Cardiovascular and metabolic actions of the androgens: Is testosterone a Janus-faced molecule?

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide and in the Western world, one-third of all deaths are attributed to CVD. A conspicuous characteristic of this healthcare epidemic is that most CVD is higher in men than in age-matched premenopausal women, yet reasons for these obvious sex differences remain poorly understood. Driven by clinical case and epidemiological studies and supported by animal experiments, a strong dogma emerged early on that testosterone (TES) exerts deleterious effects on cardiovascular health and exacerbates development of CVD and metabolic dysfunctions in men. In this review, earlier and more recent clinical and experimental animal evidence of cardiovascular and metabolic effects of androgens are discussed. The more recent evidence overwhelmingly suggests that it is progressive, age-dependent declines in TES levels in men that exacerbate CVD and metabolic dysfunctions, while TES exerts beneficial systemic hypotensive effects and protects against metabolic syndrome (MetS) and type2 diabetes mellitus (T2DM). Recent findings reveal existence of bi-directional modulation of glucose and fat homeostasis by TES in females vs males, such that age-dependent declines in TES levels in males and abnormal increases in normally low TES levels in females both result in similar dysfunction in glucose and fat homeostasis, resulting in development of MetS and T2DM, central risk factors for development of CVD, in men as well as women. These findings suggest that the long-held view that TES is detrimental to male health should be discarded in favor of the view that, at least in men, TES is beneficial to cardiovascular and metabolic health.

Orchidectomy attenuates high-salt diet-induced increases in blood pressure, renovascular resistance, and hind limb vascular dysfunction: role of testosterone.

Sex hormone-dependent vascular reactivity is an underlying factor contributing to sex differences in salt-dependent hypertension. This study evaluated the role of androgens (testosterone) in high salt-induced increase in blood pressure (BP) and altered vascular reactivity in renal blood flow and perfused hind limb preparation. Weanling male rats (8 weeks old, 180-200 g) were bilaterally orchidectomised or sham operated with or without testosterone replacement (Sustanon 250, 10 mg/kg intramuscularly once in 3 weeks) and placed on a normal (0.3%) or high (4.0%) NaCl diet for 6 weeks. The high-salt diet (HSD) increased arterial BP, renal vascular resistance (RVR) and positive fluid balance (FB). These changes were accompanied by decreased plasma nitric oxide levels. The increased BP, RVR and FB observed in the rats fed a HSD were reversed by orchidectomy while testosterone replacement prevented the reversal. Phenylephrine (PE)-induced increased vascular resistance in the perfused hind limb vascular bed was enhanced by HSD, the enhanced vascular resistance was prevented by orchidectomy and testosterone replacement reversed orchidectomy effect. Vasorelaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were impaired in HSD groups, orchidectomy attenuated the impairment, while testosterone replacement prevented the orchidectomy attenuation. These data suggested that eNOS-dependent and independently-mediated pathways were equally affected by HSD in vascular function impairment and this effect is testosterone-dependent in male Sprague-Dawley rats.

Testosterone reduces vascular relaxation by altering cyclic adenosine monophosphate pathway and potassium channel activation in male Sprague Dawley rats fed a high-salt diet.

OBJECTIVES: Male gender and high-salt diet are risk factors for hypertension. The effect of chronic exposure to testosterone is an increase in vascular tone but its influence upon responses induced by other vasoactive agents is not clear. We considered the possibility of interactions between testosterone and a high-salt diet in the mechanisms that are involved in the regulation of vascular tone. Therefore, we designed experiments to assess the involvement of the cyclic adenosine monophosphate (cAMP) pathway and potassium channel activation on vascular relaxation elicited by testosterone deficiency that was induced by orchidectomy in Sprague Dawley rats on a normal or high-salt diet. METHOD: Weanling male rats were randomly divided into eight groups (n = 6 each) that were either orchidectomized or sham operated with or without testosterone replacement (10 mg/kg body weight of Sustanon 250 intramuscularly, Organon, Holland) and were placed on a normal or high-salt (0.3% or 8% NaCl) diet, respectively, for 6 weeks. Arterial blood pressure was determined before and weekly throughout the experiment using the tail-cuff method. Relaxation responses to forskolin and diazoxide were studied in noradrenaline (0.1 µM) precontracted aortic rings. RESULTS: There was an increase in the systolic blood pressure of rats placed on a high-salt diet compared with control or orchidectomized rats. Orchidectomy elicited a reduction in the systolic blood pressure while testosterone replacement restored systolic blood pressure to values seen in intact rats. A high-salt diet reduced the relaxation response to forskolin and diazoxide but not in orchidectomized rats while testosterone replacement re-established the blunted relaxation response to forskolin and diazoxide. CONCLUSION: Inhibition of potassium channel or adenylyl cyclase activation appears to contribute to the mechanisms by which a high-salt diet increases vascular tone. These effects were counteracted by orchidectomy in male Sprague Dawley rats.