagulation (6). The initiation of coagulation by TF is a regulated process, controlled mainly by tissue-factor pathway inhibitor (TFPI). This 276-amino acid, reversible, serine protease is produced almost entirely by endothelial cells (6). TFPI contains Kunitz domains that mimic the substrate of the target protease: after binding and inhibiting FXa through one Kunitz domain, TFPI subsequently inhibits the TF-FVIIa complex through another domain (6), limiting thrombus formation to the site of TF exposure. In plasma, only 10% of TFPI is in a free active form, the majority being bound to low-density lipoproteins with little inhibitory function (6). Heparin and shear stress upregulate the expression of TFPI (6), whose free plasma levels correlate with age and with markers of endothelial dysfunction (8). Testosterone is produced in men mainly by Leydig cells, with the adrenal cortex contributing minimally (9). Total serum concentrations approximate 20–30 nM in adult men up to 55 years of age, gradually declining thereafter to about 15 nM (9). Levels below 10–12 nM suggest a condition of hypogonadism (9). Circadian variations account for evening nadirs and morning peaks (9). Up to 60–80% of testosterone is tightly bound to the sex hormone-binding globulin (SHBG), with only 1–3% unbound as free fraction and the remainder loosely linked to albumin (9). The bioavailable fraction typically comprises free and albumin-bound testosterone, but experimental studies show that cellular internalisation of SHBG-bound testosterone also occurs (10). Testosterone and its main metabolite, dihydrotestosterone, exert genomic and Correspondence to: Felicita Andreotti, MD, PhD Institute of Cardiology, Gemelli University Hospital Largo Gemelli 8, 00168 Rome, Italy Tel.: +39 0 630154187, Fax: +39 0 63055535 E-mail [email protected] Received: November 17, 2009 Accepted: November 17, 2009 Prepublished online: December 1, 2009