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PHYSICAL CAUSES OF ERECTILE DYSFUNCTION

The enjoyment of sex, although great/Is in later years said to abate/But how would I know?/I’m only seventy-eight. Anonymous

To recognize erectile dysfunction (ED) and understand its causes, it is important to remember that penile erection is a continuous neurovascular phenomenon under psychological control and requires a proper hormonal milieu for its successful achievement. Recall these physiological mechanisms of erection, described previously: under sexual stimulation, impulses from the parasympathetic and nonadrenergic/noncholinergic (NANC) nerves cause the release of nitric oxide (NO, also possibly secreted from the penile vessels’ endothelial cells). NO enters the smooth muscle cells inside the vessels in the corpora cavernosa, where it stimulates the enzyme guanylate cyclase to produce cyclic guanosine monophosphate. This activates the enzyme protein kinase G to phosphorylate (add a phosphate group) to certain proteins that are responsible for regulating the tone of the smooth muscles in the corporeal arteries and sinuses, thereby contributing to the relaxation of those vessels and the consequent inrush of blood to the penis.

By extension, you can see that any disease, injury, or disorder affecting the brain, nervous system, vascular system, endocrine system, smooth muscle of the corpora, tunica albuginea, neurotransmitters, or genitourinary system can lead to a man’s inability to obtain or maintain a firm or rigid erection for enough time to ensure sexual gratification for himself or his partner. It may also lead to his disinterest in sexual activity. (Most men may experience some difficulty in achieving and maintaining an erection at some point in their lives; such transient episodes should not be considered a sign of ongoing ED (Lewis R et al. 2004, Lue TF 2004b, Shabsigh R et al. 2005a).

PATHOPHYSIOLOGY

The wide range of organic causal factors of ED may be categorized into four general types of conditions:

  1. The inability to pump enough blood inside the penis, due to arterial disease, is the most common organic cause of ED, with an incidence of about 40%.
  2. Neurologic conditions can prevent the penile nerves’normal secretion of the neurotransmitters that relax the penile arteries and sinuses or can decrease sensation in the penile nerves, thereby precluding activation of the erectile process. (Montorsi F et al. 2003)
  3. Leakage of blood from abnormal penile veins during erection prevents the storage of blood inside the penis for a sufficient period. This leakage can be due to any pathology of the tunica, poor relaxation of the vascular sinuses, or fibrosis of the smooth muscle in the corpora.
  4. Any medical condition that affects the penile arteriogenic system can lead to its failure to dilate and fill with a large volume of blood under high pressure.

Several medical conditions are clearly associated with an increased risk of ED. One report, for example, shows the following high prevalences: ED occurs in 52% of men with hypertension, 55% of men with urinary tract symptoms, 61% of men with ischemic heart disease, 64% of men with diabetes, 86% of men with peripheral vascular disease, and 90% of men with depression (Carson CC et al. 2006). This chapter details the various major risk factors associated with ED.

AGING

It is well accepted that ED’s prevalence and severity increase with advancing age. Men over the age of 50 are usually afflicted by various organic conditions, including cardiovascular disease (CVD), diabetes, hypertension (high blood pressure), hypercholesterolemia (high cholesterol), and low testosterone; lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH); chronic neurologic conditions such as parkinsonism, stroke, and Alzheimer’s; and psychological disorders such as depression and anxiety. Any of these, as well as the use of multiple medications, may contribute to ED. About 48% of men over 50 are affected by different degrees of ED due to physical, intrapsychic, and relational factors (Corona G et al. 2004)—but this does not mean that sexual dysfunction is an inevitable consequence of aging. In the majority of men over 50, sexual interest and desire remain strong.

A specific major risk factor for ED in men 50 and older is atherosclerosis of the pudendal and cavernosal arteries. This involves the formation of plaques in the arterial walls, gradually obstructing the lumen (the open space for blood flow). Atherosclerosis can be secondary to diabetes, hypertension, and hypercholesterolemia as well as to smoking. Atherosclerosis may lead to pathological changes such as penile smooth muscle degeneration and replacement by fibrous tissue, with reduced expandability of the corpora cavernosa, leading to venous leakage (Montorsi F et al. 2003).

Prostate problems are another specific risk factor in the aging male. Several recent studies confirmed a close association between sexual dysfunction— namely, ED, ejaculatory incompetence, hypoactive sexual desire, and painful ejaculation—and moderate or severe LUTS secondary to the BPH that commonly occurs in over 50% of men after age 50. In some cases, treatment with certain alpha-blockers, Viagra, or Cialis has improved both the urinary and sexual symptoms. ED, ejaculatory problems, and LUTS may all stem from sympathetic nervous system overactivity, prostate infection or inflammation, vascular disorders in the penis and prostate, or a deficiency of NO. Typical prostate symptoms are pain in the pelvis, suprapubic area, perineum, inguinal area, scrotum, lower abdomen, and back as well as other BPH-associated symptoms such as burning on urination, frequency and/or urgency of urination, and slow urine stream.

Normal age-related physiological changes are often falsely interpreted as sexual dysfunction, when they may actually require no more than full understanding by the man and his partner and a readjustment in sexual techniques. Natural changes in a healthy man’s sexual functioning with age include the following:

  • A progressive decline in free testosterone level, caused by a decreased testicular production of testosterone, which may affect erectile and orgasmic function and decrease libido.
  • A need for more genital stimulation to elicit erection, caused by a decreased sensitivity of the penis to touch and vibration and an increased conduction time of the nerve impulses.
  • A need for more time to develop an erection, caused hy a loss of elasticity in the penile arteries and sinuses and possibly hy a decline in autonomic nervous system function.
  • A decrease in the hardness of the penis during erection, hut with rigidity still adequate for penetration and successful intercourse, and no change in the circumferential increase of the erect penis.
  • An increased time from excitation to ejaculation and a need to wait hours or even a few days before being able to develop a second erection.
  • A decline in the intensity of orgasm.
  • A decrease in the volume of ejaculated semen, caused mainly hy atrophy of the prostate and seminal vesicular glands due to low serum testosterone (some older men may even stop ejaculating any semen at all, despite having good orgasms).
  • A reduction in the number, duration, and quality of spontaneous erections during sleep, perhaps due to a decrease in required total sleep time.

With the physical and mental slowing that usually accompanies aging, men can experience a loss of self-esteem, severe anxiety, depression, stress, and a sense of inadequacy. These feelings, when not appropriately counteracted by coping mechanisms, may lead to psychogenic sexual inadequacy. A lack of sexual interest on the part of their partners (perhaps suffering from sexual disturbances themselves) also contributes to some men’s ED. In elderly men, relational problems, partner unavailability or unreceptiveness, and psychogenic disturbances such as depression, stress, or anxiety may play important causal roles in ED.

It is a misconception and a cruel myth that a man over the age of 60 cannot (or should not) function sexually. Older men need as much affection, love, understanding, tenderness, and privacy as younger men do, and perhaps more. Several studies have demonstrated that over 65% of men and women over the age of 65 are still interested in sex and are sexually active. They should be encouraged to express their sexual needs and to enjoy a fulfilling sex life without any feeling of shame or guilt. (When a sexual partner is not available, masturbation can be used to relieve sexual tensions.) It has been reported that the number of sexual encounters declines by about 75% between the ages of 30 and 65 but also that the majority of men over 60 report having regular sexual intercourse.

On the other hand, men over 60 certainly have a higher incidence of erectile failure than younger men. About 40% to 70% of men aged 40—70 complain of sexual dysfunction, with a marked decrease in frequency of sexual events after age 50. Causes of ED in this age group may include low free serum testosterone and vascular, hormonal, neurologic, psychological, and social factors. It is estimated that, despite reported sexual desire in more than 50% of males over the age of 80, less than 15% engage in sexual intercourse because of erectile failure.

A sexual and medical history and a physical examination are needed to elucidate the true nature of whatever sexual dysfunction a man may experience later in life, whether his major complaint is decreased libido, ejaculatory or orgasmic disturbance, or an erectile problem. Vascular, neurogenic, hormonal, and psychogenic factors must be assessed (and excluded) by specific testing. Therapy can then be tailored to the underlying cause of the dysfunction.

CARDIOVASCULAR CAUSES

Any severe narrowing, hardening, or clogging of the aorta, iliac vessels, and tributaries, or the penile arteries and sinuses, may result in sexual dysfunction. Vascular disease is the most common organic cause of ED, with a prevalence of about 40% of all organic factors.

About 17% of men with ED suffer from atherosclerosis, a clogging of the arteries with yellowish plaques containing cholesterol, lipoid (fatty) material, and lipophages (cells that absorb fat), which can lead to the partial or total obstruction of blood vessels. This common condition is usually associated with smoking, hyperlipidemia (elevated concentrations of any or all lipids in the blood, including cholesterol and triglycerides), obesity, and diabetes. The diminished blood flow in the penile arteries and sinuses prevents the engorgement and tumescence of the penis. It may also cause venous leakage because of poor compression of the venules against the tunica, secondary to contracted vascular sinuses.

Furthermore, a direct correlation has been found between CVD and ED (Montorsi F et al. 2006). The sexual problem may be the first sign of the presence of an occult (hidden) cardiac condition, such as ischemic heart disease, and may antedate its other clinical manifestations for months or years. This is why the penis is called the “body’s barometer” of vascular integrity. The close correlation between ED and other vascular pathology has prompted some physicians to suggest a complete cardiovascular workup for any man suffering from ED, especially if he has risk factors such as smoking, diabetes, hypertension, obesity, and hyperlipedemia.

Patients with single-vessel ischemic heart disease have better erections than those with multiple-vessel obstruction. Furthermore, men with cavernous arterial insufficiency have a significantly higher risk of developing coronary arterial disease (CAD; Speel TG et al. 2003). Other atherosclerosis-associated factors, such as reduced endothelial NOS (nitric oxide synthase, an enzyme which converts L-arginine and oxygen to produce nitric oxide), increased levels of free radicals, and high concentration of homocysteine in the vascular plaques, may contribute to ED (Kendirci M et al. 2005). Strong recent evidence suggests that depletion of NOS from the nitrergic nerves (the NANC nerves in the penis that secrete NO) may also contribute to sexual dysfunction. Other CVDs, such as congestive heart failure and aortic aneurysm (formation of an abnormal sac in the aorta’s wall), may be associated with ED.

A recent study analyzed the incidence of extragenital vascular disease in 457 patients with ED, based on echo Doppler ultrasound studies of penile arteries and carotid or lower-leg vessels suspected to contain atherosclerotic plaques. The researchers found isolated penile artery insufficiency in about 25% of the ED patients and combined penile, carotid, and lower-extremity atherosclerosis in 75% of the cases (Vicari E et al. 2005), again demonstrating a close relationship between vascular changes in the penile arteries and other arteries in the body.

In a recent Italian study, number of diseased coronary arteries, age, and diabetes were found to be independent factors in ED; ED, in turn, was associated with a fourfold risk of having CAD, as diagnosed by coronary angiography independently of other recognized risk factors. ED is frequently found in men with acute coronary syndromes and can be considered a sign of diffuse and/or coronary atherosclerosis (Montorsi F et al. 2006).

In another study, the most common vascular risk factor for the development of ED was smoking, followed by obesity and hypertension. The poorest blood flow and arterial insufficiency parameters were found in those men with ED who also had CAD (40% of the group), followed by those who also had diabetes (23.3%). Venous occlusive disease was observed in hypertensive patients (36.5%). The odds of having abnormal blood flow parameters increased with the number of vascular risk factors (Kendira M et al. 2006).

NEWSFLASH: ERECTILE DYSFUNCTION, CORONARY ARTERIAL DISEASE, AND CARDIOVASCULAR DISEASE

The association of erectile dysfunction (ED) with subsequent coronary arterial disease (CAD) in 9,457 men over 55 was reported by Thompson et al. (2006) at the American Urological Association’s 2006 annual meeting. At the start of the study, ED was noted in 57% of the men. At five-year follow-up, 11 % of the men with ED had experienced a cardiovascular disease (CVD) or cardiac event such as angina; myocardial infarction; high serum low-density lipoprotein, or LDL; cerebrovascular accident; or congestive heart failure. Therefore the hazard ratio (increased odds of acquiring a particular disease, expressed as a numeral above the normal value of 1) for CVD was 1.30 for the men with ED. The study’s authors advocate prompt investigation and intervention for men with ED who also have risk factors for CAD or CVD.

As discussed earlier, a venous leak during erection means that blood that should normally remain trapped in the penis until detumescence (loss of erection) actually escapes at the beginning of an erection or soon after its development, resulting in ED. This may be caused by leakage of blood through congenitally abnormally large veins; dysfunction or injury of cavernous smooth muscle secondary to trauma, diabetes, or atherosclerosis; or tunica albuginea weakening due to aging or Peyronie’s disease. Other neurogenic and psychogenic disorders that cause inadequate neurotransmitter release may also contribute to venous leakage, as can smoking, hypertension, high cholesterol, or an intrinsic pathology affecting the smooth muscles of the corpora. Venous leakage may be considered one of the major causes of ED, with an incidence of about 65% among men with ED.

A substantial number of men complain of unsustained erections; although they may develop a good erection, they lose it quite rapidly, often too soon for intercourse to be successful. Some of these men have a venous leak. This is in contrast to men whose ED is caused by insufficient arterial blood inflow. These men usually take a longer time to develop erections, and then, if they do achieve erections at all, they lose them more slowly. A combination of venous leakage and arterial disease is suspected in men who develop erections slowly and lose them rapidly.

To summarize, vasculogenic factors are the most common cause of organic ED. These include hardening or occlusion of the extrapenile arteries or the intrapenile vessels, hypertension, cholesterol (high levels of low-density lipoprotein, or LDL, or low levels of high-density lipoprotein, or HDL), or diabetes as well as pelvic trauma, surgery, or radiation therapy. Impaired erectile hemodynamics are reported in men with myocardial infarction (MI), coronary bypass surgery, peripheral vascular disease, cerebrovascular accident (CVA), and hypertension. The incidence of ED is about 60% in cases of MI and coronary bypass and about 10% in cases of untreated hypertension. The combination of risk factors such as diabetes, vascular diseases, hypertension, and smoking significantly increases the incidence of ED. Furthermore, as mentioned, the penis may serve as the main barometer of vascular endothelial anomalies in the rest of the body, and the occurrence of ED may herald the future development of CVD.

DIABETES MELLITUS

Some 30% to 75% of men with diabetes complain of ED, and conversely, statistics show that about one out of four men with ED has diabetes; in fact, a finding of ED may even lead to the initial discovery of a man’s diabetes. In one study, ED was the first sign of diabetes in 12% of the study group, and 50% of the diabetics developed ED within 10 years of their diabetes diagnosis (Kaiser FE, Korenman SG 1988; Israilov S et al. 2005; De Berardis 2007).

Sexual dysfunction in diabetics has been found to be age-dependent, with ED affecting 15% of those aged 30—34, versus about 55% of 60-year-old diabetics (Whitehead ED, Kyde BJ 1990, De Berardis G et al. 2007).Type 2 diabetes, which usually occurs in older people and is due to insulin resistance, is associated with a higher incidence of ED than the hereditary type 1. A recent study covering 401 men with ED followed for a period from nine years, from 1987—1989 to 1995—1998, up to 15 years (2002—2004), with no treatment, in the Massachusetts Longitudinal Aging Study revealed some interesting and unexpected findings. While about 33% of men with minimal or moderate ED exhibited ED progression, about 32%, 14%, and 31% of men with minimal, moderate, and complete ED, respectively, recovered full sexual potency. Weight loss, cessation of smoking, and improvement of overall health were the most important factors involved in the remission of ED and/or delaying its progression (Travison TG et al. 2007).

Diabetes-associated ED may be multifactorial, with both organic and psychogenic causes. Among the most important organic factors in these cases are the following:

  • Vascular disease with atherosclerosis that may be associated with diabetes; such a condition could lead to the obstruction or narrowing of the penile arteries or to a venous leak.
  • A recent experimental study revealed that impairment of NOS, the principal enzyme responsible for the synthesis of NO in the endothelial cells in the penile vessels, may represent a major cause of diabetic sexual dysfunction.
  • Other important factors in diabetes-associated ED are neuropathies, which means that the nerves of the penis and their secretion of neurotransmitters may be adversely affected by the disease.

Some sexually dysfunctional diabetic men may suffer primarily from a deficiency of testosterone or from major psychogenic disturbances. A recent study demonstrated a strong link between ED, sensory neuropathy, and decreased sexual desire independent of age in some diabetics with ED. This suggests that psychogenic factors may have marked influence in cases of diabetic ED (Nakanishi S et al. 2004).

Recent electron microscope studies in diabetic men with ED revealed pathologic changes in the nerves and smooth muscles of the cavernous tissue and penile arteries. Impaired smooth muscle relaxation in the corpora cavernosa was demonstrated in cases of ED by researchers at Boston University Medical Center. In addition, recent studies indicate that diabetes and high cholesterol may prevent full relaxation of the trabecular smooth muscle in the penile vascular sinuses, with clogging of small intrapenile arteries in the cavernous tissue, which may lead to ED.

Additional causes of ED in men with diabetes include blood hypercoagulability, secretion of vasoconstrictive substances, and replacement of smooth muscle by collagen in the corpora. Recent studies have discovered new etiologic factors that may play a major role in the sexual impairment of diabetic patients, including endothelial dysfunction, oxidative stress, neuropathy, and structural changes (Kendirci M et al. 2005).

In diabetics, increased activity of the RhoA/Rho-kinase pathway, which regulates NOS expression from the endothelial cells and also functions in the corpora cavernosa, may inhibit NO production. Overproduction of advanced glycation end-product in diabetics may also decrease the production of NO. Overproduction of reactive oxygen radicals, which can cause neurovascular deficits, and overaction of the protein kinase C pathway (involving an enzyme of the transferase class that helps produce enzymes and proteins by phosphorylation inside the cells) have also been suggested as possible causes of diabetic ED (Kendirci M et al. 2005).

Other endocrine diseases that may contribute to ED include hypogonadism, hypo- and hyperthyroidism, adrenal disorders, and hyperprolactinemia (see the following section on endocrine and hormone factors).

THE METABOLIC SYNDROME AND ERECTILE DYSFUNCTION

The metabolic syndrome was defined by a National Institutes of Health expert panel in 2001 and is characterized by the following clinical findings:

  • Waist circumference greater than 40 inches or 100 centimeters
  • Systolic blood pressure over 130 millimeters of mercury (mmHg; generated pressure that pushes a column of mercury up a tube from 0 to 200 mm high) and diastolic blood pressure over 85 mmHg; or the use of antihypertensive medications
  • HDL cholesterol less than 40 milligrams per deciliter; or the use of lipid-lowering medications
  • Self-reported diabetes
  • Triglycerides of more than 150 milligrams per deciliter

Metabolic syndrome has been demonstrated to be a precursor of cardiovascular disease (CVD), and it was found in 43% of the erectile dysfunction (ED) population, as opposed to about 24% of a matched population with an increased incidence of insulin resistance. Its early detection in younger men with ED but with no other clinical symptoms may reduce their risk of future endothelial dysfunction and CVD (Bansal TC et al. 2005). A recent study confirmed these findings and demonstrated that ED was predictive of the occurrence of the metabolic syndrome in men with a body mass index (BMI) of less than 25. This important finding emphasizes that ED could provide an early warning sign and the opportunity for early therapeutic intervention for aging men with ED who are considered, due to their low BMI, to be at higher risk of developing metabolic syndrome and subsequent CVD (Kupelian V et al. 2006a).

NEUROGENIC FACTORS

Neurologic conditions are causal factors in about 10% to 20% of ED cases. Various diseases and disorders may affect the brains sex centers or other parts of the nervous system such as the hypothalamus, pituitary gland, spinal cord, and peripheral nerves supplying the penis, all of which play important roles in sexual development and function (see chapters 3—4). Brain lesions, for example, may disturb the secretion of vital neurotransmitters, such as dopamine and oxytocin, and inhibit the transmission of neural impulses from the sex centers to the penile nerves via the spinal cord. Causes of such lesions include stroke, Alzheimer’s disease, tumor, epilepsy, CVA, infection, parkinsonism, multiple sclerosis (MS), and trauma.

Spinal cord lesions caused by conditions such as injury, tumors, infections, MS, diabetic neuropathy, herniated disk, and neurosyphilis may be associated with loss of psychogenic and possibly reflexogenic erections as well as absence of sexual pleasure, orgasm, and ejaculation. These problems are due to disturbed transmission of sensory impulses from the penis to the brain and motor stimuli from the brain to the penis. The severity of the dysfunction depends on the level and extent of the lesion, particularly in relation to the secondary sex center in the sacral spine. Any pathology involving the sacral sex center leads to the absence of both reflexogenic and psychogenic erections. Trauma to the pelvic or penile nerves, by disrupting passage of neural impulses to and from the penis, can cause sensation loss and ED.

In cases of spinal cord injury, it has been reported that about 70% of paraplegics or quadriplegics are sexually active and that about 70% of them practice alternate forms of sexual expression such as oral or genital stimulation. One study found that reflexogenic erections were present in about 95% of patients with spinal injuries above the sacral vertebrae, and that psychogenic erections were maintained in about 25% of patients with partial sacral injuries. Although erectile ability was preserved in about 90% of those patients with incomplete lesions, those erections were generally unpredictable and brief, with poor ejaculation, precluding normal sexual functioning.

HYPERTENSION

Several recent epidemiologic studies confirmed the correlation of hypertension and ED. In the past, it was estimated that about 8% to 10% of patients with untreated hypertension suffered from ED when first diagnosed with high blood pressure. More recent studies, however, have reported much higher prevalences, ranging from 26% to 41% (Rosen RC et al. 2004; Seftel AD et al. 2004). Hypertension may damage the NO-secreting vascular endothelium of the penile arteries or alter the composition of the tissue in the corpora cavernosa, leading to increased size and proliferation of the smooth muscles, increased inelastic collagen and fibrosis, and hyperactivation of the sympathetic nervous system. This may impair the ability of the penile vessels to relax and dilate to accommodate the high volume of blood necessary for erection.

Furthermore, a low level of serum testosterone, which is observed in some young hypertensive males, may alter the secretion of NO in the penile tissue, impair the responsiveness of the tissue to its action, or contribute to sexual dysfunction through the anxiety and fear it generates in the afflicted person. As an unfortunate side effect of treatment, some antihypertensive drugs, such as diuretics and certain beta-blockers, can decrease libido and exacerbate sexual dysfunction. This occurs when the drug causes a constriction of the penile arteries or when it has an antiandrogenic effect, affecting sexual desire and the ability to develop firm erections.

MEDICATIONS, DRUGS, AND ALCOHOL

Medications may represent ED’s most common etiology, with an incidence of about 25%. The general categories of these drugs include the following:

  • Antihypertensives
  • Antiarrhythmics
  • Antidepressants
  • Antipsychotics
  • Cholesterol-lowering drugs
  • Anabolic steroids
  • Anticonvulsants
  • Chemotherapeutics
  • Tranquilizers
  • Diuretics (for water elimination)
  • Cardiac drugs (such as digoxin)
  • Anticholinergics (nerve impulse blockers)
  • Peptic ulcer drugs (such as cimetidine)
  • Antiandrogens (such as estrogens)
  • Antidepressants
  • Narcotics
  • Some barbiturates and antihistamines

Several prescription medications adversely affect male potency, with some resulting in decreased sex drive and/or loss of erectile ability. The most common are antihypertensive drugs such as beta-blockers, diuretics, calcium channel blockers, and those acting centrally on the brain; some sedatives; GnRH (Gonadotropin releasing hormone) agonists used to treat advanced prostate cancer; 5-alpha reductase (Proscar or Avodart) for BPH treatment; and female hormones and antiandrogens. Among other medications associated with ED are H2 antagonists used for peptic ulcer, selective serotonin reuptake inhibitors and some other antidepressants, amphetamines, antiepileptics, and antipsychotics (Lobo JR, Nehra A 2005).

Certain over-the-counter drugs—for example, chronic use of vasoconstricting nasal decongestants—have been implicated in the development of sexual dysfunction. Use of illicit drugs (marijuana, cocaine, etc.) can cause ED as well. Small amounts of cocaine may produce sustained erections and delayed ejaculation, but chronic use of cocaine and/or opiates may lead to sexual dysfunction.

As for alcohol, minimal or moderate consumption may increase sexual enjoyment in about 45% of men and about 70% of women. Sexual arousal with alcohol consumption is usually affected by the individual’s beliefs regarding alcohol’s effect. However, chronic alcoholism, or even simply drinking large quantities of alcohol, may lead to ED, with decreased serum testosterone and increased female hormones. It may block the release of the pituitary and testicular hormones and affect the metabolism of the female hormone estrogen (in the form of estradiol) in the liver.

ENDOCRINE AND HORMONE FACTORS

As noted earlier, testosterone influences the development of the male’s reproductive system and secondary sexual characteristics. It is needed, especially in its free, or bioavailable, form in the serum, by most males for sexual arousal and proper functioning of the sex organs. It also regulates the secretion of neurotransmitters from the sex centers in the brain and spinal cord and possibly the secretion of NO in the corpora (see chapter 16). Testosterone’s involvement in erection and ED, however, is still a subject of controversy.

Experimental and clinical data show that an appropriate hormonal milieu (primarily testosterone) plays an active role in maintaining normal sexual functioning. Recent clinical studies measuring total testosterone levels demonstrate that about 5% of men complaining of ED may have low hormonal levels, while about 18% may have low levels of free testosterone (Martinez-Jabaloyas JM et al. 2006). Although testosterone is thought to facilitate erection by dilating the penile arterioles and vascular sinuses, its effect on the production of ED is still controversial (Mikhail N 2006). Elevated serum prolactin, a pituitary hormone, may cause almost 6% of ED cases and is usually associated with low testosterone. Hyper- or hyposecretion of thyroid hormones may cause sexual dysfunction as well.

The Massachusetts Male Aging Study (MMAS) assessed the impact of sex hormones on ED in 1,519 men, aged 40-70, at baseline. There was no association between total testosterone, bioavailable testosterone, and serum hormone-binding globulin (SHBG) with ED. Only increased levels of luteinizing hormone were associated with increased risk of ED, which may indicate a relationship between ED and testicular function independent of testosterone levels (Kupelian V et al. 2006b).

In certain cases, however, the major effect of decreased serum testosterone is reduced sex drive. Men who have everything intact but who have a decreased free testosterone level often get a sexual boost from a resupply of the hormone. Some older men with low serum testosterone and ED, however, may not respond to intramuscular testosterone injection. This is because most of the injected hormone binds to blood proteins such as SHBG, decreasing the free portion that can act on the tissues or causing a rapid increase in serum testosterone within 72 hours that gradually decreases over the next two to three weeks. Nowadays, optimal replacement that normalizes serum testosterone within 24 to 72 hours is achieved with patches, gel, mucoadhesive tablets, and some oral tablets.

Testosterone injections sometimes restore erectile ability in eunuchs, or in males who lost their testicles before puberty (before their bodies had manufactured testosterone for any great length of time) as well as in castrated men who lost their testicles postpuberty (after a much longer period of testosterone production). Although some castrated men may occasionally obtain and maintain adequate erections without supplemental testosterone, most do not.

As another important part of a healthful hormonal milieu, thyroid hormones can also affect sexual function and dysfunction. Excessive production of these hormones by thyroid gland overactivity (hyperthyroidism), or deficiency of these hormones due to thyroid gland underactivity (hypothyroidism), can lead to ED, loss of sexual desire, and ejaculatory disturbances.

SURGERY

In both male and female patients, surgery on the pelvis, rectum, or internal genitalia contribute to postoperative sexual dysfunction at incidences ranging from 8% to about 32%, depending on the type of surgery. Bilateral orchiectomy (removal of the testicles) for the treatment of advanced prostate cancer may cause ED by lowering testosterone to castrated levels. The nerves and blood vessels that contribute to the erectile process may be severed or injured in other surgical procedures such as retroperitoneal (beneath and behind the abdominal cavity) operations for abdominal aneurysm (an abnormal bulge in an arterial wall), aortoiliac bypass, or spinal cord surgery; radical prostatectomy (total removal of a cancerous prostate; used to treat early-stage prostate cancer, when the malignancy is usually confined to the prostate); simple prostatectomy for BPH; external sphincterotomy (surgical cutting of a sphincter muscle) for neurogenic bladder (secondary to spinal cord injury, stroke, or tumor); or radical surgery for bladder or rectal cancer.

In the particular case of radical prostatectomy, the incidence of postoperative ED varies from 20% to 100%, depending on the patient’s age and presurgical erectile capabilities, the surgical preservation of the nerves that supply the penis, and the surgeon’s experience. Furthermore, some patients may develop postoperative urinary incontinence during orgasm, which may cause them embarrassment and may make them shun any sexual encounter.

Other factors that may influence the return of normal erections after radical prostatectomy include use of phosphodiesterase drugs such as Viagra, Cialis, or Levitra, use of prostaglandin El injections or intraurethral inserts, or a combination of these medications, starting about four weeks after surgery; adequate sexual desire and interest in sex on the part of the patient; availability and willingness on the part of his sexual partner to engage in intercourse; and lack of anxiety, depression, or other psychogenic disturbances. At follow-up with patients 24 and 48 months after bilateral nerve-sparing surgery, erectile recovery ranged from about 32% to 80% (with or without pharmacological therapy).

PHYSICAL TRAUMA

Trauma to the pelvic or penile nerves from a vehicle accident, fall, gunshot wound, or pelvic fracture with bladder or urethral rupture may contribute to the development of ED. Spinal and brain injuries are discussed earlier in this chapter. A disruption of blood flow in the penile arteries can also result from an injury in adolescence such as a forceful crash of the crotch against the crossbar of a bicycle.

OBESITY, HYPERLIPIDEMIA, AND SMOKING

The bad news is that obesity associated with overeating, lack of exercise, a sedentary lifestyle, gluttony, and smoking may contribute to ED. The good news is that in about 30% of these cases, regular exercise, a balanced diet, cessation of smoking, and loss of weight may lead to recovery of sexual function without the need for any therapy.

While 26% of patients with ED have elevated serum cholesterol levels, this figure increases to about 40% to 80% if they also suffer from hypertension (Seftel AD et al. 2004). The exact mechanism for the loss of normal sexual functioning due to high levels of serum cholesterol is still unknown. Several theories, based on experimental studies in rats and rabbits, attribute their relationship to poor endothelium-dependent relaxation of the vascular bed; accumulation of the “bad” cholesterol (LDL) in plaques, clogging the penile arteries; fewer nerves or endothelial cells; and higher concentration of smooth muscle cells (Gholami SS et al. 2003). Other factors include neurologic and vascular changes, with atrophy and decreased number and size of axons (the projection by neurons emit impulses), cavernosal smooth cell degeneration, and loss of vascular endothelial growth factor (Kendirci M et al. 2005).

As for smoking, several studies have reported direct correlation between the number of cigarettes per day and the duration of smoking with ED’s development and severity, even in the absence of other risk factors. Contributors to the sexual problem include deficient endothelium-dependent smooth muscle relaxation of the penile vasculature, narrowing of the pudendal arteries, and poor rigidity during nocturnal erections. Among other factors are impaired autonomic function, endothelial damage, vasospasm of the penile arteries, decreased concentrations of NOS and NO, and increased toxic free radicals and aromatic compounds, which may cause poor arterial blood flow or lead to venous leakage in the penis.

LOWER URINARY TRACT SYMPTOMS

Benign (noncancerous) enlargement of the prostate gland may actively or passively compress the urethra (urinary channel). LUTS of urinary frequency, urgency, slow stream, hesitancy, incomplete bladder emptying, straining, postvoiding dribbling, and sometimes incontinence occur in about 40% to 50% of men over 50 who have BPH. Those symptoms may be quite annoying and affect quality of life.

Recent studies correlated LUTS (according to their degree of severity) with ED, ejaculatory incompetence, and painful ejaculations. In a study surveying 12,815 men aged 50 to 80, called the Multinational Survey of the Aging Male and conducted in the United States and six European countries, the severity of the urinary symptoms constituted a major risk factor for the development of erectile and ejaculatory disturbances, irrespective of age and other risk factors (Rosen R et al. 2003). Several as yet unconfirmed theories attribute this correlation between urinary and sexual symptoms to hyperactivity of the sympathetic nervous system in the prostate and penis, resulting in excessive contraction of the prostatic smooth muscles and penile arteries; to lack of NO in both organs; or to atherosclerotic changes in the blood vessels, with a significant decrease in penile blood flow.

Recently, much emphasis has been placed on the Rho-kinase role in both ED and LUTS secondary to BPH. RhoA is a small guanosine triphosphate protein that regulates several cellular processes, including smooth muscle contraction. Morphological changes in the prostate, penis, and bladder in patients with ED or LUTS share a common mechanism, namely, the up-regulation of Rho-kinase activity in the urinary and genital tract. This up-regulation may lead to increased sensitivity to calcium and an elevated response to contractile transmitters and mediators.

As with hypertension, some medications used to treat urinary symptoms may affect sexual fiinction.The 5-alpha reductases, such as Proscar (finasteride) and Avodart (dutasteride), may decrease sexual desire, affect sexual potency, and inhibit ejaculation. Alpha-blockers, particularly Flomax (tamsulosin), may produce ejaculatory disturbances in up to 30% of cases. This negative effect is believed to be due to the drug’s inhibitory influence on the seminal vesicles and the vas deferens or to its central actions in the brain. On the other hand, uroselective alpha-blockers, such as Flomax and Uro-Xatral (alfuzocin), as well as phosphodiesterase type 5 inhibitors (see chapter 10) may improve both the urinary and sexual symptoms. However, as per U.S. Food and Drug Administration warnings, Viagra doses above 25 milligrams should not be taken within four hours of taking an alpha-blocker. Clinical studies have confirmed the safety of combining Cialis and Flomax, or Cialis and Uro-Xatral, for the simultaneous treatment of LUTS and ED, with no serious side effects.

PEYRONIE’S DISEASE

First described by French physician, Francois de la Peyronie, in 1743, this condition is characterized by a plaque or a patch of scar tissue that forms on the tunica albuginea and penetrates into the cavernous tissue. This plaque, depending on its location, may cause penile curvature (usually dorsal, possibly other directions) or sometimes an hourglass appearance due to indentation in the middle of the shaft, with possible narrowing from the indentation toward the glans penis. This deformity may lead to vascular anomalies, which may result in ED. If untreated for a long time, about 40% of Peyronie’s disease cases progress, about 47% do not change, and about 13% spontaneously regress (Gelbard MK et al. 1990).

Peyronie’s disease afflicts about 0.4% to 16% of men worldwide. In one study of4,432 middle-aged German men, its incidence was about 3.2% (Sommer F et al. 2002). Despite extensive study, its etiology is still unknown, but there are several theories. One is genetic, based on the association of Peyronie’s disease with a genetic condition called Dupuytren’s contracture of the hands as well as with the presence of certain genes called HLA-B27 subtypes. Other theories include an autoimmune reaction forming antielastin antibodies against the body’s own tissue, abnormal wound healing due to a genetic predisposition, and injury resulting in a plaque of collagen (the protein in the white fibers of connective tissue) (Pryor J et al. 2004).

Currently the most accepted theory of the etiology of Peyronie’s disease is that repeated physical trauma during intercourse leads to bleeding, deposition of fibrin (a blood substance involved in the clotting process), inflammation in the tunica or beneath it at the septum dividing the corpora cavernosa, and overproduction of cytokines by inflammatory cells such as T lymphocytes. Cytokines are nonantibody proteins, such as platelet-derived growth factor and transforming growth factor, that contribute to an immune response by attracting other inflammatory cells, such as neutrophils, macrophages, and fibroblasts, to the site of injury. This inflammation results in overproduction of collagen and may inhibit the enzyme collagenase, which normally breaks it down. Other contributors to collagen overproduction and abnormal tissue remodeling during healing may be genetic anomalies, increased oxidative stress caused by overproduction of oxygen free radicals and possibly the enzymes (NOS isoforms) responsible for the production of NO, and obstruction of the draining vessels (Montorsi F 2005). Peyronie’s disease is also associated with other risk factors such as hypertension, diabetes, dyslipidemia, smoking, and obesity.

Diagnosis and Treatment of Peyronie’s Disease

Diagnosis of Peyronie’s disease is based on symptoms of penile angulation, pain, and possible ED and on a past medical history of trauma to the penis or other medical conditions such as Dupuytren’s contracture. Physical examination focuses on palpation (identification by touch) of the plaque in the tunica albuginea and possibly the estimation of its size and location with color Doppler ultrasonography, which can also confirm the vascular cause of the sexual dysfunction, if present. Demonstration of the degree of penile curvature during erection by a photograph or videotape taken at home, or by observation after intrapenile injection of a vasodilator in the doctor’s office, may be very helpful in deciding on future management.

Management of Peyronie s disease depends on several factors: duration, degree of deformity, presence of pain or ED, and stage of disease. No surgical treatment is advisable before at least 12 months from onset, with the stabilization of the disease for at least 3 months. Clinical manifestations of the early stage include a palpable extended plaque with pain and penile deformity during erection. Manifestations of the late stage are a harder and more localized plaque (sometimes associated with calcification), stable penile deformity, and possible ED in about 30% of these cases (Ralph DJ, Minhas S 2004).

In a case of minimal deformity with no pain or discomfort, no treatment is indicated; the patient is simply reassured and receives periodic follow-up. In a case of pain, marked curvature, and possible ED, conservative management with oral medications, locally applied electroshock wave lithotripsy (ESWL, more commonly employed to disintegrate kidney or urinary stones), or intralesional injections may be attempted, although they are usually associated with varying degrees of success.

Several medications, such as colchicine, vitamin E, potassium aminobenzoate, tamoxifen, acetyl-L-arginine, steroids, antihistamines, and others, alone or in combination, have been tried with varying success rates, but to no definitive benefit, except occasional moderate improvement of pain and curvature, or the prevention of progression in the early stages of the disease. Injection of verapamil (a cardiac drug used for the treatment of angina and some arrhythmias) or interferon alpha-2 B (a family of glycoproteins with antiviral properties, used in the immunologic treatment of some cancers) in the plaque every 2 weeks for 12 weeks or more has yielded mixed results. One study reported decreased penile curvature in about 60%, increased penile girth in about 83%, and improved sexual function in 71% (Levine LA, Estrada CR 2002); another reported no apparent benefit compared to placebo (Greenfield JM et al. 2006). Combined verapamil injection and oral propionyl-L-carnitine was more effective than either treatment alone (Cavallini G et al. 2002).

Recently, experimental injection of subtypes of the enzyme collagenase into the plaque yielded preliminary good results and may become the future treatment of choice. Using ESWL on the plaques resulted in marked improvement in about 50% of cases, with patient satisfaction of 64% in one study (Manikandan R et al. 2002), but these findings were not universally corroborated by other authors, so this method remains experimental until its efficacy is further confirmed by well-controlled studies.

In the late stage with duration over 12 months, penile deformity severe enough to preclude penetration, and failure of all conservative treatments, surgical intervention may be indicated, if accepted by the patient after an explanation of all the benefits and risks. The major reconstructive surgical interventions, provided the disease is stable for at least three months, include plication procedures, plaque incision and grafting, incisional corporoplasty, and the insertion of penile prostheses with or without modeling. The choice of the surgical procedure depends on the nature of the deformity, the degree of curvature, the stability of the disease, the magnitude of the penile deformity, the length of the erect penis, and erectile function. Plication procedures are reserved for patients with generous length, simple curvature, and normal erection or erectile dysfunction responsive to pharmacotherapy. They are simple to perform, with good cosmetic results, preservation of preoperative rigidity, and a high patient satisfaction of 45% to 100%. Their major disadvantage is penile length loss, from 0.5 centimeters to 4 centimeters in 46% to 100% of cases, and the recurrence of the angulation in 20% to 45% of cases.

Plaque incision and grafting is reserved for cases with short penile length; severe and complex deformities, such as low glass appearance; and normal sexual functioning. Its advantages include penile length preservation in 60% to 80% of the cases and high patient satisfaction of 80% to 90%. Its disadvantages include a postoperative erectile dysfunction rate of 5% to 20% and penile sensory loss. Insertion of penile prostheses with possible modeling of the penis is indicated in the presence of ED unresponsive to pharmacotherapy, with an excellent success rate and high patient satisfaction in 80% to 100% of cases.

In summary, in the absence of ED and the presence of penile curvature of less than 60 degrees, with difficulty in penetration, provided the length of the penis is adequate, plication (excision of wedge-shaped pieces of the tunica from the convex side of the penis at the site of maximal curvature, with transverse resuturing of the defects in the tunica) yields good results in the majority of cases. If the curvature is over 60 degrees and/or the penis is small, making an incision in the plaque and grafting with various natural or synthetic materials (the grafting material may consist of veins, pericardium, tunica albuginea, collagen fleece, dermis, temporalis fascia lata, dura mater, bovine or porcine small intestine submucosa (PCIS). Moreover, a new study demonstrated the presence of nonpalpable scarring of the penile septum, considered an atypical form of Peyronie’s disease, as visualized by duplex Doppler ultrasonography in 20 of 341 patients with unexplained ED (Bella AJ et al. 2006).

MISCELLANEOUS ORGANIC CAUSES

About 20% to 50% of patients treated for prostate cancer with external radiation or brachytherapy (the implantation of radioisotope seeds) subsequently develop ED. Other organic causes include arteriosclerosis (hardening of the arteries), chronic renal failure, liver failure, external or internal radiation therapy for rectal cancer, urethral rupture, and chronic obstructive lung disease. Bicycling regularly for extended periods of time may compress the internal pudendal artery against the symphysis pubis, causing hypoxia (poor oxygenation) of the penile tissue—especially if the rider leans forward—and may be associated with ED (Gemery JM et al. 2006).

Type 1 diabetes; testicular torsion (twisting) with necrosis (tissue death) during childhood; and chromosomal abnormalities such as XXY, XX, or XO chromosomal combinations in boys, instead of the normal XY, could also cause testicular deficiency, which may lead to ED and/or loss of sexual desire (see chapter 16).

Author: K. Anthony Hanash. M.D.
Source: New Frontiers in Men’s Sexual Health