Physiology of Male Sexual Response
Normal male sexual function requires (1) an intact libido, (2) the ability to achieve and maintain penile erection, (3) ejaculation, and (4) detumescence. Libido refers to sexual desire and is influenced by a variety of visual, olfactory, tactile, auditory, imaginative, and hormonal stimuli. Sex steroids, particularly testosterone, act to increase libido. Libido can be diminished by hormonal or psychiatric disorders and by medications.
Penile tumescence leading to erection depends on an increased flow of blood into the lacunar network accompanied by complete relaxation of the arteries and corporal smooth muscle. The microarchitecture of the corpora is composed of a mass of smooth muscle (trabecula) that contains a network of endothelial-lined vessels (lacunar spaces). Subsequent compression of the trabecular smooth muscle against the fibroelastic tunica albuginea causes a passive closure of the emissary veins and accumulation of blood in the corpora. In the presence of a full erection and a competent valve mechanism, the corpora become noncompressible cylinders from which blood does not escape.
The central nervous system (CNS) exerts an important influence by either stimulating or antagonizing spinal pathways that mediate erectile function and ejaculation. The erectile response is mediated by a combination of central (psychogenic) innervation and peripheral (reflexogenic) innervation. Sensory nerves that originate from receptors in the penile skin and glans converge to form the dorsal nerve of the penis, which travels to the S2-S4 dorsal root ganglia via the pudendal nerve. Parasympathetic nerve fibers to the penis arise from neurons in the intermediolateral columns of the S2-S4 sacral spinal segments. Sympathetic innervation originates from the T-11 to the L-2 spinal segments and descends through the hypogastric plexus.
Neural input to smooth-muscle tone is crucial to the initiation and maintenance of an erection. There is also an intricate interaction between the corporal smooth-muscle cell and its overlying endothelial cell lining (Fig. 48-1A). Nitric oxide, which induces vascular relaxation, promotes erection and is opposed by endothelin 1 (ET-1) and Rho kinase, which mediate vascular contraction. Nitric oxide is synthesized from l-arginine by nitric oxide synthase and is released from the nonadrenergic, noncholinergic (NANC) autonomic nerve supply to act postjunctionally on smooth-muscle cells. Nitric oxide increases the production of cyclic 3′,5′-guanosine monophosphate (cyclic GMP), which induces relaxation of smooth muscle (Fig. 48-1B). Cyclic GMP is gradually broken down by phosphodiesterase type 5 (PDE-5). Inhibitors of PDE-5 such as the oral medications sildenafil, vardenafil, and tadalafil maintain erections by reducing the breakdown of cyclic GMP. However, if nitric oxide is not produced at some level, PDE-5 inhibitors are ineffective, as these drugs facilitate, but do not initiate, the initial enzyme cascade. In addition to nitric oxide, vasoactive prostaglandins (PGE1, PGF2α) are synthesized within the cavernosal tissue and increase cyclic AMP levels, also leading to relaxation of cavernosal smooth-muscle cells.
Figure 48-1 Pathways that control erection and detumescence. A. Erection is mediated by cholinergic parasympathetic pathways and nonadrenergic, noncholinergic (NANC) pathways, which release nitric oxide (NO). Endothelial cells also release NO, which induces vascular smooth-muscle cell relaxation, allowing enhanced blood flow and leading to erection. Detumescence is mediated by sympathetic pathways that release norepinephrine and stimulate α-adrenergic pathways, leading to contraction of vascular smooth-muscle cells. Endothelin, released from endothelial cells, also induces contraction. Rho kinase activation via endothelin activity (among others) also contributes to detumescence by alteration of calcium signaling. B. Biochemical pathways of NO synthesis and action. Sildenafil, vardenafil, and tadalafil enhance erectile function by inhibiting phosphodiesterase type 5 (PDE-5), thereby maintaining high levels of cyclic 3′,5′-guanosine monophosphate (cyclic GMP). NOS, nitric oxide synthase; iCa2+, intracellular calcium.
Ejaculation is stimulated by the sympathetic nervous system; this results in contraction of the epididymis, vas deferens, seminal vesicles, and prostate, causing seminal fluid to enter the urethra. Seminal fluid emission is followed by rhythmic contractions of the bulbocavernosus and ischiocavernosus muscles, leading to ejaculation. Premature ejaculation usually is related to anxiety or a learned behavior and is amenable to behavioral therapy or treatment with medications such as selective serotonin reuptake inhibitors (SSRIs). Retrograde ejaculation results when the internal urethral sphincter does not close; it may occur in men with diabetes or after surgery involving the bladder neck.
Detumescence is mediated by norepinephrine from the sympathetic nerves, endothelin from the vascular surface, and smooth-muscle contraction induced by postsynaptic α-adrenergic receptors and activation of Rho kinase. These events increase venous outflow and restore the flaccid state. Venous leak can cause premature detumescence and is caused by insufficient relaxation of the corporal smooth muscle rather than a specific anatomic defect. Priapism refers to a persistent and painful erection and may be associated with sickle cell anemia, hypercoagulable states, spinal cord injury, or injection of vasodilator agents into the penis.
Erectile dysfunction (ED) is not considered a normal part of the aging process. Nonetheless, it is associated with certain physiologic and psychological changes related to age. In the Massachusetts Male Aging Study (MMAS), a community-based survey of men age 40–70, 52% of responders reported some degree of ED. Complete ED occurred in 10% of respondents, moderate ED in 25%, and minimal ED in 17%. The incidence of moderate or severe ED more than doubled between the ages of 40 and 70. In the National Health and Social Life Survey (NHSLS), which included a sample of men and women age 18–59, 10% of men reported being unable to maintain an erection (corresponding to the proportion of men in the MMAS reporting severe ED). Incidence was highest among men in the age group 50–59 (21%) and men who were poor (14%), divorced (14%), and less educated (13%).
The incidence of ED is also higher among men with certain medical disorders, such as diabetes mellitus, obesity, lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH), heart disease, hypertension, and decreased high-density lipoprotein (HDL) levels. Cardiovascular disease and ED share etiologies as well as pathophysiology (e.g., endothelial dysfunction), and the degree of ED appears to correlate with the severity of cardiovascular disease. Consequently, ED represents a “sentinel symptom” in patients with occult cardiovascular and peripheral vascular disease.
Smoking is also a significant risk factor in the development of ED. Medications used in treating diabetes or cardiovascular disease are additional risk factors (see below). There is a higher incidence of ED among men who have undergone radiation or surgery for prostate cancer and in those with a lower spinal cord injury. Psychological causes of ED include depression, anger, stress from unemployment, and other stress-related causes.
ED may result from three basic mechanisms: (1) failure to initiate (psychogenic, endocrinologic, or neurogenic), (2) failure to fill (arteriogenic), and (3) failure to store adequate blood volume within the lacunar network (venoocclusive dysfunction). These categories are not mutually exclusive, and multiple factors contribute to ED in many patients. For example, diminished filling pressure can lead secondarily to venous leak. Psychogenic factors frequently coexist with other etiologic factors and should be considered in all cases. Diabetic, atherosclerotic, and drug-related causes account for >80% of cases of ED in older men.
The most common organic cause of ED is a disturbance of blood flow to and from the penis. Atherosclerotic or traumatic arterial disease can decrease flow to the lacunar spaces, resulting in decreased rigidity and an increased time to full erection. Excessive outflow through the veins despite adequate inflow also may contribute to ED. Structural alterations to the fibroelastic components of the corpora may cause a loss of compliance and inability to compress the tunical veins. This condition may result from aging, increased cross-linking of collagen fibers induced by nonenzymatic glycosylation, hypoxemia, or altered synthesis of collagen associated with hypercholesterolemia.
Disorders that affect the sacral spinal cord or the autonomic fibers to the penis preclude nervous system relaxation of penile smooth muscle, thus leading to ED. In patients with spinal cord injury, the degree of ED depends on the completeness and level of the lesion. Patients with incomplete lesions or injuries to the upper part of the spinal cord are more likely to retain erectile capabilities than are those with complete lesions or injuries to the lower part. Although 75% of patients with spinal cord injuries have some erectile capability, only 25% have erections sufficient for penetration. Other neurologic disorders commonly associated with ED include multiple sclerosis and peripheral neuropathy. The latter is often due to either diabetes or alcoholism. Pelvic surgery may cause ED through disruption of the autonomic nerve supply.
Androgens increase libido, but their exact role in erectile function is unclear. Individuals with castrate levels of testosterone can achieve erections from visual or sexual stimuli. Nonetheless, normal levels of testosterone appear to be important for erectile function, particularly in older males. Androgen replacement therapy can improve depressed erectile function when it is secondary to hypogonadism; however, it is not useful for ED when endogenous testosterone levels are normal. Increased prolactin may decrease libido by suppressing gonadotropin-releasing hormone (GnRH), and it also leads to decreased testosterone levels. Treatment of hyperprolactinemia with dopamine agonists can restore libido and testosterone.
ED occurs in 35–75% of men with diabetes mellitus. Pathologic mechanisms are related primarily to diabetes-associated vascular and neurologic complications. Diabetic macrovascular complications are related mainly to age, whereas microvascular complications correlate with the duration of diabetes and the degree of glycemic control (Chap. 344). Individuals with diabetes also have reduced amounts of nitric oxide synthase in both endothelial and neural tissues.
Two mechanisms contribute to the inhibition of erections in psychogenic ED. First, psychogenic stimuli to the sacral cord may inhibit reflexogenic responses, thereby blocking activation of vasodilator outflow to the penis. Second, excess sympathetic stimulation in an anxious man may increase penile smooth-muscle tone. The most common causes of psychogenic ED are performance anxiety, depression, relationship conflict, loss of attraction, sexual inhibition, conflicts over sexual preference, sexual abuse in childhood, and fear of pregnancy or sexually transmitted disease. Almost all patients with ED, even when it has a clear-cut organic basis, develop a psychogenic component as a reaction to ED.
Medication-induced ED (Table 48-1) is estimated to occur in 25% of men seen in general medical outpatient clinics. The adverse effects related to drug therapy are additive, especially in older men. In addition to the drug itself, the disease being treated is likely to contribute to sexual dysfunction. Among the antihypertensive agents, the thiazide diuretics and beta blockers have been implicated most frequently. Calcium channel blockers and angiotensin converting-enzyme inhibitors are cited less frequently. These drugs may act directly at the corporal level (e.g., calcium channel blockers) or indirectly by reducing pelvic blood pressure, which is important in the development of penile rigidity. α-Adrenergic blockers are less likely to cause ED. Estrogens, GnRH agonists, H2 antagonists, and spironolactone cause ED by suppressing gonadotropin production or by blocking androgen action. Antidepressant and antipsychotic agents—particularly neuroleptics, tricyclics, and SSRIs—are associated with erectile, ejaculatory, orgasmic, and sexual desire difficulties.
Table 48-1 Drugs Associated with Erectile Dysfunction |Favorite Table|Download (.pdf)
Table 48-1 Drugs Associated with Erectile Dysfunction
Calcium channel blockers
Selective serotonin reuptake inhibitors
Monoamine oxidase inhibitors
If there is a strong association between the institution of a drug and the onset of ED, alternative medications should be considered. Otherwise, it is often practical to treat the ED without attempting multiple changes in medications, as it may be difficult to establish a causal role for a drug.
Algorithm for the evaluation and management of patients with ED. PDE, phosphodiesterase.
Approach to the Patient: Erectile Dysfunction
A good physician-patient relationship helps unravel the possible causes of ED, many of which require discussion of personal and sometimes embarrassing topics. For this reason, a primary care provider is often ideally suited to initiate the evaluation. However, a significant percentage of men experience ED and remain undiagnosed unless specifically questioned about this issue. By far the most common reason for underreporting of ED is patient embarrassment. Once the topic is initiated by the physician, patients are more willing to discuss their potency issues. A complete medical and sexual history should be taken in an effort to assess whether the cause of ED is organic, psychogenic, or multifactorial (Fig. 48-2).
Algorithm for the evaluation and differential diagnosis of hirsutism. ACTH, adrenocorticotropic hormone; CAH, congenital adrenal hyperplasia; DHEAS, sulfated form of dehydroepiandrosterone; PCOS, polycystic ovarian syndrome.
Both the patient and his sexual partner should be interviewed regarding sexual history. ED should be distinguished from other sexual problems, such as premature ejaculation. Lifestyle factors such as sexual orientation, the patient′s distress from ED, performance anxiety, and details of sexual techniques should be addressed. Standardized questionnaires are available to assess ED, including the International Index of Erectile Function (IIEF) and the more easily administered Sexual Health Inventory for Men (SHIM), a validated abridged version of the IIEF.
The initial evaluation of ED begins with a review of the patient′s medical, surgical, sexual, and psychosocial histories. The history should note whether the patient has experienced pelvic trauma, surgery, or radiation. In light of the increasing recognition of the relationship between lower urinary tract symptoms and ED, it is advisable to evaluate for the presence of symptoms of bladder outlet obstruction. Questions should focus on the onset of symptoms, the presence and duration of partial erections, and the progression of ED. A history of nocturnal or early morning erections is useful for distinguishing physiologic ED from psychogenic ED. Nocturnal erections occur during rapid eye movement (REM) sleep and require intact neurologic and circulatory systems. Organic causes of ED generally are characterized by a gradual and persistent change in rigidity or the inability to sustain nocturnal, coital, or self-stimulated erections. The patient should be questioned about the presence of penile curvature or pain with coitus. It is also important to address libido, as decreased sexual drive and ED are sometimes the earliest signs of endocrine abnormalities (e.g., increased prolactin, decreased testosterone levels). It is useful to ask whether the problem is confined to coitus with one partner or also involves other partners; ED not uncommonly arises in association with new or extramarital sexual relationships. Situational ED, as opposed to consistent ED, suggests psychogenic causes. Ejaculation is much less commonly affected than erection, but questions should be asked about whether ejaculation is normal, premature, delayed, or absent. Relevant risk factors should be identified, such as diabetes mellitus, coronary artery disease (CAD), and neurologic disorders. The patient′s surgical history should be explored with an emphasis on bowel, bladder, prostate, and vascular procedures. A complete drug history is also important. Social changes that may precipitate ED are also crucial to the evaluation, including health worries, spousal death, divorce, relationship difficulties, and financial concerns.
Because ED commonly involves a host of endothelial cell risk factors, men with ED report higher rates of overt and silent myocardial infarction. Therefore, ED in an otherwise asymptomatic male warrants consideration of other vascular disorders, including CAD.
The physical examination is an essential element in the assessment of ED. Signs of hypertension as well as evidence of thyroid, hepatic, hematologic, cardiovascular, or renal diseases should be sought. An assessment should be made of the endocrine and vascular systems, the external genitalia, and the prostate gland. The penis should be palpated carefully along the corpora to detect fibrotic plaques. Reduced testicular size and loss of secondary sexual characteristics are suggestive of hypogonadism. Neurologic examination should include assessment of anal sphincter tone, investigation of the bulbocavernosus reflex, and testing for peripheral neuropathy.
Although hyperprolactinemia is uncommon, a serum prolactin level should be measured, as decreased libido and/or ED may be the presenting symptoms of a prolactinoma or another mass lesion of the sella (Chap. 339). The serum testosterone level should be measured, and if it is low, gonadotropins should be measured to determine whether hypogonadism is primary (testicular) or secondary (hypothalamic-pituitary) in origin (Chap. 346). If not performed recently, serum chemistries, complete blood count (CBC), and lipid profiles may be of value, as they can yield evidence of anemia, diabetes, hyperlipidemia, or other systemic diseases associated with ED. Determination of serum prostate-specific antigen (PSA) should be conducted according to recommended clinical guidelines (Chap. 95).
Additional diagnostic testing is rarely necessary in the evaluation of ED. However, in selected patients, specialized testing may provide insight into pathologic mechanisms of ED and aid in the selection of treatment options. Optional specialized testing includes (1) studies of nocturnal penile tumescence and rigidity, (2) vascular testing (in-office injection of vasoactive substances, penile Doppler ultrasound, penile angiography, dynamic infusion cavernosography/cavernosometry), (3) neurologic testing (biothesiometry-graded vibratory perception, somatosensory evoked potentials), and (4) psychological diagnostic tests. The information potentially gained from these procedures must be balanced against their invasiveness and cost.
Treatment: Male Sexual Dysfunction
Patient and partner education is essential in the treatment of ED. In goal-directed therapy, education facilitates understanding of the disease, the results of the tests, and the selection of treatment. Discussion of treatment options helps clarify how treatment is best offered and stratify first- and second-line therapies. Patients with high-risk lifestyle issues such as obesity, smoking, alcohol abuse, and recreational drug use should be counseled on the role those factors play in the development of ED.
Therapies currently employed for the treatment of ED include oral phosphodiesterase type 5 inhibitor therapy (most commonly used), injection therapies, testosterone therapy, penile devices, and psychological therapy. In addition, limited data suggest that treatments for underlying risk factors and comorbidities—for example, weight loss, exercise, stress reduction, and smoking cessation—may improve erectile function. Decisions regarding therapy should take into account the preferences and expectations of patients and their partners.
Sildenafil, tadalafil, and vardenafil are the only approved and effective oral agents for the treatment of ED. These three medications have markedly improved the management of ED because they are effective for the treatment of a broad range of causes, including psychogenic, diabetic, vasculogenic, post-radical prostatectomy (nerve-sparing procedures), and spinal cord injury. They belong to a class of medications that are selective and potent inhibitors of PDE-5, the predominant phosphodiesterase isoform found in the penis. They are administered in graduated doses and enhance erections after sexual stimulation. The onset of action is approximately 60–120 min, depending on the medication used and other factors, such as recent food intake. Reduced initial doses should be considered for patients who are elderly, are taking concomitant alpha blockers, have renal insufficiency, or are taking medications that inhibit the CYP3A4 metabolic pathway in the liver (e.g., erythromycin, cimetidine, ketoconazole, and possibly itraconazole and mibefradil), as they may increase the serum concentration of the PDE-5 inhibitors (PDE-5i) or promote hypotension.
Several randomized trials have demonstrated the efficacy of this class of medications. There are no compelling data to support the superiority of one PDE-5i over another.
Patients may fail to respond to a PDE-5i for several reasons (Table 48-2). Some patients may not tolerate PDE-5i secondary to adverse events from vasodilation in nonpenile tissues expressing PDE-5 or from the inhibition of homologous nonpenile isozymes (i.e., PDE-6 found in the retina). Abnormal vision attributed to the effects of PDE-5i on retinal PDE-6 is of short duration, reported only with sildenafil and not thought to be clinically significant. A more serious concern is the possibility that PDE-5i may cause nonarteritic anterior ischemic optic neuropathy; although data to support that association are limited, it is prudent to avoid the use of these agents in men with a prior history of nonarteritic anterior ischemic optic neuropathy.
Table 48-2 Issues to Consider If Patients Report Failure of PDE-5i to Improve Erectile Dysfunction |Favorite Table|Download (.pdf)
Table 48-2 Issues to Consider If Patients Report Failure of PDE-5i to Improve Erectile Dysfunction
• A trial of medication on at least six different days at the maximal dose should be made before declaring patient nonresponsive to PDE-5i use
• Taking medication after a high-fat meal
• Failure to include physical and psychic stimulation at the time of foreplay to induce endogenous NO
• Unrecognized hypogonadism
Testosterone supplementation combined with a PDE-5i may be beneficial in improving erectile function in hypogonadal men with ED who are unresponsive to PDE-5i alone. These drugs do not affect ejaculation, orgasm, or sexual drive. Side effects associated with PDE-5i include headaches (19%), facial flushing (9%), dyspepsia (6%), and nasal congestion (4%). Approximately 7% of men using sildenafil may experience transient altered color vision (blue halo effect), and 6% of men taking tadalafil may experience loin pain. PDE-5i is contraindicated in men receiving nitrate therapy for cardiovascular disease, including agents delivered by the oral, sublingual, transnasal, and topical routes. These agents can potentiate its hypotensive effect and may result in profound shock. Likewise, amyl/butyl nitrate “poppers” may have a fatal synergistic effect on blood pressure. PDE-5i also should be avoided in patients with congestive heart failure and cardiomyopathy because of the risk of vascular collapse. Because sexual activity leads to an increase in physiologic expenditure [5–6 metabolic equivalents (METS)], physicians have been advised to exercise caution in prescribing any drug for sexual activity to those with active coronary disease, heart failure, borderline hypotension, or hypovolemia and to those on complex antihypertensive regimens.
Although the various forms of PDE-5i have a common mechanism of action, there are a few differences among the three agents. Tadalafil is unique in its longer half-life. All three drugs are effective for patients with ED of all ages, severities, and etiologies. Although there are pharmacokinetic and pharmacodynamic differences among these agents, clinically relevant differences are not clear.
Testosterone replacement is used to treat both primary and secondary causes of hypogonadism (Chap. 346). Androgen supplementation in the setting of normal testosterone is rarely efficacious in the treatment of ED and is discouraged. Methods of androgen replacement include transdermal patches and gels, parenteral administration of long-acting testosterone esters (enanthate and cypionate), and oral preparations (17 α-alkylated derivatives) (Chap. 346). Oral androgen preparations have the potential for hepatotoxicity and should be avoided.
Men who receive testosterone should be reevaluated after 1–3 months and at least annually thereafter for testosterone levels, erectile function, and adverse effects, which may include gynecomastia, sleep apnea, development or exacerbation of lower urinary tract symptoms or benign prostatic hyperplasia, prostate cancer, lowering of HDL, erythrocytosis, elevations of liver function tests, and reduced fertility. Periodic reevaluation should include measurement of CBC and PSA and digital rectal exam. Therapy should be discontinued in patients who do not respond within 3 months.
Vacuum Constriction Devices
Vacuum constriction devices (VCDs) are a well-established noninvasive therapy. They are a reasonable treatment alternative for select patients who cannot take sildenafil or do not desire other interventions. VCDs draw venous blood into the penis and use a constriction ring to restrict venous return and maintain tumescence. Adverse events with VCD include pain, numbness, bruising, and altered ejaculation. Additionally, many patients complain that the devices are cumbersome and that the induced erections have a nonphysiologic appearance and feel.
If a patient fails to respond to oral agents, a reasonable next choice is intraurethral or self-injection of vasoactive substances. Intraurethral prostaglandin E1 (alprostadil), in the form of a semisolid pellet (doses of 125–1000 μg), is delivered with an applicator. Approximately 65% of men receiving intraurethral alprostadil respond with an erection when tested in the office, but only 50% achieve successful coitus at home. Intraurethral insertion is associated with a markedly reduced incidence of priapism in comparison to intracavernosal injection.
Injection of synthetic formulations of alprostadil is effective in 70–80% of patients with ED, but discontinuation rates are high because of the invasive nature of administration. Doses range between 1 and 40 μg. Injection therapy is contraindicated in men with a history of hypersensitivity to the drug and men at risk for priapism (hypercoagulable states, sickle cell disease). Side effects include local adverse events, prolonged erections, pain, and fibrosis with chronic use. Various combinations of alprostadil, phentolamine, and/or papaverine sometimes are used.
A less frequently used form of therapy for ED involves the surgical implantation of a semirigid or inflatable penile prosthesis. The choice of prosthesis is dependent on patient preference and should take into account body habitus and manual dexterity, which may affect the ability of the patient to manipulate the device. Because of the permanence of prosthetic devices, patients should be advised to first consider less invasive options for treatment. These surgical treatments are invasive, are associated with potential complications, and generally are reserved for treatment of refractory ED. Despite their high cost and invasiveness, penile prostheses are associated with high rates of patient and partner satisfaction.
A course of sex therapy may be useful for addressing specific interpersonal factors that may affect sexual functioning. Sex therapy generally consists of in-session discussion and at-home exercises specific to the person and the relationship. Psychosexual therapy involves techniques such as sensate focus (nongenital massage), sensory awareness exercises, correction of misconceptions about sexuality, and interpersonal difficulties therapy (e.g., open communication about sexual issues, physical intimacy scheduling, and behavioral interventions). These approaches may be useful in patients who have psychogenic or social components to their ED, although data from randomized trials are scanty and inconsistent. It is preferable if therapy includes both partners if the patient is involved in an ongoing relationship.