Howard B. Epstein, M.D. is Associate Professor of Surgery and Chief, Division of Urology at the University of Florida Health Science Center/Jacksonville.
As we head toward the next century, there has been an explosion of new research and treatment in the area of male erectile dysfunction. All one has to do is pick up the Florida Times-Union to read about the new treatments being developed; these new developments are trumpeted in Newsweek, making it its cover story on November 17, 1997. Flip though the Wall Street Journal or the business pages of the New York Times and you see articles on why to invest in Pfizer , or TAP, pharmaceutical companies who are coming out with new oral pills for impotence. A half-page advertisement in the Business Section of the Sunday November 9, 1997 New York Times expounds on the physiology of erection, and why the Senetek drug company has a new injectable impotence drug , thereby theoretically making Senetek a good investment. Impotence is hot!!
Currently, the incidence of impotence (as defined as the inability to have a sufficient erection for intercourse) in the United States is rising, as there is increasing awareness of the problem and the fact that there are minimally invasive or non-invasive treatments available. Ten to tweny million men are affected, most of whom are over 65 years of age. The Massachusetts Male Aging Study recently reported that in noninstitutionalized men ages 40 to 70, 52% had minimal, moderate, or complete impotence. The major factors contributing to impotence include age, heart disease, diabetes mellitus(DM), hypertension, medications, and depression. If you add cigarette smoking to heart disease and hypertension, the incidence of complete impotence goes up. Diabetes is a major risk factor, causing both physiologic and psychogenic impotence. Within 5 years of the onset of DM, 60 % of patients will experience some erectile dysfunction. Chronic renal failure causes impotence: 38-80% of dialysis patients have reduced erections and up to 55% have complete impotence. After renal transplant, 10% have impotence. Hypertension is a causative factor: one recent study showed that 25% of treated hypertensive males were impotent. The incidence in untreated hypertensives was 17%, as compared to 7% in normotensive control patients.
Multiple drugs have been thought to cause erectile problems. For most drugs the mechanism of action is unknown. Medications which act on the sympathetic or parasympathetic nervous systems are frequently associated with impotence. This includes methyldopa, clonidine, guanethidine, and reserpine. Non-selective alpha-adrenergic blockers inhibit ejaculation; while beta blockers depress libido. Major tranquilizers or antipsychotics can decrease libido, leading to erectile failure. An abbreviated list of other drugs implicated in sexual dysfunction include alcohol, antihistamines, amphetamines, anti-androgens, atropine, barbiturates, cimetidine, clofibrate, cocaine, digitalis, diazepam, imipramine, marijuana, morphine, nicotine, propranolol, spironolactone, and thiazide diuretics.
A thorough discussion of the science of erection is beyond the scope of this paper. Please refer to the suggested readings located at the end of the article. Briefly, either from visual stimulation or local tactile stimulation, a cascade of hormones are released causing smooth muscle relaxation of the corpora cavernosa smooth muscle. This allows increased blood flow to pool in the corpora, causing tumescence. After orgasm, detumescence occurs, and the penis returns to the flaccid state. The sympathetic nervous system is "responsible" for flaccidity and detumescence, causing contraction of the cavernosal smooth muscle, primarily by the peripheral release of norepinephrine from the sympathetic nerve. The parasympathetic nervous system facilitates tumescence through the release of nitric oxide(NO) and vasoactive intestinal polypeptide(VIP). NO increases the production of cyclic guanosine monophosphate (cGMP), which in turn relaxes cavernosal smooth muscle.
Centrally, the brain contains numerous neurotransmitters responsible for erections. Dopamine increases libido and produces erections. Serotonin is more complex, and depending on the type of receptor, can both inhibit and facilitate sexual function. Increased levels of prolactin inhibit sexual function. Noradrenaline, an alpha-2 adrenergic agonist, inhibits sexual behavior. This is how clonidine, an alpha-2 agonist, causes impotence, and how yohimbine, an alpha-2 receptor antagonist, "works" to help sexual function.
One question often asked in trying to determine the cause of impotence is: psychogenic or organic? 10 to 15 years ago, it was said that the majority of cases (up to 70%) of impotence were psychogenic, and only 30%-50% were organic in nature. As research has expanded our knowledge in this area, today up to 80% of cases can be shown to have an organic cause. The burden to diagnosing psychogenic causes falls on the physician. If you do not ask patients directed questions about marital relations, recent loss of a loved one, lack of opportunity due to a lack of a partner or "missed" opportunities due to a lack of confidence, chances are high that the patient will not volunteer this information. Besides the routine history and physical exam, the physician should ask about the duration of the impotence, the presence or absence of morning erections, the level of libido, and obtain an inventory of sexual partners. Other characteristics that may help differentiate between psychogenic and organic causes are included in Table 1.
Table 1. Psychogenic Vs. Organic Causes |
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| Factor | Psychogenic | Organic |
Anxiety
|
Primary
|
Secondary
|
It is important to make the determination whether there is a prominent psychological problem, because instead of going through expensive tests and treatments, the patient may benefit greatly from counseling from a trained sexual counselor.
Physical exam may turn up other important clues including the presence of gynecomastia, atrophic testicles, lack of normal adult hair patterns, decreased perineal sensation, or lack of a bulbocavernosal reflex. The first three clues mentioned should lead to further endocrine testing.
Laboratory testing should be directed at identifying treatable problems, like DM. A morning serum total testosterone level (normal: 300-1000 ng/dl) is a good first endocrine test. If a patient is hypo- or hyperthyroid, obese, acromegalic, or receiving estrogen therapy, then a free testosterone level is indicated. If the test is abnormal, repeat it along with LH, FSH, and prolactin. An elevated prolactin level (>22 ng/ml) may indicate a pituitary tumor. A high LH indicates hypogonadism, and may suggest testosterone replacement therapy. However, remember that the incidence of endocrinopathy induced impotence is low, at 1.7%. So, unless the patient has a decreased libido or testicular atrophy, routine testing may not be indicated.
Impotence-specific testing is detailed in Table 2. In general, various types of testing is recommended when various conditions are present: lack of erections for most of a patient's life (especially in young patients); young patient (under 40 years old); prior pelvic surgery (abdomino-perineal resection and other colo-rectal surgery; pelvic trauma); vascular surgery (especially aorto-iliac surgery, or aortic aneurysm repair); renal transplantation; pelvic radiation therapy. Also, if the patient specifically wishes
a complete work up, the physician should explain the risks of the tests, and what information they will yield, and how that information will influence the type of treatment to be recommended. In general, most testing will not influence the treatments offered; i.e., the information yielded usually does not help our treatment decisions.
If a patient does not desire a work-up, and has none of the conditions stated above, then the physician can assess the patient's goals of therapy, and then start with a trial of oral medications and /or vacuum erection device (VED). If this initial approach does not work, the next step is to perform CIS, and if this works, treat with injection therapy or MUSE. If this does not work, consider penile prosthesis or proceed to further work up of penile vasculature, leading to vascular surgery or penile prosthesis.
Obviously, stopping smoking and alcohol ingestion helps. A low fat diet has also been shown to help. In terms of medications, changing from an offending drug to an agent in a different class will also usually improve sexual performance, although this may be minimal secondary to the underlying cause of the impotence.
As stated previously, unless there is a clear-cut underlying psychologic problem, counseling as primary therapy is rarely successful. However, when there is a component of anxiety and underlying mild psychogenic impotence, psychotherapy can help, as well as remove unrealistic expectations associated with therapy.
This should be used only if the patient is hypogonadal. Studies have shown that if the testosterone level is low-normal (i.e., not low, below the normal levels), replacement therapy will not work. Also, in the older patient (usually over 55 years old), replacement therapy should be undertaken with care, as it may speed up growth of occult prostate cancer. A digital rectal exam (DRE) and a serum prostate specific antigen (PSA) should be obtained prior to initiation of therapy, and then these 2 parameters should be monitored periodically (every 6 months). It should be noted that there are no reported cases of replacement therapy causing prostate cancer, but in the 7 reported cases, one or both of those parameters was either not checked or was abnormal, prior to therapy. Oral testosterone is not recommended, as its absorption is erratic and there is a significant risk of hepatotoxicity. Therefore, other routes of administration are preferred. Testosterone cypionate and testosterone enanthate are 2 long acting forms given intramuscularly 200 mg every 2-3 weeks. Two transdermal forms are available: Testoderm, 4-6 mg to the scrotal skin daily, and Androderm, 5 mg patch to the skin (not the scrotum). The main side effects of the skin patch are itching (7%) and skin irritation (2-5%). Liver function studies, PSA, DRE, and Hct (for polycythemia) should be checked yearly with these therapies.
Unfortunately, as a therapy for impotence in hypogonadal men, replacement therapy is disappointing, with a response rate of 9%. This is usually due to the presence of other underlying diseases also causing or contributing to the impotence.
It is an alpha-2 agonist from the bark of the yohim tree. The dose is 6 mg orally, 3 times a day. In organic impotence, it is no different than placebo. In impotence which is primarily psychogenic, is was shown to be 62% successful, vs. 16% for placebo.
It is a mild anti-depressant, and has anti-serotonergic and alpha-adrenergic blocking properties. At a dose of 50 mg orally t.i.d., it can have up to a 65% response rate. Its major side effect is sedation. It can also be used with Yohimbine together, with some success.
Prostaglandin E1 causes smooth muscle relaxation, vasodilation, and inhibition of platelet aggregation. In its Intra urethral form, called MUSE, it causes erections in about 50% of patients. Main side effects include penile burning (10.9%) and dizziness (3.8%). It comes in doses of 250 mg, 500 mg, and 1000 mg. The 250 mg dose is minimally effective, and most clinicians start at 500 mg. It can be used twice a day, prior to intercourse. The drug requires refrigeration.
Currently, 3 agents are used in various combinations. Papaverine is an alkaloid which relaxes cavernous smooth muscle and penile vessels. Phentolamine mesylate (Regitine) is a competitive alpha1 and alpha2 adrenoceptor antagonist, and also blocks serotonin receptors; it increases intracorporal blood flow. Alprostadil is prostaglandin E1, and was explained above.
Injection therapy usually starts with alprostadil alone, varying in doses from 2 ug/ml to 20 ug/ml, given with a form of tuberculin syringe into the side of the penile shaft. It causes full erections in 70-80% of patients. Side effects include pain at the injection site (16.8%), and priapism (1.3%). 2 FDA approved forms are available: Caverject, and Edex. The usual starting dose in the non-spinal cord patient is 10 ug. It is not recommended to be used more than 3 or 4 times/week.
When Alprostadil fails, combination therapy with regitine and papaverine are usually employed. The latter two drugs can cause priapism and liver dysfunction, and so, when used in much lower doses of all 3 drugs, together, up to 89% of patients are successful, and with minimal pain and side effects. This combination, called Trimix, requires the pharmacist to mix it up, and subsequently, not all pharmacies in Jacksonville will prepare this combination.
This device causes an erection by creating a vacuum around the penis, and sustaining this erection by means of a constricting band at the base of the penis. It is safe, and is a one time cost (unlike recurring drug costs). Patient satisfaction ranges from 68-83%. The main side effect is penile numbness and pain.
This is for very select patients. The results of venous leak surgery and arterial surgery in the older patient are very disappointing, usually less than 25% successful. The "ideal" patient doe not smoke, is relatively young, is not a diabetic, has an identifiable lesion on X-Ray studies, and has failed injection therapy.
These devises are surgically implanted into both corpora cavernosa, and usually represent a "final solution" after other therapies fail. They can be inflatable or semi-rigid. The cost of the prosthesis itself ranges from $500 (semirigid) to over $4,000 (inflatable). The success rate is quite high, with patient and partner satisfaction rate ranging from 60-80%. Mechanical failure of the device is 5% at 5 to 10 years. The main complication is infection (0.6%-8.9%), and patient complaint of "inadequate length".
Also known as viagra, this orally taken drug is concluding Phase 3 FDA research, and is to be reviewed by the FDA for approval in the next several months. Even if approved in early 1998, it will not be available until the end of the summer, 1998. Sildenafil is a selective inhibitor of cGMP, working locally in the penile corpora to relax the smooth muscle. Its main side effects include headache and diarrhea. Its effectiveness in phase 2 trials has ranged from 48-81%, in patients with varying types of impotence. The drug works within an hour of oral ingestion.
This agent is a dopaminergic agonist, and works centrally. It is also in Phase 3 trials, and is taken sublingual for 10 minutes prior to intercourse. Main side effects include yawning and nausea. It works well in psychogenic impotence. Phase 3 studies should conclude mid 1998, and this drug will most likely be available in early 1999.
Brand name is Vasomax, and is currently being reviewed by the FDA. Effective in 60-80% of patients. Minimal side effects. Most of the clinical studies were done outside the U.S.
This is an injectable agent currently in final stages of phase 3 studies, to be submitted to the FDA in 1998. It is VIP and phentolamine in combination, to relax smooth muscle. Less pain than alprostadil, and appears to be as effective.
These are exciting times in the area of impotence. With so many new treatments becoming available in the next 2 years, the real questions are: Cost? Just judging by the cost of recent new drugs, one can only imagine that these drugs will be expensive. Also, with all the pre-approval hype surrounding them, there is no way that they will live up to expectations of the truly impotent patients. Some researchers think that combining apomorphine with sildenafil will produce an even more effective drug. However, more patients will seek treatment, especially people who are only very mildly impotent. As physicians, we need to be prepared to discuss impotence with our patients, and prescribe these new drugs judiciously.
Suggested Reading
Campbell's Urology, 7th Edition, Volume 2, Section 6, Chapters 38, 39, 40; pages1155-1236.
Tom F. Lue, Gregory Broderic, and Ronald Lewis write 3 excellent chapters that cover the entire field in detail.
Newsweek, November 17, 1997, pages 62-69. An excellent overview to give your patients in easy to read language, with good graphics.
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