JAMA. 2004;291:2994-3003.
INTRODUCTION
DR BURNS: Mr G is a 66-year-old man with a history of hypertension and sleep apnea. He lives in a suburb of Boston with his wife and has commercial indemnity insurance.
Mr G first developed erectile dysfunction (ED) several years ago. Four months ago when he saw his primary care physician for a routine checkup, he asked about using sildenafil (Viagra). He noted decreased libido and difficulty attaining an erection. He had slight urinary urgency, but no difficulty initiating urination. He had no history of diabetes or cardiovascular disease. In the past, he had used a dental device to treat his sleep apnea but was no longer using one. His other past medical history was a colonic adenoma found on a screening colonoscopy in 2001. His medications were aspirin (81 mg daily), hydrochlorothiazide (12.5 mg daily), and ibuprofen (600 mg 4 times a day as needed). His wife had metastatic breast cancer and was doing well with maintenance therapy. He was working part-time and noted considerable stress due to a home renovation project.
On physical examination his blood pressure was 150/90 mm Hg; his heart rate was 76/min; his lungs were clear to auscultation; and his heart had regular rate and rhythm without murmurs, rubs, or gallops. The abdomen was soft and nontender, without organomegaly. Genitourinary examination revealed small soft testicles and a smooth firm prostate that was minimally enlarged without nodules. His pulses were bilaterally intact.
Laboratory evaluation for secondary causes of ED included the following values: prolactin (4.9 µg/L [reference range, 2-20 µg/L]), thyroid-stimulating hormone (1.7 mIU/mL [reference range, 0.27-4.2 mIU/mL]), total testosterone (505 ng/dL [17.5 nmol/L]; reference range, 270-1100 ng/dL [9.4-38.2 nmol/L]), free testosterone (1.0 ng/dL [0.03 nmol/L]; reference range, 1.5-3.5 ng/dL [0.05-0.12 nmol/L]), and prostate-specific antigen (PSA) (1.4 ng/mL [reference range, 0-4 ng/mL]).
Atenolol (25 mg daily) was added to improve his blood pressure control. He was given a prescription for sildenafil (50 mg to take as directed).
Two months later, Mr G was seen at a follow-up examination. At that visit, his blood pressure was well controlled with hydrochlorothiazide (12.5 mg) and atenolol (25 mg). He noticed no change in his sexual difficulties with the addition of atenolol. Mr G stated that after reading the patient information sheet about potential adverse effects of sildenafil, he decided not to take the medication. His primary care physician suggested that he see an endocrinologist or urologist about beginning testosterone replacement. Mr G is concerned about the potential adverse effects of testosterone therapy. He wonders about the pros and cons of the different treatment options for male sexual dysfunction.
MR G: HIS VIEW
I'm not quite sure if it started when my wife was getting sick, but that's when it became more noticeable. Not the same desire, and physically it changed. The erection wasn't there. It becomes an embarrassment. That's how I felt about it. So you know, I really didn't say anything. I never investigated it. Maybe I'm from the old school that's very private. But the only thing that I ever knew that they would do is the implants, the Viagra [sildenafil], or the testosterone.
I think Viagra and the testosterone need to be better explained. It seems like they're always putting a mystery to it. The side effects can be a lot worse than what people tell you. They'll say, with Viagra, 10% of the people may have this side effect. But if you're among those 10%, wouldn't you like to know about it first? The only way that I found out about the side effects was I went to the drug store and asked for a printout as to what it does and how it works. Even the pharmacist said, "I don't know all the side effects, because some of them are so minuscule that they're not printed." But if you're affected by it, it makes a big difference.
I'm not very keen on taking medication. So I'd have to do quite a bit of thinking about it, you know. And right now, I'm undecided.
DR K: HIS VIEW
Mr G actually came to me and asked me for a prescription for sildenafil. He said that he had a normal libido. It wasn't an issue of libido so much as initiating and maintaining erections. One thing that's happened as a result, I think, primarily because of advertising by the drug company that makes sildenafil, is that people come in and actually raise the issue much more easily than they used to.
In someone like this patient, particularly with a borderline low or a low free testosterone value, who probably would respond to either testosterone or sildenafil, what would Dr Morgentaler recommend? I'd like to know whether he thinks that every gentleman who is given a prescription for testosterone should get a prostate biopsy. I'd also like his opinion on whether primary care physicians should be managing much of this by themselves and when the urologist is particularly useful.
AT THE CROSSROADS: QUESTIONS FOR DR MORGENTALER
What is the definition of male sexual dysfunction? How prevalent is it? What are the causes and pathophysiology of ED? What evaluation should be undertaken for a man with sexual dysfunction? What are the medical treatment options? When should a patient be referred to a urologist for sexual dysfunction? What are the surgical treatment options and when should they be considered? What are the risks and benefits of each? What do you recommend for Mr G?
DR MORGENTALER: Mr G is a 66-year-old married man who presents with a history of diminished libido and ED of several years' duration. The onset of symptoms began when his wife became ill. The history suggests various possibilities regarding etiology: psychological (temporal relationship to wife's illness), vascular (age and hypertension as risk factors), or hormonal (low serum testosterone level). Although sildenafil was prescribed, Mr G never tried it. Mr G expressed concerns about the risks of treatment for sildenafil as well as for testosterone.
Mr G presents with a set of common, yet vexing problems for the primary care physician. What kind of evaluation is required for a man with sexual dysfunction? In a case such as this, how does the clinician decide whether to treat first for hypogonadism (low serum testosterone level) or ED, and how to balance risks vs benefits for treatment of a quality-of-life issue such as male sexual dysfunction?
Male Sexual Dysfunction
Male sexual dysfunction can be broadly separated into several major categories, as outlined in Box 1. The introduction of sildenafil, the first of the oral phosphodiesterase inhibitors, in 1998 has created widespread recognition of ED as a primary form of sexual dysfunction in men, and there is gathering interest as well in hypogonadism. However, there is far less awareness of ejaculatory disorders and of anatomical abnormalities of the penis such as Peyronie disease, an inflammatory condition of the penis that results in palpable plaque or curvature with erection.
Box 1. Classification of Male Sexual Dysfunction
It is of the utmost importance to distinguish which of these conditions is present when a man complains of sexual dysfunction, recognizing that more than one may be present in a given individual.1 This is particularly true in older men, since both ED and hypogonadism become increasingly prevalent with age. A common error is to assume that any sexual complaint in a man represents ED, which may lead to inappropriate and ineffective treatment.2 For example, sildenafil is generally not helpful for men with a primary complaint of diminished libido.3
Mr G presents with symptoms of both ED and diminished libido. Sildenafil, as a treatment for ED, may be a reasonable first step. However, successful treatment of patients like Mr G requires an approach that addresses both conditions. Participation by the partner is always encouraged and can be extremely useful; however, many men prefer to address their sexual dysfunction as a personal issue without involvement of their partner, and this wish must be respected.
A Second Sexual Revolution
The advent of oral contraceptives, coupled with the women's liberation movement in the 1960s, ushered in major changes in sexuality and sexual attitudes and has often been termed a "sexual revolution." The introduction of sildenafil in 1998 has created a second sexual revolution, not only because it is the first effective and safe oral medication for the treatment of ED, but also because it has widely affected social attitudes and behaviors regarding sexuality.1-2 Men, as well as women, are now much more likely to raise the topic of sexual dysfunction with their physicians, and it has become a common scenario for patients like Mr G to specifically request a prescription for Viagra (sildenafil) by name. Sexual dysfunction can lead to depression and a profoundly altered sense of self-esteem that negatively affects many relationships; increased awareness and treatment are thus to be greatly encouraged, due to the profound benefits in life satisfaction that may result.2
Epidemiology of ED
Erectile dysfunction is one of the most common chronic disorders affecting men and becomes increasingly prevalent with age. Data from the Massachusetts Male Aging study showed that 52% of men aged 40 to 70 years reported some degree of ED.4 A similar prevalence of ED has also been found in numerous countries worldwide, affecting greater than 40% of men older than 60 years of age in Finland,5 Italy,6 Japan,7 the United Kingdom,8 Australia,9 and Iran.10
Risk factors for ED include age, diabetes mellitus, hypertension, hyperlipidemia, coronary and peripheral vascular disease, smoking, obstructive voiding symptoms, obesity, renal failure, and alcoholism.4, 11 It is difficult to estimate the relative prevalence of these various etiologies, particularly since more than one may be a contributing factor for many affected men.
Medications are also a common contributing factor. The most common offenders include antihypertensive medications, digoxin, antidepressants, spironolactone, -adrenergic agents, and testosterone-lowering medications, such as gonadotropin-releasing hormone agonist/antagonists. New-onset ED associated with a new medication, or an increased dosage, suggests medication as the likely cause. However, this may occur on either a physical or psychogenic basis, since sexual function may be compromised by fears associated with beginning any new treatment, particularly related to cardiovascular health. For instance, the -blocker class of antihypertensives has generally been considered one of the most common causes of medication-induced ED.12 However, in a study of 96 men with newly diagnosed cardiovascular disease and without ED, 31% reported ED after beginning treatment with atenolol (50 mg) and being informed of its sexual adverse effects. In contrast, only 3% of men who were similarly treated reported ED when they were blinded as to the study drug.13 Nevertheless, the development of new or worsening sexual dysfunction of any type in temporal association with initiation of a new medication should prompt consideration of discontinuation of the medication. Treatment with a phosphodiesterase type 5 (PDE 5) inhibitor may be indicated depending on individual circumstances and the medical necessity of the new medication.
There is growing evidence that ED itself represents a risk factor for subsequent development of cardiovascular events, since it is often a manifestation of atherosclerotic disease.14-15
Pathophysiology of ED
Erection occurs as a coordinated event involving psychic arousal and increased arterial inflow to the corpora cavernosa of the penis in response to parasympathetic nerve signaling via the S2-4 nerve roots, together with trapping of blood within the corpora cavernosa via a veno-occlusive mechanism mediated by smooth muscle relaxation12 (Figure 1). Psychic arousal and sexual behavior is facilitated by androgen priming of the anterior hypothalamus/preoptic area.16 Flaccidity occurs in response to sympathetic influences. Corporal smooth muscle relaxation is mediated by the conversion of guanosine triphosphate (GTP) to cyclic guanine monophosphate (cGMP), under the influence of nitric oxide.17-18 The medications sildenafil, vardenafil, and tadalafil act by inhibiting the metabolism of cGMP by PDE 5, which is found almost exclusively in the corpora cavernosa.19
Erections may fail due to inadequate psychic arousal (eg, anxiety, depression); inadequate hormonal priming of sexual centers in the brain (eg, low testosterone); inadequate nerve signaling to the penile vessels (eg, spinal cord injury, multiple sclerosis, radical prostatectomy); arterial insufficiency (eg, atherosclerosis, vascular surgery, pelvic/perineal trauma); or impaired veno-occlusive ability within the corpora cavernosa (eg, radiation, Peyronie disease, atherosclerosis).1
Evaluation of the Man With ED
Face-to-face evaluation provides the best opportunity to explore the physical and psychological aspects of male sexual dysfunction and allows for identification of modifiable risk factors that may have an impact on general health, such as low serum testosterone level, diabetes mellitus, hypertension, hyperlipidemia, smoking, alcoholism, and depression. Creation of a therapeutic relationship may be critical for a successful outcome, since initial treatment attempts are often less than completely satisfactory.
The Sexual History. The primary goals of the sexual history are to identify the problem, assess its severity, and determine the degree to which the patient and/or his relationship has been affected. The diagnosis of ED is made by history alone and is defined by the inability to achieve or maintain an adequate erection for satisfactory sexual function.1 If ED is present, it is useful to try to determine whether the problem is likely to be organic (physical) or psychological in etiology, since this may influence treatment. Complicated psychosocial issues should be referred to a mental health professional. In Mr G's case, it is noteworthy that he describes his difficulties as occurring around the time of his wife's illness. This is not an uncommon presentation and suggests a psychological contribution to the sexual dysfunction. Some men may understandably feel hesitant or guilty about initiating sex when their partner has been ill, even when the partner encourages the activity.
I recommend a set of questions that are direct and nonjudgmental (Box 2).20 The use of clear terminology, such as the words "penis," "erection," and "orgasm," is helpful, particularly since this gives the patient the opportunity to use similar language without concern that he is using offensive terms. Two questions that have been particularly valuable in my experience are: "What happens when you try to have sex?" and "Is the penis usually hard enough to go inside your partner?"
The intermittent or sudden inability to have a firm erection suggests a psychogenic etiology. Low sexual desire suggests the diagnosis of hypogonadism, depression, or a medication effect. Inability to maintain an erection is most often due to poor veno-occlusive function of the penis, but it is helpful to ask whether softening of the penis happens before or after orgasm, since men with premature ejaculation may describe their symptoms similarly.1
Physical Examination. A directed physical examination should be performed for the man with sexual dysfunction. Specific items to be evaluated include assessment of general health, vigor, mood, and blood pressure. The presence of gynecomastia should be noted. The penis should be palpated to identify the presence of penile plaque, which is indicative of Peyronie disease. Testicular size and consistency should be noted, since small, soft testicles are associated with low serum testosterone level. Peripheral pulses should be evaluated. Neurological assessment should include a digital rectal examination (DRE), since nerve roots S2-4 mediate both erection and anal tone. The prostate should be assessed for size and for the presence of nodularity or asymmetry.
Diagnostic Tests. The goal of diagnostic testing in the primary care setting is to identify abnormalities that may contribute to sexual dysfunction, such as an endocrinopathy, or treatable medical conditions that may be associated with ED, such as diabetes and hyperlipidemia. For this reason, based on clinical experience, I recommend routinely performing the following blood tests in men who present with ED: hematocrit, glucose, total and free testosterone, prolactin, and a lipid profile. Tests of thyroid function and hemoglobin A1C are optional. The luteinizing hormone level should be measured if the history suggests hypogonadism. Men with penile curvature or premature ejaculation do not require diagnostic testing but should be referred to an appropriate specialist, usually a urologist. Testosterone levels should be considered in men with difficulty achieving orgasm unless their symptoms are clearly related to medications known to have this adverse effect, such as the serotonin reuptake inhibitor class of antidepressants.21
A variety of testosterone assays exist. Total testosterone has been used most frequently; however, since the majority of circulating testosterone is bound tightly to sex hormone–binding globulin and is not biologically functional, exclusive reliance on the total testosterone assay will result in underdiagnosis of hypogonadism. Although there is as yet no consensus regarding what serum level defines hypogonadism, values less than 300 ng/dL (10.4 nmol/L), and in some cases 350 ng/dL (12.1 nmol/L), are often used as an inclusion criterion for clinical trials. Unfortunately, the reference ranges for serum testosterone provided by many laboratories are overly generous at the lower range, resulting in categorization of too many results as normal when in fact they suggest hypogonadism.22 The measurement of bioavailable or free testosterone appears to be more useful. Although there is debate regarding the accuracy of the widely used analog assay for free testosterone,23 my experience is that it aids considerably in the identification of hypogonadal men who might benefit from treatment.24 There is no basis for the use of age-adjusted reference values for testosterone, since men of any age will experience similar symptoms at low testosterone levels.
More sophisticated tests, such as nocturnal penile tumescence and rigidity monitoring25-26 or penile Doppler ultrasound of the cavernosal arteries,27 can provide additional functional information but are not necessary in the initial evaluation.
Oral Phosphodiesterase Inhibitors
Treatment must be tailored to the individual. Some men may not desire treatment at all. Others, perhaps like Mr G, are interested primarily in gathering information about treatment options before initiating therapy.
The oral phosphodiesterase inhibitors—sildenafil, vardenafil, and tadalafil—represent first-line therapy for men with ED. Sildenafil and vardenafil have similar pharmacokinetic properties, with peak serum concentrations at approximately 1 hour and a half-life of 4 to 5 hours.3, 28 Tadalafil has a considerably longer half-life of approximately 18 hours, with evidence that erectile function continues to be enhanced for at least 36 hours.29 Although to date no head-to-head clinical trial results between these drugs have been published, their overall clinical efficacy appears to be fairly similar, with minor differences in results likely due to variations in the patient populations studied.3, 28, 30 For example, in a double-blind randomized study of 532 men, successful intercourse was achieved in 69% of men receiving 100 mg of sildenafil compared with 22% of men receiving placebo.3 In a study of 348 men using tadalafil (20 mg), 59% successfully reported intercourse at 36 hours, compared with 28% in the placebo group.30 And in a multicenter, double-blind, placebo-controlled trial, 69% of men receiving vardenafil (20 mg) successfully reported completing intercourse, compared with 22% receiving placebo.28
Approximately half of men with diabetes mellitus or more advanced coronary and peripheral vascular disease report benefit.31-32 A success rate of roughly 30% has been noted following radical prostatectomy.33 An attempt at treatment with oral agents is warranted only if the nerves have been spared, and even then, success is unlikely unless at least partial return of erections has occurred.
Patient education is critical for optimal response to sildenafil. This includes informing the patient to take the medication on an empty stomach and to time sexual activity so that it occurs within 1 to 6 hours, as well as explaining that sexual activity of some sort is necessary to obtain a positive effect. If an initial starting dose of 50 mg is ineffective, I recommend increasing the dosage immediately to 100 mg: nothing is gained by repeated attempts at a subtherapeutic dose. Similar instructions should be provided for vardenafil. However, instructions regarding the timing of intercourse may be considerably liberalized for tadalafil due to its prolonged duration of effect, although peak concentration occurs somewhat later, at 2 hours.
Limitations. Many men who fill prescriptions for sildenafil never refill them, and many others, like Mr G, receive a prescription but never fill it. Reasons for this include ambivalence about taking a medication for sex, cost, concerns regarding risk, and negative partner attitudes regarding sex or the medication. Many men and their partners believe that sexual activity should be natural and spontaneous, and they object to the planning required for successful use of oral medications. Still others may hope that their own sexual abilities will return with time or with resolution of personal problems.
Risks. The phosphodiesterase inhibitors have undergone extensive clinical study and have a fairly benign safety profile when taken as directed.3, 28, 30 The single important contraindication is the use of any nitrates, either on a chronic or intermittent basis, due to the potential for significant hypotension. Sildenafil also should not be taken within 4 hours of -adrenergic blockers,34 and vardenafil should not be used at all with them.35 The most common adverse effects are headache (15%), flushing (10%), nasal/sinus congestion (8%), dyspepsia (7%), and transient color vision changes (3%).3, 27, 29 Mr G should be reassured that priapism is extremely rare and treatable, and that he may safely take sildenafil in combination with his antihypertensive medications, atenolol and hydrochlorothiazide.36
Cardiovascular Effects. The relationship of PDE 5 inhibitors and cardiovascular health has been extensively studied. Daily administration of tadalafil (20 mg) for 26 weeks in healthy men or patients with mild ED resulted in blood pressure changes similar to those observed after placebo administration.37 Sildenafil studies have revealed a minor reduction in systolic and diastolic pressures of 2 to 8 mm Hg without appreciable change in heart rate.38
The cardiac effects of sildenafil during exercise in men with suspected coronary artery disease was studied in a randomized, double-blind, crossover study of 105 men with ED who underwent supine bicycle echocardiograms 1 hour after taking sildenafil or placebo. No negative effect of sildenafil was seen with regard to symptoms, exercise duration, or ischemia.39 Similar safety was noted in a double-blind single-dose crossover study using vardenafil (10 mg) or placebo in 41 men with stable exertional angina who underwent exercise tolerance testing.40 No differences were noted between vardenafil and placebo with regard to exercise time or time to first awareness of angina, but vardenafil did significantly prolong the time to ischemic threshold.
A persistent concern among men and their partners is that sildenafil or its competitors might cause a myocardial infarction, based on early reports of sudden death reported in the lay press. An unquantified number of these anecdotal cases were clearly related to the contraindicated simultaneous use of nitrates. Nevertheless, the data regarding PDE 5 inhibitors and coronary artery disease have been reassuring. Cardiac catheterization for severe coronary artery disease was performed in 14 men before and 45 minutes following administration of sildenafil (100 mg), resulting in no negative hemodynamic effects.41 Moreover, an investigation of reports of sildenafil-associated deaths showed no difference from expected death rates,42 and the rate of cardiac events in England among users of sildenafil appeared to be no higher than that of the general population.43 Nevertheless, it must be recognized that sexual activity itself is associated with a small risk of myocardial infarction,44 and cardiovascular assessment should be considered prior to treatment of ED in any patient considered at increased risk for a cardiac event.
Since cardiovascular disease often coexists with ED, the Princeton Consensus Panel was convened to review existing data and provide recommendations regarding the treatment of sexual dysfunction in men with heart disease.45 Those recommendations indicate the need for no additional evaluation prior to treatment for men in a low-risk group, including those with controlled hypertension; mild, stable angina; history of uncomplicated myocardial infarction; and mild valvular disease. A high-risk group was identified in whom treatment of sexual dysfunction should be withheld until further safety data could be accumulated. This group included men with unstable or refractory angina, uncontrolled hypertension, high-grade congestive heart failure, myocardial infarction within the previous 2 weeks, high-risk arrhythmias, obstructive cardiomyopathy, and moderate to severe valvular disease. Men with intermediate risk, eg, those with moderate angina or recent myocardial infarction (<6 weeks), should undergo further cardiac evaluation before restratification into one of the other groups.
Other Treatment Options for ED
Treatment options for ED, benefits, and approximate costs are presented in Table 1. Penile injections with vasoactive medications are effective in 70% to 80% of patients, have an onset of action within 10 minutes, and are nearly painless.46-47 They represent the most common treatment for men who take nitrates or have had no success with phosphodiesterase inhibitors and are used by approximately 10% of men with ED. Alprostadil48-49 is most frequently prescribed but can cause an unpleasant burning sensation in about 20% of men. Papaverine and phentolamine can be used to avoid this problem or used in combination with alprostadil for greater efficacy.50 In a study of 615 cases of men using penile injection therapy, penile fibrosis was noted in 3%, and 4% of men experienced a prolonged erection, representing 0.3% of injections.47 Although less than half of men taught to use penile injection therapy continue to use this therapy for more than a few years,51 satisfaction rates among users are comparable to men who use sildenafil as therapy for ED.52
Intraurethral suppositories of alprostadil avoid penile injection but are less effective and require the use of a tourniquet at the base of the penis for optimal results.53 Initial treatment should occur in a health care environment with proper monitoring due to the rare occurrence of syncope.
Vacuum constriction devices offer a noninvasive yet mechanical treatment and is used by approximately 5% of men with ED.54 A plastic cylinder is placed around the penis and negative pressure is created, drawing blood into the penis. A tourniquet is placed at the penile base once adequate rigidity has been achieved, trapping blood within the corpora cavernosa. Some men find this treatment ideal, although many others find it cumbersome or unappealing.
Surgical implants remain a highly successful and satisfying treatment for men whose condition has failed oral therapy and find other treatment options unsatisfactory.55-56 Nevertheless, the number of procedures performed is relatively low compared with the estimated population of men with ED. A review of 372 cases using the AMS 700CX inflatable prosthesis (American Medical Systems Inc, Minnetonka, Minn) revealed 86% device reliability after 5 years, and 79% of men continued to use it for intercourse at least monthly.56 In a study of 434 patients implanted with the Mentor alpha-1 inflatable prosthesis (Mentor, Santa Barbara, Calif), functional results were similar, with patient satisfaction rates of greater than 80%, and partner satisfaction rates slightly lower than this.57 The appearance and sensation of the penis is quite natural, and psychologically, many men say they feel their problem has been "fixed" after placement of a penile prosthesis. The primary risks are device failure (2% at 2 years; 14% at 5 years) and infection in 2% to 3% of cases.55-56,58
Other Oral Therapies. Apomorphine is a centrally acting oral medication that has shown mild clinical efficacy in the treatment of ED,59 but is not available in the United States. Yohimbine is a plant-derived -adrenergic inhibitor with limited efficacy in the treatment of ED.60 Despite aggressive marketing, no data support the assertion that nutritional supplements, herbal therapies, or vitamins have any beneficial effect in the treatment of ED.1
Hypogonadism
When a man like Mr G presents with symptoms such as diminished libido and ED in association with a low serum testosterone level, the condition is termed hypogonadism.21 Other symptoms and signs of hypogonadism include depressed mood; reduced energy, muscle mass, and strength; reduced bone density; anemia; fatigue; and impaired cognition. Less well-recognized sexual symptoms of hypogonadism include difficulty achieving orgasm, diminished intensity of the orgasm, reduced sexual sensation in the penis, and reduced ejaculate volume.21
Hypogonadism is quite common, since testosterone levels decline 1% per year beginning around 40 years of age.61-62 Thus, the male population at risk for both ED and hypogonadism overlaps considerably. A major issue for clinicians caring for patients like Mr G is whether to first treat his ED, his hypogonadism, or both in combination. Treatment of hypogonadism results in reliable improvement in the symptoms of diminished libido and feelings of enhanced sexuality.63-64 However, ED itself may not respond as well, particularly in older men, due to coexisting vascular pathology.
Forms of Testosterone Supplementation. Forms of testosterone treatment include intramuscular injections every 1 to 3 weeks with testosterone esters (cypionate or enanthate) or topical daily treatments with gels or patches. Gels have become the favored mode of treatment for many patients due to their high efficacy in restoring physiological testosterone levels,65 ease of use, and infrequent skin irritation, the last representing a significant limitation in acceptance of the patches.66 Oral agents available in the United States all share a significant risk of hepatotoxicity,67 and their use is therefore discouraged. An informal survey of Boston pharmacies in April 2004 revealed a monthly treatment cost of approximately $220 for gels and $24 for injections.
Risks of Testosterone Treatment. Testosterone supplementation within the physiological range is generally well tolerated. Risks include erythrocytosis in as many as 50% of men receiving injections, but in only 5% of men using gels or patches.21 Gynecomastia, peripheral edema, exacerbation or de novo sleep apnea, acne, and mild weight gain occur in less than 2% of men.64 Testicular atrophy can occur, more prominently in younger men. In addition, men must be advised that fertility will be impaired while receiving exogenous testosterone due to negative feedback on pituitary gonadotrophins.68 Exacerbation of bladder outlet voiding symptoms is uncommon. Transdermal preparations are associated with local skin reactions in 3% to 5% of men using gels and as many as 40% of men using patches.21 There is no evidence that testosterone supplementation represents a risk for cardiovascular disease; on the contrary, some studies suggest that it may even be beneficial.69-71 Although testosterone treatment may reduce high-density lipoprotein cholesterol, total cholesterol is generally reduced as well, resulting in a neutral net effect.72 Liver toxicity does not seem to be associated with transdermal or intramuscular preparations of testosterone.21
One must also consider the risks of failing to treat men with hypogonadism. These may include depression, diminished sense of vitality, sexual dysfunction, anemia, and reduced bone mineral density.21
Testosterone and the Prostate
The greatest concern of clinicians regarding testosterone replacement therapy (TRT) is possible stimulation of an occult prostate cancer. This follows from the work of Huggins et al in the 1940s,73 who showed that prostate cancer was androgen-sensitive by following chemical markers in an uncontrolled study of 8 men with metastatic prostate cancer who underwent bilateral orchiectomy. Nevertheless, the limited clinical trials to date have shown a risk of prostate cancer in men undergoing TRT of approximately 1%, a rate not different from untreated men undergoing screening.74 Moreover, population-based studies have failed to demonstrate that men with higher levels of testosterone are at any increased risk of developing prostate cancer or that men with low testosterone levels are somehow protected against developing prostate cancer.75-78 Furthermore, only 1 of 20 hypogonadal men at high risk for prostate cancer based on a prior history of prostatic intraepithelial neoplasia developed cancer after 1 year of testosterone treatment,24 suggesting that TRT may not adversely affect progression of prostate cancer.
Who Should Be Referred for Prostate Biopsy in Association With TRT?
Men with an elevated PSA level or an abnormal DRE finding should undergo biopsy prior to initiation of TRT. Prostate biopsy should also be performed if the PSA rises above the normal range or the DRE becomes abnormal during treatment. There is ongoing debate whether the historical upper PSA threshold of 4.0 ng/mL should be lowered to 2.6 ng/mL.79-80 A rapid rise of PSA is a further indication for biopsy, since this may be a sign of prostate cancer as well. Bhasin and colleagues recommend biopsy for a rise of 1.0 ng/mL or greater within the first 6 months of treatment, and for any rise of 0.4 ng/mL per year after that time.74 Although most clinicians currently reserve prostate biopsy for the indications above, it has been my own practice to perform prostate biopsy prior to initiation of TRT in all men age 45 years or older, since 14% of hypogonadal men with a normal DRE and PSA less than 4.0 ng/mL have biopsy-detectable prostate cancer.81 There is evidence that high-grade prostate cancer, Gleason 8-10, is particularly associated with low testosterone.82
Once treatment has been initiated, men should be monitored with PSA and DRE, as well as hemoglobin or hematocrit, 2 to 3 times within the first year, and 1 to 2 times per year thereafter.21, 74
Who Should Treat the Man With ED?
Most men with ED can be effectively treated by their primary care physicians. Men with physical abnormalities of the penis, such as Peyronie disease, should be referred to a urologist. If oral medication fails or is contraindicated, then the man should be referred to a specialist in sexual dysfunction, which in most cases will be a urologist. Sexual problems related to hypogonadism may also be treated by the primary care physician or referred to a urologist or endocrinologist. Referral to a psychotherapist is indicated for significant personal or relationship issues that appear to be more complicated than a straightforward complaint of ED or low sexual desire.
The Competing Issues of Hypogonadism and ED
The 2 primary treatment options offered to Mr G, testosterone and sildenafil, have widely different actions. Sildenafil effectively improves blood flow to the penis, thus aiding erection, but has no direct effect on libido. Testosterone supplementation, on the other hand, has a wide variety of potential benefits, including improved erections, libido, mood, strength, and sense of well-being. Men who respond to TRT often report that they "feel normal again."
As a rule, I treat hypogonadal men with TRT first, since this may offer a more complete response than addressing ED alone. If ED does not respond to testosterone treatment, I then prescribe a PDE 5 inhibitor. If the man has experienced benefits from TRT, such as improved libido, he may continue both treatments together. If no symptomatic improvement resulted from TRT itself, it is my practice to discontinue it. However, some clinicians choose to continue treatment to address the metabolic effects of hypogonadism.
Recommendations for Mr G
I would first offer Mr G a trial of TRT in the form of a topical gel, adjusting dosage and mode of therapy as needed to achieve physiological testosterone levels. It is my own practice to perform prostate biopsy before initiating treatment because of the substantial prevalence of biopsy-detectable cancer in this population. However, this approach is impractical for nonurologists, and a reasonable alternative strategy is to monitor with PSA and DRE at 3, 6, and 12 months, reserving biopsy for worrisome changes. If Mr G noted improvement in ED and libido with testosterone supplementation, I would continue this treatment indefinitely. If he notices no benefit at all despite mid- to high-normal testosterone levels, I would discontinue the testosterone trial. I would then offer treatment with one of the oral PDE 5 inhibitors. If libido improves with TRT but ED persists, I would continue TRT and add a PDE 5 inhibitor to the treatment regimen.
Given Mr G's concerns regarding risks, I would reassure him that both testosterone and PDE 5 inhibitors have been widely studied and both appear to have good safety profiles. I would specifically add that sildenafil by itself has not been found to be dangerous for the heart, that it can be taken together with his antihypertensive medications, and that priapism is extremely rare and treatable. I would emphasize that he will require monitoring of his prostate and hematocrit indefinitely while receiving TRT. I would then encourage him to begin treatment if he wishes.
It is my own belief that the mission of physicians must include doing our best to improve the quality of life of our patients. Given the importance of sexuality in human life, I encourage clinicians to become knowledgeable in the area of male sexual dysfunction to ably assist their patients to experience full, satisfying, and loving lives.
QUESTIONS AND DISCUSSION
A PHYSICIAN: You mentioned that sildenafil worked in 80% of psychogenic and 65% of organic cases of ED. What about placebo response in each group?
DR MORGENTALER: The placebo response depends greatly on the study population. Trials that include populations of men with psychogenic ED, as in the first published study of sildenafil, showed 80% efficacy for the highest dose of sildenafil for some measures, with a corresponding placebo response rate as high as 50%.3 Studies of men with more significant medical conditions demonstrate efficacy in 40% to 60%, with a placebo response rate of 10% to 15%.32
A PHYSICIAN: If a man has a nest of prostate cancer cells present on biopsy, would you still offer him testosterone therapy or would you recommend other treatments?
DR MORGENTALER: The single absolute contraindication to testosterone therapy is the presence of prostate cancer,74 and I would not offer testosterone therapy to a man with untreated prostate cancer. Historically, this contraindication has been extended to all men with a history of prostate cancer, with the thought that quiescent cancer cells may be stimulated by testosterone supplementation. But, in my opinion, a blanket contraindication doesn't make sense. We withhold testosterone therapy from hypogonadal men who underwent radical prostatectomy 5 to 10 years ago with an undetectable PSA level even though they are likely cured of their cancer. Why can't we treat them? If their own testosterone level were normal, no one would suggest these men should be castrated.
Another example is that we often give testosterone-lowering treatments to men as an adjunct to radiation therapy for prostate cancer. Afterward, testosterone levels typically return to normal, but not always. Even if those men are highly symptomatic, with hot flashes, low energy, and absent libido, we do not give testosterone because of their history of prostate cancer. But if their testosterone levels spontaneously returned to normal, we say that's fine. This is an artificial distinction. Why should we penalize the man who remains symptomatically hypogonadal?
A PHYSICIAN: Could you comment on the recreational use of sildenafil in men without ED?
DR MORGENTALER: The mythology of Viagra on the street is that it can turn any man into a sexual superstar.2 The ease of obtaining sildenafil via the Internet has essentially demedicalized PDE 5 inhibitors for a substantial number of men without ED who use it for recreational purposes. Some of my own patients without ED have reported that sildenafil provides them with greater rigidity and a shortened refractory interval. However, the effects of the recreational use of PDE 5 inhibitors have not been well studied. My major concern is the psychological impact of taking these medications for younger men who are not yet in a stable relationship. I have seen cases where men who lack for nothing except confidence secretly take sildenafil every time they go on a date, in the hope that it will help them please their partner. However, this can create obstacles for a solid intimate relationship. Apart from issues of authenticity, trust, and honesty, it seems to me that the key psychological cost of using sildenafil recreationally is that, by relying on a pharmacologic enhancement to his sexuality, a man loses an opportunity to achieve what we all look for in relationships—namely, to be loved and accepted for whom we really are.
AUTHOR INFORMATION
Corresponding Author: Abraham Morgentaler, MD, Men's Health Boston, One Brookline Place, Suite 624, Brookline, MA 02445 (
amorgent@yahoo.com).
This conference took place at the Medicine Grand Rounds of Beth Israel Deaconess Medical Center, Boston, Mass, on May 29, 2003.
Acknowledgment: We thank the patient and his doctor for sharing their stories with us.
Author Affiliation: Dr Morgentaler is Director, Men's Health Boston, and Associate Clinical Professor of Surgery (Urology), Harvard Medical School, Boston, Mass.
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Addendum: Useful Questions in the Sexual History
What actually happens when you try to have sex?
Is the penis ever firm enough to go inside your partner?
Does your penis ever become firm?
Upon awakening?
With masturbation?
How long has this been a problem?
Did anything happen, medically or socially, around the time that this problem began?
Any new medications around the time that the problem began?
What do you think is causing the problem?
How has this affected you? Your partner? Your relationship?
Are you interested in treating the problem?
Are you able to have an orgasm?
Is there any new curve when you have an erection?
What treatments, if any, have you tried so far?
