Testosterone is reported to have an acute vasodilating action in vitro , an effect that may impart a favourable haemodynamic response in patients with chronic heart failure. However, the effect of chronic testosterone exposure on general vascular reactivity is poorly described. In the present study, fresh subcutaneous resistance arteries were obtained from patients with heart failure ( n =10), healthy controls ( n =9) and men with androgen-deficiency ( n =17). All arteries were studied using a wire myograph to examine the effect of cumulative additions of testosterone (1 nmol/l–100 μmol/l) compared with vehicle control following maximal pre-constriction with KCl (1–100 μmol/l). The vascular reactivity of arteries from androgen-deficient patients was examined further by recording tension concentration curves to cumulative additions of noradrenaline (1 nmol/l–100 μmol/l) and U46619 (1–300 nmol/l), followed by relaxation concentration curves to additions of ACh (acetylcholine; 10 nmol/l–30 μmol/l) and SNP (sodium nitroprusside; 10 nmol–30 μmol/l) respectively. In all cases, statistical analysis was performed by ANOVA. Patients with proven androgen-deficiency were treated according to clinical recommendations for a minimum of 3 months and further arteries ( n =19) were taken for experimentation using the same protocol. In all groups, testosterone was confirmed to be an acute concentration-dependent vasodilator at concentrations ≥1 μmol/l ( P =0.0001). The dilating effect of testosterone was augmented in patients with androgen-deficiency prior to treatment, and this effect was abrogated following appropriate testosterone replacement. Testosterone therapy significantly reduced the normal vascular dilating response to ACh and SNP ( P <0.01) and significantly increased the contractile response to noradrenaline ( P <0.01), but not U46619. Testosterone is an acute dose-dependent vasodilator of resistance arteries. Physiological testosterone replacement attenuates general vascular reactivity in androgen-deficient subjects. The numerous perceived benefits of testosterone replacement may be offset by a decline in vascular reactivity and, therefore, further studies and careful monitoring of patients is recommended.

Testosterone decreases myocardial ischaemia in men with coronary artery disease via a coronary vasodilatory action. However, long-term therapy may increase the risk of prostatic carcinoma via activation of the nuclear AR (androgen receptor). In the present study, we have investigated the mechanism of testosterone-induced vasodilatation using isolated rat coronary arteries and thoracic aortae from control and AR-deficient testicular-feminized mice. Vasodilatation induced by testosterone, T-3-OCMO [testosterone 3-( O -carboxymethyl)oxime] or T-3-OCMO conjugated to BSA was initially measured in preconstricted vessels that had undergone endothelial denudation or incubation with flutamide (10 μM). Cellular fluorescence was also measured in primary aortic SMCs (smooth muscle cells) following exposure to the above fluorescent-labelled agents. Subsequently, vessels were incubated with testosterone (100 μM) or vehicle prior to constriction with KCl (1–100 mM). Testosterone-induced vasodilatation was unaffected by endothelial denudation, flutamide treatment, AR deficiency or conjugation to BSA. Cells exposed to T-3-OCMO–BSA (10 μM) had a higher fluorescence than control cells (32.8±4.5 compared with 14.5±1.8 arbitrary units respectively; P <0.01). Incubation with testosterone (100 μM) reversibly attenuated coronary vasoconstriction to KCl (1–100 mM; 0.08±0.09 compared with 0.79±0.08 mN/mm respectively; P <0.0001). Testosterone-induced vasodilatation is independent of the vascular endothelium and nuclear AR, and is initiated at the SMC membrane, which contains testosterone binding sites. A direct calcium antagonistic action is implicated.

The effect of smoking on androgen levels is important given the recent interest in the link between low levels of androgens and the development of cardiovascular disease. Numerous studies examining the effects of cigarette smoking on the levels of total and free testosterone have reported conflicting findings, but there has been no accurate assessment of the effects of cigarette smoking on the levels of bioavailable testosterone [not bound to sex hormone-binding globulin (SHBG)]. We attempted to determine whether smoking affects the level of bioavailable testosterone. We undertook a case-control study of 25 healthy male smokers and 25 healthy never-smokers, matched by age and body mass index. Early morning levels of total, free and bioavailable testosterone, 17β-oestradiol, SHBG and cotinine were determined and compared between the two groups. Levels of total (18.5 ± 4.6 ± nM versus 15.1 ± 4.9 ± nM, P = 0.01) and free testosterone (462 ± 91 ± pM versus 402 ± 93 ± pM, P = 0.03) were found to be higher in smokers compared with non-smokers respectively, as was SHBG (34.1 ± 12.8 versus 28.1 ± 9.0 ± nM, P = 0.06). There were no significant differences in the levels of bioavailable testosterone (3.78 ± 1.59 versus 3.51 ± 1.26 ± nM, P = 0.49) or 17β-oestradiol (44.5 ± 11.4 versus 42.3 ± 11.5 ± pM, P = 0.50) between smokers and non-smokers respectively. These data suggest that cigarette smoking has no significant effect on the biologically active fraction of testosterone, but may influence the levels of total and free testosterone through changes in the levels of SHBG.