Do androgens play a beneficial role in the regulation of vascular tone? Nongenomic vascular effects of testosterone metabolites

Abstract

The marked sexual dimorphism that exists in human cardiovascular diseases has led to the dogmatic concept that testosterone (Tes) has deleterious effects and exacerbates the development of cardiovascular disease in males. While some animal studies suggest that Tes does exert deleterious effects by enhancing vascular tone through acute or chronic mechanisms, accumulating evidence suggests that Tes and other androgens exert beneficial effects by inducing rapid vasorelaxation of vascular smooth muscle through nongenomic mechanisms. While this effect frequently has been observed in large arteries at micromolar concentrations, more recent studies have reported vasorelaxation of smaller resistance arteries at nanomolar (physiological) concentrations. The key mechanism underlying Tes-induced vasorelaxation appears to be the modulation of vascular smooth muscle ion channel function, particularly the inactivation of L-type voltage-operated Ca(2+) channels and/or the activation of voltage-operated and Ca(2+)-activated K(+) channels. Studies employing Tes analogs and metabolites reveal that androgen-induced vasodilation is a structurally specific nongenomic effect that is fundamentally different than the genomic effects on reproductive targets. For example, 5alpha-dihydrotestosterone exhibits potent genomic-androgenic effects but only moderate vasorelaxing activity, whereas its isomer 5beta-dihydrotestosterone is devoid of androgenic effects but is a highly efficacious vasodilator. These findings suggest that the dihydro-metabolites of Tes or other androgen analogs devoid of androgenic or estrogenic effects could have useful therapeutic roles in hypertension, erectile dysfunction, prostatic ischemia, or other vascular dysfunctions.

Fig. 1.

Genomic and nongenomic mechanisms of action of androgens in the vascular smooth muscle (VSM) cell. a: Endothelium-dependent mechanisms, presumably involving endothelium-derived relaxing factors, particularly nitric oxide (NO), would seem to be responsible for the relaxing effect of testosterone (Tes) at physiological (<100 nM) but not at supraphysiological or pharmacological (>100 nM) concentrations. The incremental increase in cGMP reflects NO production, which induces vasorelaxation. Likewise, Tes and its metabolite 5β-dihydrotestosterone (5β-DHT) at pharmacological concentrations (>10 μM) induce endothelium-independent relaxation. b: Tes shares the same molecular target as the dihydropyridines [the α_1C-subunit of L-type Ca²⁺ channels; voltage-operated Ca²⁺ channel (VOCC)] to elicit a powerful and direct channel blockade at physiological concentrations (36 nM) (17, 58, 59), restricting extracellular Ca²⁺ entry and diminishing intracellular Ca²⁺ concentration ([Ca²⁺]_i) in the VSM cell to induce vasodilation (relaxation). 5β-DHT, a much weaker androgen than Tes, is a pure VOCC blocker at a broad range of concentrations (from nanomolar to micromolar) (41). c: Tes but not 5β-DHT, at pharmacological concentrations (above 1 μM), activates VOCCs, increasing extracellular Ca²⁺ entry and increasing [Ca²⁺]_i to induce vasoconstriction (contraction) (41). d: Tes at supraphysiological concentrations (>100 nM) activates voltage-operated K⁺ channels or large-conductance Ca²⁺-sensitive K⁺ channels, increasing K⁺ efflux to induce VSM hyperpolarization and vasorelaxation (8). e: Tes but not 5β-DHT at pharmacological concentrations (>30 μM) is capable of increasing cGMP and cAMP production (8, 41). f: Genomic actions of Tes and 5α-DHT are mediated by the cytosolic androgen receptor (AR). 5α-DHT has the highest affinity for the AR and mediates many androgenic effects, whereas 5β-DHT has little affinity and is without biological effects (14).

Fig. 2.

Metabolic pathways of androgens. Tes can be bioconverted into 17β-estradiol via the enzyme P-450-aromatase or into its immediate 5-reduced dihydro-metabolites: 5α-DHT (via the enzyme 5α-reductase) and 5β-DHT (via the enzyme 5-β-reductase). Subsequently, these dihydro-androgens undergo a 3α- or 3β-hydroxylation via the enzymes 3α- or 3β-hydroxysteroid dehydrogenase (HSD) to produce the tetrahydro-androgens (3α,5α-; 3β,5α-; 3α,5β-; and 3β,5β-reduced metabolites). Note the 3-dimensional conformation of the androgen molecules: Δ4,3-keto structure (Tes), 5α/trans-conformation (5α-reduced metabolites), and 5β/cis-conformation (5β-reduced metabolites). These molecular conformations reveal that minor changes in the orientation of C₅ in the A-ring can result in major changes in the efficacy and potency of nongenomic vascular effects of the androgen molecule (e.g., 5α-DHT vs. 5β-DHT; see text for details).