The molecular science of erection physiology has established that
phosphodiesterase 5 (PDE5) serves an important biological role in the penis. Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory
nitric oxide (NO) signaling pathway, 3', 5'-cyclic
guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered
PDE5 inhibitors such as
sildenafil,
tadalafil, and
vardenafil comprise a foremost intervention for
erectile dysfunction (ED). New investigation of PDE5 regulation in the penis has suggested alternative roles for the
enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of
androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of erectile disorders including
hypogonadism-associated ED, recurrent ischemic
priapism, penile vasculopathy, and penile
fibrosis. This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying existing and emerging therapeutic strategies for erectile disorders.