Androgens are essential for male sexual maturity. Testosterone regulates gonadotropin secretion and muscle development; dihydrotestosterone mediates all other aspects of male sexual maturation, including hair growth, acne, male pattern baldness, and spermatogenesis. In adults, androgen deficiency results in loss of sexual interest and impaired seminal emission. The frequency, magnitude, and latency of nocturnal penile erections are reduced. However, studies have shown that erection in response to visual sexual stimulation is preserved in hypogonadal men, suggesting that androgen enhances but is not essential for erection (_{Bancroft and Wu, 1983}).

In a longitudinal study of middle-aged men for 7-10 years, it was noted that total testosterone level declined at 0.8% per year of age, whereas both free and albumin-bound testosterone declined at about 2% per year. Sex hormone-binding globulin increased at 1.6% per year. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and prolactin rose longitudinally. The significance of these hormone changes in the pathogenesis of ED is not clear (_{Feldman et al, 2002}).

Neurotransmitters & Pharmacology of Erection

Neural control of penile erection involves the adrenergic, cholinergic, and nonadrenergic-noncholinergic (NANC) neuroeffector systems. Adrenergic nerves mediate intracavernous smooth-muscle contraction, which maintains the penis in a flaccid state. Cholinergic nerves may contribute to smooth-muscle relaxation and penile erection through (1) inhibition of adrenergic nerves via inhibitory interneurons and (2) release of nitric oxide (NO) from the endothelium by acetylcholine (_{Saenz de Tejada et al, 1988a}). The principal neurotransmitter for penile erection is NO from parasympathetic, NANC nerve terminals. Once blood rushes into the sinusoids, the shear stress can also release NO from endothelium to augment smooth-muscle relaxation and erection (_{Ignarro et al, 1990; Hurt et al, 2002}). In addition, oxygen tension (_{Kim et al, 1993}) and substances secreted by endothelium lining the sinusoidal spaces may also be involved in penile erection and detumescence. These include prostaglandins (_{Saenz de Tejada et al, 1988b}), endothelins (_{Holmquist, Andersson, and Hedlund, 1990}), and angiotensin (_{Becker et al, 2001}). The agents capable of inducing erection and causing detumescence are summarized in

Table 37-2. Although the actions of different agents vary, when given in large doses, all erection-inducing agents cause the smooth muscles to relax, and all detumescence-inducing agents cause them to contract.

Molecular Mechanism of Smooth-Muscle Contraction & Relaxation

Smooth-muscle contraction is regulated by Ca²⁺. When the cytosolic free Ca²⁺ increases from a resting level of 120-270 to 500-700 nM, calmodulin-4 Ca²⁺ complex binds to the myosin light-chain kinase (_{Murray, 1996}). The activated kinase then phosphorylates the light chain, which ceases to inhibit the myosin-actin interaction and initiates a contraction cycle.

When cytosolic free Ca²⁺ falls to the resting level, the Ca²⁺ dissociates from calmodulin, which in turn dissociates from the myosin light-chain kinase, thus inactivating it. Dephosphorylated myosin light chain resumes its action of inhibiting the binding of the myosin head to actin and relaxes the smooth muscle (_{Murray, 1996}).