Laboratory Tests

Medical Treatment of Erectile Dysfunction

Several medications can produce erections adequate for sexual intercourse despite neurologic injury or vascular insufficiency. They can also restore erections in men experiencing psychogenic erectile dysfunction and in those taking psychotropic medication.

Many physicians prescribe yohimbine, a centrally acting α₂-adrenergic antagonist (see Chapter 21). This medicine may slightly increase sympathetic vasomotor activity, provide mild psychologic stimulation, and create an aphrodisiac sensation. Although yohimbine may alleviate psychogenic erectile dysfunction, it does not help in cases of sexual function due to medical or neurologic illness. Moreover, it often causes anxiety.

Testosterone injections are popular mostly because they may increase muscle mass, especially in body builders, and provide psychologic stimulation. However, except in cases of hypogonadism, testosterone injections have no effect on sexual function and, in high doses for long periods, they may induce prostate cancer.

In contrast, intracorporeal injections of vasoactive medicines – although briefly painful – are effective. They induce erections in men with spinal cord damage, peripheral neuropathy, or vascular disease. The most effective medicines are papaverine, a nonspecific smooth-muscle relaxant; phentolamine, an α-adrenergic antagonist; and alprostadil, a synthetic prostaglandin E₁. A man with erectile dysfunction can inject these medicines – individually or as a mixture – into the base of his corpus cavernosum (the vascular erectile tissue of the penis).

Phentolamine-induced erections illustrate an important physiologic distinction. In contrast to α-adrenergic antagonists, such as phentolamine, causing erections, adrenergic agonists, such as epinephrine (see later), soften erections – by respectively increasing or reducing blood flow into the penis.

Using an alternative treatment, men insert a short, thin alprostadil suppository into the urethra. Although initially uncomfortable, it leads to an erection by greatly promoting blood flow into the penis. This method, unlike with sildenafil (Viagra) treatment, does not require physical stimulation to achieve an erection.

Sildenafil and related medicines – tadalafil (Cialis) and vardenafil (Levitra) – have simplified the treatment of erectile dysfunction and dispensed with expensive and lengthy testing. To a greater or lesser degree they assist men with erectile dysfunction from age-related changes, diabetes, MS, spinal cord injury, and nerve damage from prostate surgery. Furthermore, they often correct erectile dysfunction associated with anxiety, decreased libido, depression, or other psychiatric disturbances. They also partially or completely reverse sexual dysfunction caused by psychotropic medications in both sexes (see later).

Sildenafil and related medicines have a well-established mechanism of action. Under normal circumstances, psychologic or tactile sexual stimulation provokes parasympathetic neurons to produce and release the neurotransmitter nitric oxide (NO) within the penis. NO, in turn, promotes the production of cyclic guanylate cyclase monophosphate (cGMP). In turn, cGMP dilates the arteries, promotes blood flow, and creates an erection. After an enzyme, cGMP-phosphodiesterase, metabolizes cGMP, the erection subsides.

As their primary mechanism of action, these medicines – phosphodiesterase inhibitors – inhibit cGMP-phosphodiesterase. The resulting increased cGMP concentration promotes blood flow in the penis (Fig. 16-4).

FIGURE 16-4 As its mechanism of action, sildenafil inhibits cyclic guanylate cyclase monophosphate-phosphodiesterase (cGMP-PDE). The resulting increase in cGMP leads to smooth-muscle relaxation, which promotes vascular congestion in the penis and thus an erection. NO, nitrous oxide; PDE, phosphodiesterase, which metabolizes cGMP but is inhibited by sildenafil.

Hardly a panacea, phosphodiesterase inhibitors help only about 60% of men with erectile dysfunction. In particular, they are often ineffective in men older than 70 years, with diabetes (especially when it is uncontrolled), undergoing cancer chemotherapy, or who smoke. In addition, they carry some risk. In addition, men taking nitroglycerin, other nitrates, doxazosin, or most α₁-adrenergic antagonists should not also take phosphodiesterase inhibitors because excess vasodilation may lead to orthostatic hypotension.

Invasive treatments are rarely satisfactory. Delicate and tedious arterial reconstructive procedures are usually disappointing, except in men with localized vascular injuries. Surgically implanted devices, such as rigid or semirigid silicone rods or a balloonlike apparatus, can mimic an erection. Unfortunately, implants are costly, unesthetic, and prone to infections and mechanical failures. In contrast, silicone penile implants have never been accused, like silicone breast implants, of causing rheumatologic or MS-like symptoms (see Chapter 15).

Age-Related Changes

In men aged 50 years and older, although their libido generally remains intact, erections decrease in rigidity and duration. Their penis, like bodily areas, begins to lose sensitivity to touch and vibration. Also, these men’s refractory period between orgasms, which was 20 minutes when they were in their sexual prime, at age 18 years, lengthens to days to weeks. Their serum testosterone concentration decreases, but changes correlate poorly with erectile function. For example, although restoring testosterone concentrations reverses a diminished libido, it does not improve erectile dysfunction.

One credible explanation for their erectile dysfunction implicates the normal age-related increased smooth-muscle tone throughout the body. Not only does increased arterial wall smooth-muscle tone cause or contribute to essential hypertension, it also leads to reduced blood flow into the penis.

Other factors common among middle-aged and older men that may cause or at least predispose them to erectile dysfunction include hypertension, atherosclerotic disease, smoking, alcohol abuse, and television viewing time. Whether in isolation or as a group, these factors also blunt the response to phosphodiesterase inhibitors.

Spinal Cord Injury

Spinal cord injury produces a triad of symptoms that varies according to the injury’s level and whether it partially or completely transects the spinal cord:

In addition, upper cervical cord injuries compromise the respiratory center. They also release the sympathetic nervous system from CNS control.

Poliomyelitis and Other Exceptions

Several neurologic illnesses can be so devastating that the untrained physician might assume that their victims have lost their sexual capacity. However, evaluations may reveal that many patients with these illnesses have retained sexual desire and function.

For example, two relatively common motor neuron diseases, poliomyelitis (polio) and amyotrophic lateral sclerosis (ALS) (see Chapter 5), devastate the voluntary motor system. Polio often left survivors confined to wheelchairs and braces, but with stable deficits. ALS, in contrast, causes progressively greater disability that usually results in death after several years. Nevertheless, both these illnesses spare victims’ intellect, sensation, involuntary muscle strength, and ANS functions. Thus, they allow patients normal sexual desire and function, genital sensation, bladder and bowel control, and fertility.

Similarly, most extrapyramidal illnesses (see Chapter 18), despite causing difficulties with mobility, do not impair sexual desire, sexual function, or fertility. For example, adolescents with athetotic cerebral palsy and other varieties of congenital birth injury – even those with marked physical impairments – often have intact libido and sexual function. Among older patients, those with Parkinson disease have preserved sexual drive; however, it may remain unexpressed until dopaminergic medications, such as levodopa and ropinirole, allow it to re-emerge. Moreover, neurologic conditions, such as frontal lobe trauma, frontotemporal dementia, and Alzheimer disease, that cause loss of inhibition sometimes lead to sexual aggressiveness.

Diabetes Mellitus

Retrograde ejaculation and erectile dysfunction eventually affect almost 50% of diabetic men. These sexual impairments result not only from ANS and PNS injury, but also from atherosclerosis of the genital arteries (see later). Erectile dysfunction is associated with age greater than 65 years, duration of diabetes longer than 10 years, obesity, and the frequently occurring complications of diabetes, such as retinopathy, neuropathy, and peripheral vascular disease. Although phosphodiesterase inhibitors alleviate erectile dysfunction in many men with various illnesses or conditions, they provide uncertain benefits to diabetic men (see later).

The data conflict regarding sexual impairment in diabetic women. Some investigators found that 35% of diabetic women were anorgasmic and that sexual impairment was related to neuropathy; however, others found that diabetic women were not especially prone to sexual impairment and that even those with profound neuropathy experienced full sexual function. All agree, though, that diabetic women are prone to vaginal infections and that, while they remain fertile, miscarriages and fetal malformations often complicate their pregnancies.

Urinary incontinence often accompanies sexual dysfunction in both diabetic men and women because the bladder and genitals share a common ANS innervation. Lack of innervation allows the bladder to dilate excessively and lose its tone. In addition, patients with diabetes-induced sexual dysfunction typically experience other complications of ANS impairment, such as anhidrosis and orthostatic hypotension. However, they do not necessarily have other complications of diabetes, such as retinopathy, nephropathy, or peripheral vascular disease.

Multiple Sclerosis

Sexual impairment can be the most bothersome and sometimes even the sole symptom of MS (see Chapter 15). Patients in an early stage of the disease may have few persistent neurologic deficits, but, as attacks recur, the incidence of sexual impairment rises. When sexual impairment occurs, urinary bladder dysfunction accompanies it in 90% of cases. MS-induced sexual impairment is also often associated with paresis and spasticity of the legs. Although spinal cord involvement probably underlies most cases of MS-induced sexual impairment, psychiatric comorbidity contributes. Whatever the precise mechanism, sexual dysfunction greatly reduces quality of life in MS patients and their partners.

Between 70% and 90% of male MS patients experience sexual impairment, particularly erectile dysfunction. Less frequently, the illness also causes premature ejaculation, retrograde ejaculation, and anorgasmia. Decreased sperm production, another complication, impairs fertility. Phosphodiesterase inhibitors help correct erectile dysfunction and improve quality of life in most affected men.

Among female MS patients, a somewhat smaller proportion – between 50% and 75% – have sexual dysfunction. In these women, MS causes decreased sexual desire, inadequate vaginal lubrication, and anorgasmia. Nevertheless, they remain fertile.

Medication-Induced Impairment

More than 100 medications impair one or another aspect of sexual function. Several categories are consistently responsible. Antidepressants, antipsychotics, and antiepileptics constitute a major category. Another one is the standard antihypertensive medicines, such as clonidine, thiazide diuretics, and β-blockers. However, the newer antihypertensive agents, including angiotensin-converting enzyme inhibitors and the calcium-channel blockers, cause little or no sexual impairment.

Although many psychiatric patients are prone to sexual dysfunction because of their disorder, psychotropic medications may precipitate or exacerbate it. In both men and women, such medication-induced sexual dysfunction is primarily dose-related. Medication-induced sexual dysfunction also correlates with medications’ suppression of dopamine activity and its correlate, elevated serum prolactin concentration; increase in serotonin activity; and inhibition of NO synthetase.

In general, dopamine-blocking antipsychotic medications’ sexual side effects are consistent with the hypothesis that decreased dopamine activity, usually accompanied by increased prolactin concentration, leads to sexual dysfunction. For example, typical antipsychotics routinely decrease libido, impair erectile function, and cause other sexual problems in both men and women. In contrast, clozapine, olanzapine, quetiapine, and several other atypical antipsychotics carry a relatively low risk of sexual side effects. Interestingly, almost all typical and atypical antipsychotic agents on rare occasions cause priapism (see later).

Even though dopamine plays little role in their mechanism of action, tricyclic, heterocyclic, monoamine oxidase inhibitor, and selective serotonin reuptake inhibitor (SSRI) antidepressants also routinely lead to sexual dysfunction. This side effect often so troubles patients that they fail to comply with their medication regimen.

SSRIs more so than tricyclic antidepressants delay or prevent orgasm. Furthermore, approximately one-third of men taking SSRIs experience erectile dysfunction. These medicines also interfere with vaginal lubrication. For any particular SSRI, the rate of adverse sexual side effects greatly varies among different studies.

When an antidepressant causes sexual side effects, physicians may prescribe a phosphodiesterase inhibitor, such as sildenafil, which frequently alleviates the problem. Sometimes switching from one to another antidepressant is helpful. Several reports show that bupropion and trazodone have a lower association with sexual side effects than conventional antidepressants.

Anticholinergic medications, which psychiatrists often prescribe to counteract antipsychotic medication-induced parkinsonism, also cause sexual impairment. In addition, these medicines cause other bothersome symptoms that reflect ANS dysfunction: dry mouth, orthostatic hypotension, urinary hesitancy, and accommodation paresis (see Chapter 12). According to some studies, many antiepileptic drugs depress serum testosterone levels in men, which might impair their sexual function.

On the other hand, physicians treating men with premature ejaculation may capitalize on certain psychotropic medications’ delaying orgasm. For example, clomipramine (Anafranil) and sertraline (Zoloft) may prolong their arousal and delay their orgasm.

The Klüver–Bucy Syndrome

In the classic laboratory model that produced the Klüver–Bucy syndrome, neurosurgeons performed bilateral anterior temporal lobectomies, which included removing both amygdalae (Greek, almond [the shape of the amygdalae]), on rhesus monkeys. Postoperatively, the animals displayed aggression and rampant, indiscriminate heterosexual and homosexual activity. In addition, as if they had lost their vision, the monkeys continually grasped objects and placed inedible as well as edible ones in their mouth. The investigators labeled this behavior psychic blindness or oral exploration (terms related to visual agnosia, see Chapter 12).

When even fractions of the Klüver–Bucy syndrome occur in human children or adults, they constitute a dramatic example of limbic system injury. Although the human Klüver–Bucy syndrome also results from bilateral temporal lobe injury, the usual causes consist of herpes simplex encephalitis, frontotemporal dementia, including Pick disease, bilateral posterior cerebral artery infarctions, and paraneoplastic limbic encephalitis – conditions that have a predilection for striking the temporal lobes. Conditions that affect the brain diffusely or nonspecifically, such as anoxia, trauma, and Alzheimer disease, sometimes predominantly injure the temporal lobes and also may cause this syndrome.

The manifestations of the human version differ considerably from those that occur in monkeys. Only about one-half of humans show any increase in heterosexual activity or masturbation. Most only speak or gesture in an aggressive or sexually suggestive manner. Showing a variety of oral exploration, humans with the Klüver–Bucy syndrome tend to eat excessively and smoke or drink compulsively; however, they rarely become obese. Whatever their behavior, other manifestations of temporal lobe injury, such as amnesia, aphasia, and dementia, place more of a handicap. In particular, children with the Klüver–Bucy syndrome, which usually results from hypoxic cerebral damage, are most impaired by the amnesia.

Other Conditions

Certain medications and drugs of abuse, including hallucinogens, amyl nitrate, “ecstasy,” and L-dopa preparations, may increase sexual interest and activity. Although numerous other substances are purported to have aphrodisiac qualities, their effect is minimal or nil, and many may be dangerous. For example, sildenafil, despite its ability to enhance erectile function, is not an aphrodisiac because it requires stimulation to be effective and does not affect the libido.

Another neurologic cause of heightened sexuality is damage to the inhibitory centers of the frontal lobes. Loss of inhibition may unleash suppressed sexual interest in patients with Alzheimer disease, frontotemporal dementia, vascular dementia, and traumatic brain injury. However, other neuropsychologic manifestations of these illnesses – impaired cognitive function, reduced executive ability, and apraxia – often leave patients’ actions rudimentary and clumsy.

Although complex partial epilepsy is usually associated with hyposexuality (see Chapter 10), its seizures sometimes induce activity with sexual overtones. For example, during a seizure, patients may tug at their clothing, partially undress, or even engage in rudimentary masturbation. However, the seizures do not cause frank, interactive sexual activity.

Disturbances in the hypothalamic–pituitary axis occasionally lead to decreased sexual activity. Hypothalamic tumors, for example, may induce a ravenous appetite, but without accompanying increased sexual activity. Also, the Kleine–Levin syndrome (see Chapter 17) includes increased rudimentary sexual activity, which is almost always masturbation, along with hypersomnia.

In contrast to those few examples of neurologic illnesses increasing sexuality, most decrease it. Lesions of the pituitary, hypothalamus, and diencephalon usually cause hyposexuality. For example, in Sheehan syndrome (see Chapter 19), women experience weight loss, amenorrhea, lack of sexual interest, and other symptoms of hypothalamic–pituitary insufficiency. Strokes with or without comorbid depression usually reduce both sexual interest and physical ability.

Although the libido resists mild fatigue, hunger, and fear, pain almost always dampens it. Patients with chronic pain not only have comorbid depression, they also take potent analgesics, such as opioids, that reduce sexual interest or function.

Neurologic Sequelae of Sexual Activity

Despite its pleasures, sexual activity occasionally produces several untoward neurologic consequences. In the simplest scenario, vigorous activity may precipitate a stroke because of exercise-induced hypertension or herniate a lumbar intervertebral disk because of low back strain. A migraine-like headache during sex (coital cephalalgia, see Chapter 9) occasionally occurs. In a rare but more worrisome scenario, a powerful “thunderclap” headache during sex sometimes signals the onset of a subarachnoid hemorrhage. Thus, when sexual activity precipitates a unique headache, neurologists generally recommend further evaluation, including magnetic resonance imaging and angiography, as the first step in identifying an aneurysm. Whether sexual activity produces a cardiac arrhythmia, hypertension or, because of a Valsalva maneuver, hypotension, it may cause an episode of transient global amnesia (see Chapter 11).