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Professions: Topics:
August 1, 2010



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Improving Erectile Function:
Detection, Prevention, and Treatment of ED

“Man survives earthquakes, experiences the horrors of
illness, and all the tortures of the soul.
But the most tormenting tragedy of all time is,
and will be, the tragedy of the bedroom.”

—Chekov1

INTRODUCTION

Men's health is traditionally perceived as building muscle, adding inches to our chests while finding the 15 minutes of perfect aerobic exercise to ensure health, longevity, and sculpted bodies. We wish to eat fat yet remain thin. We want to know the six no-fail seduction tricks to win our women's hearts, if not desires.2 Men cannot exclude their desire for sexual vitality. Though perhaps not as obsessed with sex as during adolescence and shortly beyond, health care providers should incorporate healthy sexual function into the concept of health. It remains the most often unspoken, yet primary function men wish to maintain and even augment through the aging process.

With the advent of an oral agent as first-line therapy for the treatment of erectile dysfunction (ED), the path to discussion of ED and its treatment often winds through the primary care practitioner's office. Thus, the goal of this monograph is to help those health care providers who are on these front lines better handle the issues related to what can be defined as a new paradigm of men's health and male sexual function.

MYTHS OF MALE SEXUAL HEALTH

Sexual Activity and Men

Table 1. Reported Sexual Activity

83% of men 39-50 years had sex weekly4

68% of women 39-50 years had sex weekly4

95% of men 46-50 years had sex weekly3

28% of men 66-71 years had sex weekly3

71% of 70 to 80-year olds had sex weekly6

40% of 80-year-olds had regular sex activity5

Society has long held strong beliefs that sexual activity becomes less important to the aging male and the aging couple. It is rarely dealt with in the public media, and is not a topic most health care providers wish to acknowledge openly. Yet, while studies report that 80% to 90% of men between the ages of 40 to 50 years have sex weekly, 70% of men in their 70s still have sex weekly (Table 1).3-6 Clearly, sexual activity and function is of great importance to the aging male.

Another well established myth of sexual medicine is that the cause of most cases of ED is psychological. Chekhov, also a physician, writes in “Misery”1: “Man survives earthquakes, experiences the horrors of illness, and all the tortures of the soul. But the most tormenting tragedy of all time is, and will be, the tragedy of the bedroom.” It is now apparent that ED is caused by myriad organic factors including arterial, endocrine, and neurogenic issues, and abnormalities at the cavernosal level (eg, venous leakage). These factors are strongly related to a man's systemic health and subsequent underlying disease states and their therapies. As Chekhov so clearly elaborates, once a man experiences a failure in making love, he almost always feels a sense of anxiety about his performance; a cloud of uncertainty prevails.

Therefore, ED is an important health concern of all men, not just the aging male. It affects up to 40 million men in the United States.7 It may indicate the presence of a serious underlying medical disorder. In the Massachusetts Male Aging Study,8 after adjusting for age, ED had a 39% incidence in men with cardiovascular disease, a 29% incidence in diabetic men in good control (46% in those with poor control), up to 90% incidence in men with depression, and between a 60% to 90% association with dyslipidemias. In the same study, the combined prevalence of minimal, moderate, and complete ED was 52% (Figure 1). Although not caused by advancing age, ED is associated with aging. The prevalence of moderate or complete impairment increased from 8% to 40% in men between the ages of 40 and 70 years.9 It is associated with many common medications including oral hypoglycemic agents, antihypertensives, and antidepressants.10,11 Finally, ED is a common consequence following two of the most common surgeries performed in men: colectomies and radical prostatectomies.

The Disparity

Despite the prevalence of ED and first-line oral therapy for its treatment, ED is not often addressed by the primary care physician, and studies note that sexual issues are documented in as few as 2% of primary care physicians' charts.12 Yet, more than 70% of adult male patients consider sexual matters to be an appropriate topic to be raised by the primary physician.13 How odd that this disparity should exist, given that ED compromises multiple aspects of a patient's life, including contributing to poor self-image, increasing anxiety and depression, and serving as a significant cause for unsatisfying interpersonal relationships. As noted above, sexual function may influence a man's general health perception.

What is often poorly understood is the concept of curability of ED.14 This is defined as certain populations of men with ED who are not just treatable, but curable. Such groups include young men with traumatic arterial occlusive disease or those with traumatic isolated crural venous leakage. These injuries are often related to bicycle injuries. In addition, other curable populations include men with primary psychogenic ED, endocrinopathic ED, and, perhaps, arteriogenic ED.

Thus, it is vital that physicians inquire about sexual function at the appropriate moment of the patient encounter. Such moments will be detailed later, but it is known that if providers do not ask, patients will not be likely to initiate discussions of a sexual nature even when they perceive a problem. In one investigation, 71% of patients thought the physician would dismiss their sexual concerns, 68% feared the clinician would be embarrassed, and 76% thought that there would be no medical treatment.15

In summary, the primary care physician can identify the high-risk groups and individuals for ED, and screen for co-morbidities. The long-term, personal relationship with the patient is an asset in discussing and resolving sexual problems. Longitudinal care is well suited to treat and follow-up uncomplicated ED. Primary care physicians can refer patients with complex ED patterns to either an ED specialist or urologist. However, most patients prefer to be treated whenever possible by their primary care provider, who, together with the ED specialist or urologist, can improve men's overall health care.

PATHOPHYSIOLOGY OF ORGANIC ED AND PATIENT WORK-UP IN THE PRIMARY CARE SETTING

As illustrated in Figure 2, 70% of ED is primarily vasculogenic in etiology, with the remaining causes relating to pharmacologic, operative, neurogenic, and hormonal influences.16-20 All of these have a psychological overlay. The clinician should ask about sexual function during the health surveillance visit, in as normative a fashion as one asks about tobacco use, alcohol use, exercise, and diet. Some clinicians prefer to pose these questions during the formal review of systems. This author prefers to do so during questioning about the social and lifestyle history component of the physical exam. Other clinicians are more comfortable using questionnaires that patients complete prior to the visit, including the Sexual Health Inventory for Men (SHIM, Table 2).21 Nothing is more valuable than the provider asking the question(s) about sexual function. Even if the patient's response is a brief “It's fine!” the purpose will be served for validating sexual function as an appropriate topic for more elaborate discussion at a future visit. The author also asks about sexual function during follow-up visits, after beginning patients on medications for common conditions. Examples include antihypertensives, antidepressants, and oral hypoglycemic agents as indicated earlier. However one asks the question, such inquiries need to be sensitive to the patient's cultural, religious, and educational background.

Table 2. Patient Self-Assessment Questionnaire: Evaluating ED Severity (SHIM)21

OVER THE PAST 6 MONTHS:
1. How do you rate your confidence that you could get and keep an erection?
Very low
Low
Moderate
High
Very high
 
1
2
3
4
5
2. When you had erections with sexual stimulation, how often were your erections hard enough for penetration (entering your partner)?
No sexual activity
Almost never
or never
A few times (much less than half the time)
Sometimes (about half
the time)
Most times
(much more than half the time)
Almost always or always
 
0
1
2
3
4
5
3. During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?
Did not attempt intercourse
Almost never or never
A few times (much less than half the time)
Sometimes (about half the time)
Most times (much more than half the time)
Almost always or always
 
0
1
2
3
4
5
4. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?
Did not attempt intercourse
Almost never or never
A few times (much less than half the time)
Sometimes (about half the time)
Most times (much more than half the time)
Almost always or always
 
0
1
2
3
4
5
5. When you attempted sexual intercourse, how often was it satisfactory for you?
Did not attempt intercourse
Almost never or never
A few times (much less than half the time)
Sometimes (about half the time)
Most times (much more than half the time)
Almost always or always
 
0
1
2
3
4
5
             
SHIM = Sexual Health Inventory for Men.
High scores (>17) = mild or no ED. Low scores (<11) = moderate or severe ED.

It is important to recognize that not so long ago, the question: “Are you sexually active and with whom?” was asked in assessment of determining possible risk factors for sexually transmitted diseases. Now, with the availability of oral therapy, the question has become: “Are you satisfied with your sexual activity (functioning)?” How this is accomplished is reflective of the health care provider's own level of comfort in these matters, and either of the following questions might also be asked: “How is your sex life?” or “Are you experiencing any problems with your sexual function?” Any of these questions or others like them are likely to elicit a brief patient response.

It then encumbers the clinician to clarify the duration, type, severity, and level of distress of the problem. Most male sexual dysfunction falls into the category of arousal disorders, ie, ED. However, many men experience mixed sexual dysfunction, which may include issues of diminished libido and orgasmic difficulty. Whatever the nature of the problem, it takes only a few moments of time to elucidate the nature, severity, and level of distress to the patient. Yet each of these is vital to establishing a treatment plan based on shared expectations.

Medical History

Once the problem is established, the medical history should highlight the following22,23:

  • List of current medications taken, including OTC and herbal drugs
  • Tobacco, alcohol, and illicit drug use
  • Pelvic trauma or genital/pelvic surgery
  • Past medical history noting the presence of diabetes, hypertension, thyroid, or other endocrine disorder
  • History of depression or anxiety
  • Sleep history to exclude sleep apnea as a contributing cause

Physical Exam

Physical examination should highlight the following:

  • Blood pressure
  • Vascular examination noting the presence/absence of pulses and bruits
  • Neurologic exam for peripheral neuropathy (eg, sensory sense)
  • Endocrine examination for signs/symptoms of thyroid or adrenal disease, hypogonadism, gynecomastia, small (<3x2 cm or 15 cc) atrophic testes, absent body hair, thyromegaly
  • Penile examination for loss of elasticity of penile shaft or nodularity suggesting Peyronie's disease with a history of penile curvature or shortening

Laboratory Tests

Laboratory tests should include the following:

  • Serum glucose, creatinine, and lipid profile
  • Free testosterone or total testosterone (especially with the triad of hypogonadism symptoms: diminished libido, diminished energy, and fatigue)
  • Serum luteinizing hormone (LH) and prolactin levels if total testosterone is low, especially in an individual under the age of 50
  • Thyroid stimulating hormone (TSH) and prostate-specific antigen (PSA) levels

It is thus evident that ED is a harbinger for the presence of established co-morbidities in men, and the physical and laboratory screening should focus on the presence or absence of these disease states. Of 521 patients with ED examined for co-morbidities in a large sexual dysfunction clinic, 39% had hypertension, 37% were found to be hypogonadal, and 34% experienced medication-related ED. Sixty-eight percent were thought to have primarily organic etiologies, 8% psychogenic, and 24% mixed. Ninety-nine percent of those patients with hypogonadism had a concomitant medical condition.24 The relationship between ED and other co-morbid disease states will be explored in greater detail shortly.

WHY TREAT ED? THE RELATIONSHIP OF SEXUAL DYSFUNCTION TO CO-MORBIDITIES IN MEN

The major risk factors for ED have long been known and include diabetes mellitus, prostate disease, peripheral vascular disease, coronary artery disease, hyperlipidemia, hypertension, and cigarette smoking. Lumbar disk disease and other neurologic risk factors, as well as obstructive sleep apnea and, finally, depression, can be added to this list. Clearly, ED is a symptom associated with the chronic medical conditions common in the primary care practitioner's office.

Diabetes Mellitus

Over 15 million patients in the United States have been diagnosed with diabetes mellitus, and another 5 million remain undiagnosed. Estimated ranges of moderate to severe ED in the diabetic male extend from 25% to 70%.25,26 Diabetes is a documented correlate of ED in the Massachusetts Male Aging Study, and is reported to account for 40% of organic ED. The primary causes of ED in the diabetic male appear to be neuropathic (specifically autonomic dysfunction) and vascular (involving both arteriosclerosis and endothelial cell alteration). Finally, diabetic patients also appear to have nitric oxide secondary messenger perturbations,27 disturbances in those pathways that allow nitric oxide to increase cellular levels of cyclic GMP that acts to relax cavernosal tissue in the penis.

Efficacy with oral agents ranges from 57% with sildenafil to 72% with vardenafil (a yet to be FDA-approved PDE-5 inhibitor) in response to the global efficacy question or general assessment question (GAQ): “Has the treatment you have been taking over the past 4 weeks improved your erections?”

Most importantly, glycemic control appears to correlate with severity of ED.28 Therefore, improved management of diabetic patients with the newer oral insulin-sensitizing agents not only translates into fewer complications and reduction of morbidity and mortality, but also improved erectile function.

Depression

Depression is often characterized by decreased quality of life, altered relationship dynamics, and an elevated sympathetic tone. The Massachusetts Male Aging Study follow-up found the positive independent association between depression and ED was 1.82 times, that is, ED was 82% more likely in men with depression.

Predictors of ED and depression include diabetes, heart disease, hypertension, low physical activity, heavy drinking and smoking, low education level, change in marital or employment status, and poor life satisfaction and/or future expectations. Depression therapies are associated with ED, specifically known as SSRI-associated sexual dysfunction. Erectile dysfunction alone may be a cause of depression.

Of great interest is the relationship between cardiovascular disease, ED, and depression. These variables are a mutually reinforcing triad (Figure 3).29 Of particular relevance, patients with sexual dysfunction have a likely comorbidity of cardiovascular disease and depression, as well as the potential increased risk for cardiac morbidity and mortality.30

Lumbar Disk Disease

It is known that lower lumbar disk herniations can rarely compress the cauda equina, and that S2-S4 compression impairs the neural signaling required for adequate erectile function. Intervention in the form of disk decompression has been shown to result in an improvement in erectile function, and may allow a patient who is a PDE-5 nonresponder to respond upon re-challenge.31 A nonresponder is defined as a male who has not achieved efficacy despite adequate dosing and attempts at following proper instructions in the use of these agents.

ED may also be an outcome of other neurologic diseases, including multiple sclerosis, Parkinson's disease, and other peripheral neuropathies. Patients with upper motor spinal cord injuries appear to respond well to PDE-5 inhibitors. Neurologic risk factors for ED include diabetes, cerebrovascular accident, lumbar disc disease, multiple sclerosis, pelvic surgery, pelvic radiation therapy, and peripheral neuropathy.32

Hypogonadism

Low serum testosterone levels are noted in up to 36% of patients with ED. However, the correction of sexual dysfunction with testosterone replacement therapy alone is poor, with treatment response at approximately 35%.33

Signs and symptoms of deficient testosterone may include loss of libido, ED, depression, lethargy, osteoporosis, loss of muscle mass and strength, and possible regression of secondary sexual characteristics including pubic hair and testicular size. Changes in behavior may include an inability to concentrate, diminished interest in activities, sleep disturbance, and depressed mood. It is obvious that many of these symptoms can be overlooked; thus, measurement of serum testosterone assays by equilibrium dialysis method (and not salivary testing) is recommended for the majority of patients who present with ED.34

The normal range for serum total testosterone levels during the early morning hours in healthy, young men aged 20 to 40 years is approximately 300 ng/dL to 1000 ng/dL. Total testosterone serum levels <200 ng/dL clearly indicate hypogonadism and suggest that these men may benefit from testosterone replacement therapy (TRT, Figure 4).35 Determinations of total testosterone levels between 200 ng/dL and 400 ng/dL should be repeated and testing should include the measurement of free testosterone.36

A number of systemic illnesses may suppress testosterone levels, including the following: cirrhosis, chronic renal failure, sickle cell anemia, thalassemia, hemochromatosis, HIV infection, amyloidosis, chronic obstructive pulmonary disease, rheumatoid arthritis, chronic infections, and inflammatory or debilitating conditions. Hypogonadism may be central (hypothalamic or pituitary) or testicular in origin. Therefore, after a low testosterone level has been determined, serum LH and prolactin levels should be measured, especially in men under 50 years of age. Men with a subnormal LH and/or elevated prolactin level should be further evaluated by MRI of the sella turcica area to visualize both the hypothalamus and pituitary gland.

Table 3. Commercially-Available Testosterone Preparations37,38

Type Generic Trade Dosing
Injectable Testosterone   cypionate Depo®-
testosterone		 100 mg/wk or
200 mg/2 wks
  Testosterone   enanthate Delatestryl® 100 mg/wk or
200 mg/2 wks
Oral Testosterone   undecanoate Andriol® 120-240 mg/d
Transdermal Testosterone
  patch		 Androderm®
Testoderm®		 6 mg/d
5 mg/d
  Testosterone
  gel		 AndroGel® 5-10 g/d
Treatment options for testosterone deficiency are noted in Table 3.37,38 Absolute contraindications for TRT include the following: documented prostate cancer, existing or prior history of breast cancer, and hematocrit >55. Relative contraindications include: hematocrit >52%, untreated severe sleep apnea, severe obstructive symptoms of benign prostatic hyperplasia (BPH), and advanced congestive heart failure. Data for long-term risks and benefits of TRT are limited. The risk/benefit ratio remains to be clarified.

Prior to implementation of TRT, baseline measurements of hematocrit, PSA, and a digital rectal exam of the prostate are performed. Efficacy and adverse effects are assessed at 6 to 12 weeks following initiation of TRT, again at 6 months, and then annually. This includes evaluating the clinical response (which may include the validated Androgen Deficiency in Aging Men or ADAM questionnaire), testosterone levels with a goal of mid-normal range, hematocrit, PSA, and digital rectal examination of the prostate at 6 months.39 The ADAM questionnaire developed at St. Louis University is one of three currently validated questionnaires addressing symptoms and findings related to hypogonadism.40

Table 4. Issues in Testosterone Supplementation and Risk of Prostate Cancer41-45

Many older men have microscopic foci of prostate cancer; T might make these subclinical foci grow41,42

Older men with low T levels may have prostate cancer43

PSA levels and prostate columns increase after T administration44,4,5

More intensive PSA screening might lead to greater number of biopsies and diagnoses of subclinical cancers41,42

 

Table 5. Interpretation of PSA During Androgen Therapy46,47

Change in serum prostate-specific antigen (PSA) of >1.5 ng/mL between measurements 3 to 6 months apart should be verified46,47

—Persistent PSA increase of >1.5 ng/mL warrants urologic evaluation46
When sequential PSA levels are available for >2 years, a PSA velocity of >0.75 ng/mL/year warrants evaluation47
The issues of prostate cancer risk and testosterone repletion are summarized in Tables 4 41-45 and 5.46,47 Testosterone replacement therapy does not cause prostate cancer, but may accelerate the growth of occult (eg, unknown to patient or physician) prostate cancer. Therefore, the protocol for TRT also includes periodic digital rectal examination of the prostate and PSA analysis, noting the sequential increase of PSA levels over time, and the ominous nature of a velocity of increase exceeding 0.75 ng/mL/year.46,47

The issue of whether TRT improves the efficacy of oral PDE-5 inhibitor drugs remains unclear.

Sleep Disorders

Forty-eight percent of men with sleep disorders have ED.48,49 Fifty percent of men with decreased nocturnal erectile activity have some form of sleep disorder.50 Finally, treatment of the sleep apnea syndrome may lead to improvement in erectile function.51 Apneic events have long been associated with oxygen desaturation and multiple cardiovascular complications.

Vascular Disease

The association of ED and cardiovascular disease is greater than would be expected on the basis of age and gender alone. In the Massachusetts Male Aging Study, ED was associated with increasing age and several atherosclerotic vascular disease risk factors. An elevated low-density lipoprotein (LDL)-cholesterol level or reduced high-density lipoprotein (HDL)-cholesterol level, diabetes mellitus, hypertension, or smoking at entry into the prospective cohort study was associated with a nearly fourfold increased risk of developing ED for any single factor present, with a greater likelihood of developing ED if multiple risk factors were present. In essence, the risk factors for ED are the same as those for coronary artery disease.52-54

Several studies have examined the issue of whether the presence of vasculogenic ED can serve as a predictor of asymptomatic ischemic heart disease. Clearly, the reverse assumption is true, and the greater the extent of heart disease, the greater the likelihood of ED. Dhabuwala and colleagues noted that 42% of their male patients who experienced a myocardial infarction (MI) reported ED.55 Morley and others observed that ED is present in two-thirds of men at the time of MI, and this incidence of penile vascular impairment has been demonstrated repeatedly in patients with coronary artery disease and other vascular risk factors.56 Shabsigh and coworkers have consistently noted that the incidence of ED was higher in patients with one vascular risk factor than in those with none, and that the severity of ED as noted in the proportion of abnormal vascular findings significantly increased as the number of risk factors increased.57 More recently, Greenstein and associates reported the outcome of a study, the first of its kind, to demonstrate that self-reported erectile function correlated with the number of afflicted coronary vessels in 40 men undergoing coronary angiography due to ischemic symptoms.58 Men with multi-vessel pathology were more likely to experience ED than were men with single-vessel disease. A positive correlation between the extent of ischemic heart disease and the degree of ED is clearly demonstrated.

Cardiovascular disease is clearly a predictor of ED. More than 64% of men hospitalized for an MI had ED prior to the event, and greater than 57% of men prior to coronary artery bypass surgery had ED.59 Both pelvic vascular surgery and angioplasty have been documented to improve erectile function. This all appears reasonable given that both ED and vascular diseases are endothelial dysfunction states. A healthy endothelium of the vascular wall is central to adequate vascular function and is influenced by multiple risk factors (eg, smoking, diabetes, atherosclerotic disease) that result in subsequent oxidative stress and endothelial cell dysfunction.60

ED is a predictor of occult dyslipidemias. Men presenting with ED have a significant risk of dyslipidemias. Billups found that of 89 men between 23 and 64 years of age who underwent penile Doppler ultrasonography and fasting lipid screening, 55% had some abnormal cholesterol level; 92% of these had evidence of penile arterial disease.61

Together, these data beg the question: “Is vasculogenic ED a predictor of occult coronary artery disease?” Occult coronary artery disease increases with age. Studies by nuclear imaging have suggested that by age 70 more than 33% is occult.62 In this context, the physician treating ED will confront cardiovascular disease as a co-morbidity in a significant number of patients. Of 50 men with ED who were prescribed sildenafil, 20 (40%) had significant coronary occlusions, with more than 56% of these men having a positive exercise treadmill test (ETT).63 These findings have been replicated by Kim and others who also examined potential predictors of asymptomatic ischemic heart disease in patients with vasculogenic ED.64 In almost 100 patients given pharmacologic erection tests and classified as responders or nonresponders, 50% of nonresponders had two or more cardiovascular risk factors. Of these, approximately 16% experienced ischemic changes on ETT.

Should all asymptomatic men who present with ED undergo noninvasive cardiac testing? Clearly, that argument cannot yet be made with certainty. But these men should undergo thorough cardiovascular risk assessment including evaluation for hyperlipidemia, hypertension, diabetes mellitus, and peripheral vascular disease. Further testing can thus be individualized based on the number of cardiovascular risk factors.

Finally, regarding the issue of potential tachyphylaxis with long-term sildenafil use, it is felt that the majority of men who initially respond well to sildenafil and on follow-up report a decrease in erectile function have worsening vascular disease or other concomitant disease states associated with ED. Many of these same men who report decreased efficacy also have poorly controlled lifestyle issues such as smoking, obesity, or sedentary behavior.65

In summary, it is the author's belief that clinicians should view ED as one of the most useful clinical tools available to help detect, manage, and improve the cardiovascular health in men.

TREATMENT OF ED: NEW ORAL AGENTS

The availability of sildenafil citrate (Viagra®), a phosphodiesterase type-5 (PDE-5) inhibitor and the first effective oral agent for ED, has dramatically increased the number of men seeking treatment and shifted much of the management for ED to primary care physicians. (Note that caffeine also is a weak PDE-5 inhibitor; anecdotal reports suggest that caffeine improves erectile function.66)

Sildenafil and other PDE-5 inhibitors inhibit the enzyme at low concentrations, binding to cyclic guanosine monophosphate (cGMP) sites, thereby increasing the release of nitric oxide, which mediates relaxation of penile vascular smooth muscle. Blood accumulates within the corpus cavernosum causing penile erection. Since the mechanism of the PDE-5 inhibitor class requires sufficient nitric oxide release mediated through sexual stimulation, it is not surprising that there is a “learning” effect in some patients who are reinitiating sexual activity. Although about two-thirds of men respond with the first two doses of sildenafil, the remaining begin to respond only upon subsequent dosing, reaching a maximum threshold of response after 6 to 8 doses.67

Two other oral erectogenic agents are expected to become available in the near future. Both are also PDE-5 inhibitors. A portion of the ring structure of vardenafil and sildenafil is similar to that of caffeine; the ring structure of tadalafil is different but, nevertheless, it appears to have the same mechanism of action as vardenafil and sildenafil. Pharmacokinetically, vardenafil and sildenafil have similar elimination half-lives (t 1/2 3.9 hours and 3.8 hours respectively), while the half-life of tadalafil is markedly longer (17.5 hours).78

The release of these new PDE-5 inhibitors will greatly expand the primary care clinician's choices for first-line ED therapy, and, in addition, will raise important questions for the clinician. First, how should one choose between these three drugs? Second, how do the new drugs differ from sildenafil, the benchmark during the past 5 years of oral treatment of ED? To date, the PDE-5 inhibitors have accumulated a tremendous amount of reassuring safety and efficacy data.

While response rates to sildenafil are high, depending on the underlying cause of ED, up to 20% to 40% of patients may fail to respond to PDE-5 inhibition.68 Twelve percent of men may discontinue the drug within 2 years due to lack of efficacy, yet it remains uncertain if this is due to actual loss of efficacy, inadequate follow-up, or worsening control of underlying co-morbid disease states. In controlled clinical trials, discontinuation rates due to insufficient clinical response over 2 to 3 years are reported to be only 2.1%.69 Finally, only 1% to 3% of men discontinue sildenafil because of adverse effects.70

Clearly, current pharmacologic treatment of ED can be improved upon and individualized with regard to efficacy, pharmacokinetics, and adverse effects. But significant attention must be given to the overall management of the ED patient to allow such therapies to deliver optimal outcomes.

To understand the new oral agents in the absence of controlled head-to-head clinical trials, it is important to examine some of their distinguishing features, including selectivity, onset and duration of action, safety, and efficacy in disease states commonly seen by the primary practitioner.

Selectivity and Potency

Selectivity is an important issue because there are no pure PDE-5 inhibitors. In addition to inhibiting PDE-5, both sildenafil and vardenafil also produce modest PDE-6 inhibition effects at the upper limits of therapeutic doses (PDE-6 inhibition affects the retinal cones, thereby resulting in the blue vision experienced by some users of sildenafil and vardenafil).71 These effects are absent with tadalafil. In vitro selectivity for PDE-6 is sildenafil>vardenafil>tadalafil (Figure 5).72 In contrast, only tadalafil has definite PDE-11 inhibition at therapeutic doses, although the significance of this is not yet clear. In vitro selectivity for PDE-11 is tadalafil>sildenafil>vardenafil. PDE-11 is present in the pituitary, heart, testes, and corpus cavernosum. Its inhibition does not appear to lower sperm counts.

Potency of enzyme inhibitors is often documented in terms of their 50% inhibitory concentration (IC50), which is defined as the concentration of the compound required to produce 50% inhibition of the enzyme. The lower the IC50, the greater the biochemical potency. The IC50 (in nM) for vardenafil is 0.7 versus 6.7 for sildenafil and 9.0 for tadalafil (Figure 6).73 This implies that it takes 1/90th of the amount of vardenafil to achieve the same PDE-5 inhibition as sildenafil. How this translates to clinical efficacy remains unclear at this time, and biochemical potency should not be confused with clinical potency, since many other factors such as drug absorption, distribution, and elimination also contribute to potency.74

Table 6. Pharmacokinetics of PDE-5 Inhibitors78

  Sildenafil Tadalafil Vardenafil
Peak Blood Level
(tmax h) 		1.16±0.99 2.0 0.66
(0.25-3.0)
Duration of Action
(t1/2 h) 		3.82±0.84 17.5 3.9±1.31
Maximum Concentration
(Cmax ng/mL) 		327±236 378 20.9±1.83
Area Under
Concentration Curve
(Cmax ng x h/mL) 		1963±859 8066 74.5±1.82
None of these agents works immediately or without sexual stimulation. Most studies suggest that they have an onset of action of 30 to 60 minutes, although there have been reports that vardenafil may be effective in as few as 15 to 16 minutes. In general, the onset of action varies from individual to individual, and may be lengthened for both sildenafil and vardenafil with interference in their absorption by food. The absorption of tadalafil appears to be independent of the action of food, which is most likely related to its longer Tmax (Table 6).75-78

Duration of Action

This is an exciting area of differentiation between the three agents. The reported duration of action (t1/2) of sildenafil and vardenafil is approximately 4 to 5 hours; for tadalafil, it is between 17 to 21 hours. While tadalafil may provide some men greater confidence in erectile function without regard to time and allow for greater spontaneity, one must fully understand the implications of prolonged PDE-5 inhibition, especially in those with concomitant heart disease. Because of tadalafil's prolonged duration of action, it will take up to 4 days to eliminate the drug completely from the body. This could potentially extend the duration of adverse effects or delay intervention with nitroglycerin during an adverse cardiac event.

Adverse Effects and Safety

Safety is clearly an important concern given that many men treated for ED have identical risk factors for cardiovascular disease. A careful assessment of cardiovascular status before prescribing treatments for ED and/or advising the resumption of sexual activity is recommended.79 To date, there is no evidence that any PDE-5 inhibitor has direct adverse cardiovascular effects. In fact, the reverse may be true, as recent studies suggest that sildenafil may delay exercise-induced ischemia and angina.80

These are well-tolerated agents, which have similar adverse effects that are mild to moderate in intensity and lessen with use. The most common adverse events resulting from vasodilation are headache, nasal congestion, facial flushing, and dyspepsia. There appears to be a greater incidence of myalgia and low back pain with tadalafil, although the etiology of the myalgia remains unclear. None of the PDE-5 inhibitors has significant drug interactions noted except for an absolute contraindication with concomitant use of nitrates. All of these agents are contraindicated with the concomitant use of nitroglycerin. Sildenafil and all agents in this class potentiate the nitrate-induced vasodilation effect of hypotension.

Efficacy

Table 7. PDE-5 Inhibitors: Present and Future Efficacy Measurements

Evaluation Methods are often presented in the form of 3 questions:

Sexual Encounter Profile (SEP):

— SEP Q2 (Rigidity, Mean Success Rate):
  “Were you able to insert your penis into your partner's vagina?”
— SEP Q3 (Maintaining):
  “Did your erections last long enough to have successful intercourse?”
   

Global Assessment Question (GAQ):

—

“Has the treatment you have been taking over the past 4 weeks improved your erections?”

Efficacy is often evaluated through a series of questions (Table 7). A placebo-controlled study demonstrated an improvement from a baseline of 51% penetration rate (SEP Q2) to 75% and 81% respectively at 10 mg and 20 mg doses of vardenafil determined at 12 weeks, without change at 26 weeks (Figure 7).81 In the same study, the maintenance rate (SEP Q3) improved from 30% with placebo to 65% in both the 10 mg and 20 mg groups at 12 weeks. Finally, a phase III multi-center trial evaluated the efficacy of vardenafil at doses of 5, 10, and 20 mg versus placebo in 508 patients with hypertension, BPH, and diabetes.82 In response to the GAQ after 12 weeks of treatment, 65% of patients in the 5 mg treatment group, 72% in the 10 mg group, and 81% in the 20 mg group responded positively, in contrast to an average placebo response rate of 39%.

The GAQ data gleaned from the Vardenafil Prostatectomy Study rose from a 12.5% positive response with placebo to 65.2% with 20 mg at 12 weeks, and in the Vardenafil Diabetes Study rose from a 13% positive response with placebo to 72% with 20 mg at 12 weeks.83,84

Tadalafil is a highly potent and selective inhibitor of PDE-5. Padma-Nathan et al found the following in response to the GAQ at 12 weeks, with a 35% response to placebo: 42% improvement at 2.5 mg, 50% improvement at 5 mg, 67% improvement at 10 mg, and 81% improvement at 20 mg.85 The efficacy rates are also comparable to vardenafil in response to the GAQ in the diabetic population with a 32% response to placebo, 51% at 5 mg, 61% at 10 mg, and 76% at 20 mg. Tadalafil also scored high in patient response to SEP Q3 (ie, successful intercourse). The percentage of successful intercourse attempts ranged from 32% with placebo to 61% at 10 mg, and 75% at 20 mg.

In contrast, sildenafil's efficacy at 12 weeks with 50 mg is 87% vs 35% with placebo in men with mild to moderate ED; and 65% vs 12% placebo in men with severe ED.86 When comparing the efficacy data of these PDE-5 inhibitors, however, one must use caution given that there are no head-to-head comparative trials and that different patient populations may impact treatment outcomes.

CARDIOVASCULAR DISEASE AND PDE-5 INHIBITORS

With the introduction of sildenafil, many physicians were concerned that administration of sildenafil to men with ischemic coronary artery disease would result in a “steal syndrome” by dilating nondiseased arteries. This diverted blood flow might then result in exacerbation of ischemic disease during the physical exertion of sexual intercourse. Hermann et al assessed the systemic, pulmonary, and coronary hemodynamic effects of oral sildenafil (100 mg) in 14 men with severe stenosis of at least one coronary artery (>70% lesion) who were scheduled to undergo percutaneous coronary revascularization.87 Coronary blood-flow velocity and flow reserve were assessed in 25 coronary arteries, including 13 severely diseased arteries and 12 without stenosis. Oral sildenafil produced only a small decrease (<10%) in systemic arterial and pulmonary arterial pressures, and it had no effect on pulmonary-capillary wedge pressure, heart rate, or cardiac output. Coronary flow reserve at baseline was lower in the stenosed arteries than in the nondiseased arteries and increased significantly in both groups following administration of sildenafil. It was thus concluded that no adverse cardiovascular effects of oral sildenafil were detected in men with severe coronary artery disease and that a small positive effect on coronary blow flow reserve was seen. In another recent study by Halcox et al, it was verified that sildenafil dilates epicardial coronary arteries, improves endothelial cell dysfunction, and inhibits platelet activation in patients with coronary artery disease.88 Further, it has an intermediate effect on myocardial ischemia compared with isosorbide dinitrate and placebo. This is not surprising given that sildenafil was originally conceived as an anti-anginal drug.

From placebo-controlled and open-label phase II/III clinical trials including men with ischemic heart disease, the following conclusions can be made:

  • There is no evidence for an increase in MIs or other serious cardiovascular events in patients treated with sildenafil compared to those taking placebo.89 Furthermore, the number of spontaneous reports of deaths among sildenafil users falls within the range of mortality rates from heart disease described in epidemiologic studies.
  • In a retrospective analysis of 357 men reporting a history of stable ischemic heart disease, 70% reported improved erections (SEP Q2) taking sildenafil versus 20% with placebo.90
  • The effects of sildenafil in men with severe coronary artery disease have been evaluated using hemodynamic monitoring. The medication exerted no effect on heart rate, cardiac output, or other central cardiac parameters. Coronary blood flow reserve increased by 13% in both stenosed and nonstenosed arteries following treatment.91
  • In men with coronary artery disease assessed by stress echocardiography following administration of sildenafil, an average of 7 mm Hg systolic blood pressure reduction was noted with no change in exercise capacity or hemodynamic response to exercise.92

Implications for therapy based on these data are as follows:

  • No significant additional risk exists with the use of PDE-5 inhibitor therapy in men with stable cardiac disease.
  • Modest reductions in blood pressure occur with PDE-5 drug therapy, with no orthostatic effects.
  • Co-administration of organic nitrates and PDE-5 inhibitors produces a synergistic effect in lowering blood pressure to a significant degree.

A slight risk of developing ischemia or infarction is associated with sexual activity as noted in the Myocardial Infarction Onset Study, which concluded that the relative risk of an MI occurring in the 2 hours after sexual activity was 2.5—a risk no greater than that associated with anger and unaccustomed physical exercise.93 Thus, the risk of MI associated with sexual intercourse, though small, is real. Only 0.9% of all myocardial infarctions are thought to be associated with sexual activity.94 Therefore, it is more likely that an MI after taking sildenafil as directed is more likely to be due to the activity of sexual intercourse rather than the medication itself.

Table 8. High-risk Patient: Princeton Guidelines95

Unstable or refractory angina

Uncontrolled hypertension

LVD/CHF (NYHA class III/IV)

Recent MI (<2 wk); CVA

High-risk arrythmias

Hypertrophic obstructive and other cardiomyopathies

Moderate/severe valvular disease

 

Table 9. Indeterminate-risk Patient: Princeton Guidelines95

Three major CAD risk factors, excluding gender

Moderate, stable angina

Recent MI (>2, <6 wk)

LVD/CHF (NYHA class II)

Noncardiac sequelae of atherosclerotic diseases such as CVA, PVD

In summation, these drugs are highly efficacious and safe in the cardiac patient as determined through extensive study and experience with sildenafil. However, the risk of MI and sexual activity must be assessed according to the Princeton Consensus Guidelines, with a risk stratification of the patient. The primary care practitioner must become comfortable with this stratification of risk for each patient who enters the office and presents with the concomitant co-morbidities of ED. By following these simple guidelines, patients can be assured about the safety of these agents and the general safety of sexual intimacy, something often not adequately addressed in the cardiac patient (Tables 8 and 9).95

 

CONCLUDING THOUGHTS

This is a most difficult time in primary care practice. The frustrations of working within the constraints of managed care, with focus on increased volume of patient flow to offset lowered reimbursements, have driven some physicians to establish “boutique practices” for a limited number of patients providing more individualized care for a fee. Yet the patient-physician relationship and the trust ensued remains a rewarding and vital domain of the patient encounter. Physicians may feel multiple pressures, yet they continue to do their best to connect to patients and provide timely, effective, and preventative care.

There are compelling reasons why primary care practitioners should be interested in diagnosing and treating ED. They are often the first to address the topic with their patients. ED is both a sign and symptom of common co-morbid disease states in men. Patients are often grateful following discussions about sexual matters and show their gratitude with increased enthusiasm for better health and increased confidence and loyalty to their physician.

Table 10. Practical Approach to ED Management: Code Properly for Reimbursement

ICD-9 Codes Applicable to Erectile Dysfunction
607-84 Organic erectile dysfunction
302-72

Psychosexual dysfunction with inhibited sexual excitement

In reality, there is a minimal increase in the clinician's time to manage these issues satisfactorily, if they are raised in the settings described earlier. Patients are more satisfied and maintain greater regularity with attendance to their appointments. Word-of-mouth endorsements occur with resulting new referrals. Such professional service is reimbursable, by coding for organic ED (Table 10). Finally, it blends the art of medicine with the physiology of a domain sacred to most individuals—sexual function and emotional intimacy—with evidence-based science.

Men's health is thus far greater than male sexual health. It encompasses empowering men to seek medical attention earlier, live healthier and less risk-taking lifestyles, and experience greater connectedness to family and friends. It should focus on age-appropriate screening and preventative care. It is the author's belief and experience that by raising issues of sexual health, one can establish a rapport to achieve these goals. Erectile dysfunction can provide a window into male cardiovascular health, similar to the examination of the fundus of the eye. It is one more effort to acknowledge male vulnerability and address their complete health care needs.

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