In 1999, over 1.2 million new cases of invasive cancer were diagnosed in the United States. More than half of these cases occurred in men. Over 80% of men afflicted with cancer consider future reproductive and sexual function to be a principal concern.
The surgical, chemotherapeutic, and radiation therapies used to treat cancer can adversely influence erectile and sexual function. Significant basic and clinical research performed in the past decade have led to a better understanding of the mechanism of erection at the organ, cellular, and molecular level. New directed developments in clinical research have led to effective local and systemic treatments for erectile dysfunction.
The pathophysiology of erectile dysfunction in cancer patients is often multifactorial, involving both psychogenic and physiologic mechanisms. In order to effectively treat erectile dysfunction in cancer patients, providers must understand the mechanism of erection and be familiar with the effects of a variety of treatment regimens. Such knowledge will enable clinicians to help the majority of patients resume a satisfying sexual relationship after treatment of their malignancy.
This article will provide an overview of the pathophysiology of erectile dysfunction, as well as outline useful treatment regimens. Effects of specific cancer treatments on male sexual function will be addressed as they relate to the pathophysiology of erectile dysfunction.
The erectile bodies of the penis are the paired corpora cavernosa located on the dorsal aspect of the penile shaft (Figure 1). Each corpus is covered by the relatively inelastic bilaminar tunica albuginea. The corpora are loosely separated in the midline by fibrous septa that permit cross-flow of blood between the two corpora.
The arterial blood supply to the cavernosal sinusoids is provided by cavernosal arteries that run through the center of each corpus. The cavernosal artery is a branch of the penile artery, which, in turn, is a branch of the internal pudendal artery. The cavernosal artery branches into a series of smaller helicine arterioles that provide arterial inflow to the caver-nosal sinusoids. Venous drainage of the sinusoids ultimately leads to small emissary veins that run under the tunica albuginea, draining to superficial veins on the exterior of the penile shaft.
Cavernosal smooth muscle cells surround the cavernosal sinusoids, which are lined by endothelial cells. When the penis is in a flaccid state (Figure 2), the cavernosal smooth muscle cells are contracted, which keeps the sinusoids collapsed.
The erectile cascade begins with a neural impulse triggered by local penile stimulation or activation from the central nervous system (CNS) during erotic sensation or stimulation. This impulse travels down spinal nerve routes S2-S4 to the penile nerves. The cavernosal branches of the penile nerves follow the anterolateral aspect of the prostate gland and enter each corpus.
When the nerve impulse reaches the corpora, it initiates the release of nonadrenergic, noncholinergic neurotransmitters. The principal neurotransmitter in the cavernosal smooth muscle is nitric oxide, which initiates and potentiates cavernosal smooth muscle relaxation. Once the cavernosal smooth muscle has relaxed, blood flow through the helicine arterioles increases, filling the cavernosal sinusoids (Figure 2). The expanding cavernosal sinusoids increase penile tumescence.
As the sinusoids fill with blood, the penile emissary veins become compressed against the tunica albuginea, thereby decreasing venous outflow. At a critical point, vascular inflow exceeds outflow and the penis becomes rigid. Detumescence occurs after ejaculation when cavernosal smooth muscle contraction is restored, decreasing sinusoidal inflow and increasing venous outflow.
The greatest advance in understanding the erectile cascade was the discovery of the molecular mechanism that initiates an erection. This discovery led to the development of directed pharmacotherapy to restore erections in men with erectile dysfunction. Multiple pathways ultimately lead to the release of intracellular calcium (Ca++) and cavernosal smooth muscle relaxation.
The principal metabolic pathway that causes cavernosal smooth muscle relaxation is mediated by the release of nitric oxide and the stimulation of the guanylate cyclase system (Figure 3). Guanylate cyclase converts guanosine triphosphate (GTP) to cyclic guanosine 3¢,5¢-monophosphate (cGMP) inside the cavernosal smooth muscle cell, and cGMP initiates the release of intracellular Ca++. Type 5 phosphodiesterase converts cGMP back to GTP and triggers the return of Ca++ into the cell, thereby causing smooth muscle contraction and detumescence.
Alternate pathways that can initiate intracavernosal smooth muscle Ca++ release include the adenylate cyclase system and separate inducible potassium (K+) channels. In addition to nitric oxide, vasoactive intestinal peptide and prostaglandin E1 act as nonadrenergic, noncholinergic neurotransmitters to initiate the erectile cascade.
Cavernosal smooth muscle contraction is enhanced by chronic alpha-adrenergic tone that maintains the penis in its flaccid state. Pharmacologic alterations in adrenergic tone may enhance or inhibit the erectile mechanism.
Erectile dysfunction is not a solitary entity, but rather, is a symptom of many different disease states. It is important to understand this concept when evaluating the multifactorial nature of erectile dysfunction in cancer patients, as well as when utilizing different regimens to effectively treat erectile dysfunction in a variety of patients. Several pathophysiologic mechanisms may be in effect in patients with cancer and in those who have received anticancer therapy. Breaking down the mechanism of erectile function into its component parts will facilitate an understanding of the pathophysiology of erectile dysfunction in cancer patients.
The neurologic mechanism involved in attaining or maintaining an erection can be adversely affected by cancer or its treatments. Central nervous system disease can alter the initiation of erection by inhibiting the erotic or erectogenic centers. Spinal cord impingement by tumor or peripheral nerve or nerve root involvement can prevent the transmission of a neural impulse to initiate the erectogenic cascade. Extirpative surgery, such as radical prostatectomy or abdominal perineal resection, can damage the cavernosal nerves as they transverse the surface of the prostate.
In cases in which the neural mechanism has been injured, the local mechanism for erection is intact, but the signal never reaches the corpora cavernosa. Pharmacotherapeutic agents that rely on an intact neural mechanism (ie, sildenafil(Drug information on sildenafil) [Viagra] or apomorphine(Drug information on apomorphine) [Britaject]) will be far less effective in patients whose pelvic nerves have been injured. Locally acting agents (ie, intracavernosal injections or transurethral therapy) can be highly effective in such cases and may be used in lower doses because of the hypersensitivity that develops in cases of nerve injury.
Erection is principally a vascular event. Disease processes that adversely affect penile blood flow are the most common causes of erectile dysfunction. Arteriogenic erectile dysfunction is usually a small-vessel disease (atherosclerosis), but a large pelvic tumor can also inhibit penile blood flow. Diabetes mellitus can contribute to erectile dysfunction by accelerating small-vessel disease; local diabetic neuropathy may also play a role.
Anticancer therapy can cause vasculogenic erectile dysfunction by limiting penile blood flow and damaging the pudendal or penile arteries. The cavernosal arteries are less than 1 mL in diameter and can be easily injured by pelvic or perineal surgery. Arteriosclerosis is also accelerated by radiation therapy. Small-vessel disease and cavernosal smooth muscle injury can be caused by pelvic or perineal ionizing radiation. Erectile dysfunction occurs in over 90% of patients receiving pelvic irradiation.
Veno-occlusive dysfunction is a term to describe failure of the passive venous outflow obstructive mechanism. In patients with this condition, arterial inflow is adequate, but the sinusoids fail to trap blood.