Sponsored by an educational grant from Solvay
While in women sex steroids substantially fluctuate as a function of ovarian cyclicity, in men testosterone (T) is relatively constant and high, allowing the male to be always ready to take advantage of sexual opportunities. Male sexual activity is characterized by a T-driven synchronization of sexual desire, arising in the brain, and its transmission to the periphery, allowing penile erection. The most important pathway underlying the penile erection is the nonadrenergic/noncholinergic signaling, which through the release of nitric oxide (NO), leads to an intracellular increase of cyclic GMP (cGMP), the main secondary messenger mediating tumescence in the penis. Interestingly, both cGMP formation and degradation are affected by testosterone (T). In fact, beyond to the well-known role of T in regulating sexual desire and NO release, recent experimental evidences, from our and other groups, showed that T also regulates the expression of phosphodiesterase type 5 (PDE-5), the hydrolytic enzyme involved in cGMP breakdown. This antithetic role of T seems to be the main way through which the peripheral hormonal regulation of penile erections occurs. Because T positively controls both the initiation (NOS) and the end (PDE-5) of the erectile process, its net effect on erection is null. Hence, erections are still possible in hypogonadal conditions where a decreased cGMP formation, due to impaired NO production, is counterbalanced by a reduced cGMP hydrolysis. The main action of T is therefore to timely adjust the erectile process as a function of sexual desire, therefore finalizing erections to sex. Restoring by TRT normal androgen levels in hypogonadal subjects has the main effect to transform a still possible erection in a sexual act. Another important aspect of TRT is to positively regulate penile PDE-5 expression, the main target of PDE-5 inhibitors (PDE-5i), an obligate step for their efficacy. Without PDE-5, PDE-5i are almost ineffective.
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