Role of sex steroids and nitric oxide in male sexual function

Nitric oxide (NO) is the main final effector for penile erection achievement and maintenance in men and it constitutes a crucial target for therapeutical strategies addressed to the treatment of erectile dysfunction. The role of sex steroids penile NO pathway is still unclear, but some data suggest a positive role of androgens. In order to study the effects of sildenafil on human sleep- related erections according to the state of androgenization, we recently evaluated the effects of sildenafil (S) or placebo (P) on sleep-related erections in hypogonadal (H) men with very low testosterone levels: !200ng/dl (6.93nmol/L), before (HKT) and during (HCT) testosterone replacement treatment (T) and in control (C) subjects. Sleep-related erections were impaired in hypogonadal men before testosterone treatment (HKTCP) when compared with control subjects taking placebo (CCP). Testosterone alone (HCTCP) and sildenafil alone (HKTCS) restored normal sleep related erections, however, the combined treatment (sildenafil C testosterone) resulted in the maximum positive effect on sleep-related erections parameters. The effects of testosterone plus sildenafil resulted higher than the sum of the effects of both drugs used alone. Sildenafil administered at bedtime improves sleep-related erections in hypogonadal men, suggesting that the nitric oxide pathway may be pharmacologically enrolled and enhanced despite low serum testosterone. Furthermore, these data strongly support the idea of a synergic effect of sildenafil and testosterone on sleep-related erections. In clinical practice this concept is supported by the evidence that testosterone treatment restores sildenafil efficacy in subjects with erectile dysfunction and low to low-normal serum testosterone, who were non-responder to sildenafil alone. The combined treatment seems to be efficacious also in subjects with metabolic diseases such as diabetes mellitus. Whether or not estrogens are able to modulate NO pathway within the penile tissue remains to be ascertained in detail, but an androgen-estrogen cross-talk seems to be involved in the pathophysiology of male penile erection, but concerning estrogens dose-response and in vivo studies are lacking.