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Nonoperative Management of Impotence
0022 -534 7/88/1391 -0002$2.00/0 Vol. 139, J:anuary Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
Review Article NONOPERATIVE MANAGEMENT OF IMPOTENCE ROBERT P. NELSON From the Department of Uro/,ogy, Medical University of South Carolina, Charleston, South Carolina
lI I
As more insight is gained into the etiology of the disease, many men who formerly were considered to suffer from purely psychological erectile dysfunction currently are being recognized as candidates for aggressive treatment of the organically caused problems. Subsequently, treatment modalities have become more varied, such that to treat sexual dysfunction adequately physicians must constantly keep abreast of new developments. The increasing popularity of nerve-sparing radical retropubic prostatectomy is an example of the importance that patients and physicians have placed on the preservation of potency. 1 • 2 In this article alternatives to the surgical option of implantation of the penile prosthesis in the treatment of erectile dysfunction are reviewed. These options, mostly medical in nature, should be discussed thoroughly with the patient before any surgical intervention is begun. Sexual counseling before and during nonoperative therapy remains a cornerstone for the multifactorial treatment of erectile difficulties. Oral medications, such as isoxsuprine hydrochloride and yohimbine, are inexpensive with extremely few side effects, and injectable testosterone also has proved to be useful in selected patients.3 • 4 Additionally, recognition of pharmacological side effects, such as those with antihypertensives and antidepressants, may lead to the selection of alternative medications with less erectile dysfunction. 5 Self-injection ofvasoactive drugs into the corpora is gaining popularity, especially in patients with nonvasculogenic erectile dysfunction. 6 Additionally, vascular intervention with hypogastric arterial dilation in patients with the Leriche syndrome and arterial revascularization in selected patients, such as those with arterial disruption from pelvic trauma and venous ligation for abnormal venous efflux, are becoming increasingly popular in this country.7 • 8 Additionally, the option of external vacuum devices has proved to be a safe, simple and inexpensive method in an increasing number of patients. 9 - 11 Although none of these treatments can surpass the greater than 90 per cent success rate with a penile prosthesis, implant surgeons must continue to evaluate erectile dysfunction patients critically as candidates for a prosthesis, since patient dissatisfaction is increasing and malpractice claims in sexual dysfunction comprise the third highest within the field of urology. 5 Thus, there is no substitute for extensive patient education and a thorough evaluation of all options available to patients before implantation of a penile prosthesis.
sician must evaluate patient motivation for surgery and outline the expectations of the patient and partner, particularly those of penile size and concealability. Patients must be identified who, although motivated for an operation, will not respond well, such as when the procedure might precipitate emotional problems, especially if complications arise. Finally, after patients .have been fully evaluated for surgical implantation, the patient and partner must be prepared for postoperative adjustments, such as routine postoperative care and emotional reactions to the device and its use. The most common causes of sexual dysfunction in men are vascular, endocrine, neurological and psychogenic in nature. Of necessity, there frequently is an overlap of the 4 etiologies, such as in diabetic patients who have vascular and neurological components. The physician also should be aware that even though a specific organic etiology for the sexual dysfunction can be identified, there frequently is much psychogenic overlay associated. Of secondary importance as etiologies are drug-induced sexual dysfunction, which is becoming increasingly more apparent, and end organ problems, such as Peyronie's disease, phimosis, microphallus and chordee. The recognition of pharmacological impairment of sexual function mandates a thorough medication and drug history. Recent evidence has associated tobacco smoking with erectile dysfunction, documenting a statistically significant history of smoking in patients with erectile dysfunction compared to the general population. The adverse effects appear to emerge primarily in the small peripheral vasculature as documented by statistically significant abnormal penile brachia! index values compared to patients who did not smoke. 12 Cigarette smoking also appears to cause penile venous channels to open, resulting in decreased numbers of erections and decreased erectile time.13 Obvious drugs of abuse potential, such as marijuana and alcohol, can decrease libido and testosterone levels, cause gynecomastia and interfere with sperm production. Cimetidene and clofibrate are antiandrogens and along with metoclopramide hydrochloride they can cause increased prolactin secretion.5 Central nervous system depressants and anticholinergic agents have been associated with sexual dysfunction. The phenothiazine anti-psychotic agents, such as chlorpromazine and thioridazine, are particularly strong sedatives with side effects. These and the anticholinergic tricyclic antidepressants can block dilation of the arterial supply to the corpus cavernosum and corpus spongiosum. Thioridazine, tricyclic antidepressants, haloperidol and meprobamate have been associated with increased prolactin secretion. Changing from one of the older tricyclic antidepressants, such as amitriptyline or imipramine, to a new drug, such as trazodone, which has little anticholinergic affect, can be of significant benefit in improving erectile function. 5 Drugs used to treat hypertension also are a significant cause of sexual dysfunction. Spironolactone is an antiandrogen that lowers testosterone and increases testosterone clearance, causing gynecomastia and decreased libido. Central sympatholytic
GOALS OF THERAPY
The primary task for the physician caring for patients with sexual dysfunction is to identify the treatment goals of therapy. The initial goal should be to determine the primary complaint and the cause of the sexual dysfunction. This goal also implies identifying factors that initially may have caused and then maintained the dysfunction, in addition to the reaction of the spouse to the problem and the over-all relationship of the patient and his sexual partner. Another goal is to identify which patient will benefit from nonoperative treatment. Also, assuming that organic causes have been documented, the phy2
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NONOPERATIVE MANAGEM ENT OF IMPOTENCE
agents, through peripheral or central adrenergic blockade, interfere with dilation of the arterial supply to the corpora and, possibly, block autonomic transmission needed for emission and antegrade ejaculation. Additionally, reserpine and methyldopa elevate serum prolactin levels and further interfere with sexual function. 5 • 14 JJ-Blockers, especially propranolol, are a significant cause of sexual dysfunction. Their ability to penetrate the central nervous system causing central sympatholytic effects depends on their lipophilic nature. Some of the newer JJ-blockers, such as atenolol, are water soluble and have less potential for these serious effects. 5 JJ-Agonists, such as the angiotensin converting enzyme inhibitor captopril and calcium channel blockers have not been associated with sexual dysfunction to a significant degree. It must be remembered that some of the dysfunction from antihypertensives is owing to the primary disease of atherosclerosis and its changes in the ·pelvic vasculature, resulting in some degree of pelvic vascular insufficiency. Also, some of these antihypertensive agents, such as guanethidine and methyldopa, have a-blocking activity and _are associated with ejaculatory incompetence, increasing the possibility of a psychological basis for the erectile dysfunction. 5 MEDICAL TREATMENT OF ERECTILE DYSFUNCTION
Low or low normal serum testosterone levels may suggest 3 endocrinologic syndromes. If luteinizing hormone secretion is low, hypogonadotropic hypogonadism from primary pituitary failure is entirely possible. Normal or elevated luteinizing hormone levels may suggest hypergonadotropic hypogonadism resulting from primary testicular failure. Also, hyperprolactinemia resulting in decreased libido and, possibly, gynecomastia is seen with depressed testosterone levels. In this instance bromocriptine or surgical ablation of a localized pituitary tumor is indicated. 14 Some patients with low or low normal serum testosterone levels after pituitary dysfunction has been ruled out will benefit from injection of 200 mg. testosterone enanthate every 2 to 3 weeks. If this is the etiology of the dysfunction the patient should have a rather dramatic and immediate response. He then can be started on oral methyl testosterone, since other forms of testosterone are not absorbed well from the gastrointestinal tract, with the knowledge that it may increase the incidence of prostatic carcinoma. Isoxsuprine is a JJ-adrenergic receptor stimulant that in some studies has been effective in patients who have been heavy smokers. The side effects are rare and the dosage is 10 to 20 mg. orally 3 times daily.3 Yohimbine is a presynaptic a-2 receptor blocker that decreases outflow of blood from the corporeal tissue. It also probably works on upper levels in the brain to increase libido. Yohimbine has rare side effects, including anxiety and a possible mild antidiuretic action through a release of antidiuretic hormone. It is contraindicated in cases of renal dysfunction. Patients on antihypertension medication should be watched closely, since blood pressure changes may occur. A dose of 5.4 to 6 mg. orally 3 times daily has been effective in many patients.4 The physiology of erection indicates the necessity of JJ-adrenergic stimulation and a-receptor blockade, so that the ·combination of isoxsuprine and yohimbine sometimes is effective in patients refractory to one or the other. Psychological factors, either primary or secondary, frequently have a major role in the multifactorial etiology of erectile dysfunction. Frequently, these patients manifest a significant amount of depression and they may not be maintained on oral antidepressants. Trazodone has little anticholinergic effect, and has demonstrated efficacy in patients who are switched from other antidepressants and shown to have vasoactive potential when injected directly into the corpus cavernosum resulting in erections. 15 Therefore, I have found it useful to consider patients for maintenance on this medication after the initial visit. Indeed, in my experience this medication has
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proved to be useful sometimes in conjunction with other oral medications. Patients with diabetic neuropathy sometimes present with significant amounts of pain in conjunction with the erectile dysfunction. This pain usually is owing to the neuropathic state that results from sorbitol deposition on Schwann's cells owing to aldose reductase enzyme activity. Previous authors have shown that aldose reductase inhibitors can be useful in reversing the neuropathy that causes the neurological component of diabetic impotence, so as to to improve erections in a select group of diabetic patients. 16 Although pure aldose reductase inhibitors currently are not available to the practicing physician, other agents with partial activity, such as amitryptyline, diphenhydramine, phenytoin, imipramine and carbamazepine, have demonstrated partial activity as aldose reductase inhibitors and may be considered in diabetic impotent patients who present with a significant degree of pain. 17 If the patient has failed medical therapy and penile tumescence studies demonstrate excellent erectile function, then psychogenic options and sexual counseling should be discussed. For some of these patients and also for those with documented organic dysfunction, the physician should discuss with the patient and partner the desire for other options, such as no sex whatsoever. Many women and some men are in need of close attention, such as hugging and caressing, and direct sexual activity is not mandatory. Additionally, some men initially seek consultation for the erectile dysfunction to make sure that they do not have a more serious condition, such as cancer or some other systemic illness that will directly affect the over-all quality of life. The patient and partner also may choose manual stimulation to orgasm without actual vaginal penetration. SELF-INJECTION WITH VASOACTIVE DRUGS
Papaverine (60 mg. injected intracorporeally) can be a useful clinical diagnostic tool. In a normal patient this drug causes arterial dilation, venous constriction and sinusoidal relaxation by bypassing the normal cavernosal nerve stimulation mechanism, and an erection will occur in 3 minutes or less. Patients with hormonal or neurological impotence also will have an excellent response to the injection, with initiation less than 5 minutes and duration longer than 60 minutes. Patients with mild psychogenic disturbances generally will have a good response to this test and subsequent treatment may build self confidence markedly, such that they may be cured with several injections. However, patients with moderate or severe psychogenic problems may have a poor response to the papaverine, possibly owing to increased adrenaline outflow. Patients with vasculogenic impotence will have a markedly delayed onset of erection with markedly reduced quality, length, circumference and duration.15' 18 A good erection but markedly reduced duration indicates a possible steal syndrome or venous incompetence. 6 • 7 • 15• 18 The addition of phentolamine further increases arterial flow and has little or no effect on venous compression. This a-blocking agent allows for lower doses of papaverine, while possibly reducing the most severe side effects of priapism and corporeal fibrosis. Sexual stimulation also enhances papaverine by releasing neurotransmitters. The combination of these 2 agents in a therapeutic protocol should be successful in greater than 70 per cent of all patients. This effect is age-dependent and related directly to the presence of vascular disease, such that the best candidates for these self-injections are those with neurological disease. 6 • 18 Patients must sign an informed consent, and undergo a selfinjection training period, liver function tests and an electrocardiogram. At monthly intervals they receive new supplies of these agents and undergo repeat liver function studies. The general recommended dose is 30 mg. papaverine per mg. phentolamine such that 1 cc will result in the delivery of about 25 and 0.86 mg., respectively. Vascular impotence will require higher doses of these agents. In more than 50 of my patients
4
NELSON
this dosage schedule has resulted in erection satisfactory for intercourse in 84 per cent. Several of these patients subsequently have received a penile prosthesis. For young patients and especially those with neurological disease, much lower doses of the combination agents can be used, initially as low as 1/10 to 3/10 cc increased in increments until adequate erections are obtained. 5 • 15 The most significant short-term complication is that of a prolonged erection, which if nonpulsatile should be aspirated. If this prolonged erection develops into a pulsatile priapismtype state, then epinephrine (1 mg. in 1 l. saline, or possibly dopamine or norepinephrine) at a dose of 0.001 mg./cc (1 µ,g./ cc) can be injected intracorporeally as 10 to 20 cc irrigant, which then is aspirated. Prolonged erections of more than 4 hours if treated do not result in priapism. Actual cases of priapism are uncommon if physicians and patients are careful to treat prolonged erections. Some cases of subclinical Peyronie's disease (cavernosal fibrosis), 15 approximately 4 per cent in 1 series,6 have been reported. Vasovagal reaction, bradycardia, hypotension, dizziness and facial flushing also are uncommon events and can be treated easily with atropine. Subcutaneous hematoma is an easily treated problem. Possible other complications include liver toxicity and heart rhythm changes, and they are rarely if ever reported. Liver function problems appear to be reversible when the drugs are stopped. 5, 6. 1s Most likely during a long treatment period corporeal fibrosis, which may result in a Peyronie's disease state, will be the limiting factor with any combination of papaverine, since the pH of about 3 to 4 with this agent will cause sclerosis. 5 Thus, it is important that doses of papaverine be kept minimal and that other agents be found that also may cause smooth muscle relaxation. A patient also may develop tolerance to these particular drugs. I believe that this condition could be secondary to depletion of the neurotransmitters available in the corporeal tissue, which may be an acceleration of the over-all erectile dysfunction state. Therefore, other agents must be investigated continually. Lue and Tanagho documented 6 groups of medications that possess smooth muscle relaxing properties and are capable of inducing penile erections when injected intracorporeally. 15 One group includes the smooth muscle relaxants, papaverine and nitroglycerin. It is noteworthy that nitroglycerin paste has been reported to be associated with erections and severe spousal headache in at least 1 instance in the recent literature. 19 Another group of agents are the a-blockers, which include phenoxybenzamine and phentolamine. Calcium channel blockers, such as verapamil, and polypeptides, such as vasoactive intestinal polypeptides, are 2 other groups. The /3-agonist isoproterenol and antidepressants, such as trazodone, or antipsychotic agents, such as thorazine, also induce penile erection when injected intracorporeally. The latter 2 agents possibly may be associated with significant priapism events. Prostaglandin El also has been implicated in the induction of penile erection. 20 Histological studies reveal that the framework of the sinusoids is made of smooth muscle in addition to the walls of the arteries and veins. These pharmacological agents release neurotransmitters and relax the smooth muscles, resulting in decreased peripheral resistance and sinusoidal space enlargement. 15, 1s VASCULAR INTERVENTION
Normal erection depends on a 6-fold increase in arterial inflow. 15 Obviously, patients with significant systemic or local arterial disease will not be able to provide an adequate increase in arterial inflow after appropriate nervous stimuli. Those with the Leriche syndrome have been considered candidates for percutaneous hypogastric arterial dilation. In carefully selected patients direct vascular intervention has been associated with long-term success. If young patients with local disease second-
ary to pelvic trauma or perineal straddle injuries, documented by internal pudendal arteriography, can be selected good results can be expected by anastomosis of the inferior epigastric artery to the dorsal penile artery on the side of the best flow. In this group of highly selected patients satisfactory results can be obtained in more than 70 per cent. 8 Patients with significant risk factors, such as myocardial infarction, hypertension, prolonged cigarette smoking, claudication and so forth, who have evidence of systemic vascular disease are poor candidates for arterial revascularization. Bennett and associates have popularized the procedure by Virag, termed the V-5 in this country, in which the epigastric artery is anastomosed to the dorsal vein, which then is sutured to the corpora in a side-to-side fashion after ligation of the vein proximally and removal of a segment. 7• 8 Initial results in selected patients have shown some benefit but, generally, success can be expected in less than 50 per cent over-all. A select number of patients initially have good erections that disappear during a short period. When studied with papaverine and infusion cavernosography, abnormal venous drainage can be documented. Ligation of the deep dorsal vein at the base of the penis has been effective in greater than 75 per cent of these patients. It is possible that long-term followup may reveal progressive erectile deterioration if collateral venous circulation develops. 7 • 21 Although revascularization procedures cannot boast the greater than 90 per cent patient-partner satisfaction statistics for penile implants, new patients continue to desire restoration of erection naturally if possible and this will continue to stimulate revascularization research. Radiologists also have become active in the diagnosis and treatment of patients with arterial and venous disease. Transluminal angioplasty has been shown to be at least temporarily effective in patients who have demonstrated lesions either in the hypergastric or pudendal arterial system. Bookstein demonstrated some minimal and transient improvement in blood flow through the internal pudendal artery with percutaneous balloon angioplasty. 22 Others have had partial success in treating erectile dysfunction caused by venous leakage with detachable balloons and coils. 23 These methods obviously are in their infancy and further clinical trials are indicated to prove the efficacy on a long-term basis. TREATMENT WITH EXTERNAL DEVICES
Some patients have become candidates for treatment with external devices, such as the Osbon Erec Aid system, which has been used in several thousand patients to date with great success. This is a vacuum-type device that essentially suctions blood into the penis. 9 Recently, 2 other devices were introduced: the vacuum constriction device 10 and a new glass clear silicone rubber device that sheathes the penis and holds it erect, permitting sexual intercourse as long as the device is worn. The latter device was used in 240 cases demonstrating its safety, efficacy and reliability. 11 These devices should be presented additionally to patients before consideration for a penile prosthesis. CONCLUSION
The diagnosis and treatment of erectile dysfunction require a multidisciplinary approach, since the etiology of this problem almost always is multifactorial. Some studies have shown that almost 10 per cent of the men who undergo penile prosthetic implantation ultimately never use the device 24 and, coupled with the increasing malpractice claims regarding urological prosthetic surgery, it is imperative that physicians who treat these patients become more aware of other options before they implant a penile prosthesis, which really is a last resort. I have developed an approach to these patients that I believe is pragmatic, starting with the most easily tolerated and least expensive forms of therapy initially, and proceeding up to more complicated and somewhat invasive treatments if the former
NONOPERATIVE MANAGEMENT OF IMPOTENCE
do not improve erection. Oral medications have proved to be of immense benefit in a significant number of patients and, frequently, they result in some improvement in function that also may improve the psychological status. Awareness of pharmacological side effects on erectile dysfunction should lead to alternative medications with less interference. Self-injection of the penis with vasoactive drugs is becoming increasingly popular and when new agents become available to reduce some of the potential side effects this form of treatment may result in unlimited success. As discussed, some highly selected patients may be candidates for either arterial revascularization or venous ligation if appropriate studies reveal these to be the etiologies of the impotence. External devices should be presented to patients, since they are particularly inexpensive and simple. Only if the patient rejects these forms of therapy or, indeed, fails any or all of them should a penile prosthesis be considered. It is gratifying that the penile prosthesis can produce a greater than 90 per cent satisfaction rate. With this in mind the patient always should have an optimistic outlook as to the ultimate solution for the erectile dysfunction.
10. 11. 12. 13. 14.
15. 16.
REFERENCES 1. Walsh, P . C. and Mostwin, J . C.: Radical prostatectomy and cystoprostatectomy with preservation of potency. Results using a new nerve-sparing technique. Brit. J. Urol., 56: 694, 1984. 2. Walsh, P. C. and Donker, P. J.: Impotence following radical prostatectomy: insight into etiology and prevention. J . Urol., 128: 492, 1982. 3. Elist, J ., Jarman, W. D. and Edson, M.: Evaluating medical treatment of impotence. Urology, 23: 374, 1984. 4. Morales, A., Surridge, D . H. C., Marshall, P . G. and Fenemore, J .: Nonhormonal pharmacological treatment of organic impotence. J. Urol., 128: 45, 1982. 5. Nelson, R. P.: Pathophysiology, diagnosis, and management of erectile dysfunction. In: Urology Annual, 1987. Edited by S. Rous. Norwalk, Connecticut: Appleton & Lange, vol. 1, pp. 139169, 1987. 6. Zorgniotti, A. W . and Lefleur, R. S.: Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133: 39, 1985. 7. Bennett, A. H., Rivard, D. J ., Blanc, R. P. and Moran, M .: Reconstructive surgery for vasculogenic impotence. J . Urol., 136: 599, 1986. 8. Virag, R.: Revascularization of the penis. In: Management of Male Impotence. Edited by A. H. Bennett. Baltimore: The Williams & Wilkins Co., chapt. 17, pp. 219-233, 1982. 9. Witherington, R.: The Osbon Erecaid System in the management
17. 18.
19. 20. 21. 22. 23.
24.
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of erectile impotence. Read at annual meeting of Southeastern Section, American Urological Association, Marco Island, Florida, p. 46, March 17-20, 1985. Nadig, P .: Utility of the vacuum-constriction device for men who have failed penile prostheses. J . Urol., part 2, 135: 232A, abstract 512, 1986. Gerow, F. J.: The erectaid tumescence assistance device. J . Urol., part 2, 135: 232A, abstract 513, 1986. Condra, M., Morales, A., Owen, J ., Surridge, D. H . and Fenemore, J .: The effect of tobacco smoking on erectile function: initial results. J. Urol., part 2, 131: 234A, abstract 524, 1984. Juenemann, K.-P., Lue, T . F., Luo, J.-A., Benowitz, N. L., Abozeid, M. and Tanagho, E. A.: The effect of cigarette smoking on penile erection. J . Urol., 138: 438, 1987. Krane, R. J .: Sexual function and dysfunction. In: Campbell's Urology, 5th ed. Edited by P. C. Walsh, R. F . Gittes, A. D. Perlmutter and T . A. Stamey. Philadelphia; W. B. Saunders Co., vol. 1, sect. VI, chapt. 13, p. 700, 1986. Lue, T. F. and Tanagho, E. A.: Physiology of erection and pharmacological management of impotence. J. Urol., 137: 829, 1987. Carson, C. C., III, Porretta, T., Bertram, R. A., Herman, S. H . and Feinglos, M . N .: The aldose reductase inhibitor in the treatment of diabetic impotence. Read at annual meeting of Southeastern Section, American Urological Association, Marco Island, Florida, p. 46, March 17-20, 1985. Buse, J .: Personal communication. Abber, J.C., Lue, T. F., Orvis, B. R., McClure, R. D. and Williams, R. D.: Diagnostic tests for impotence: a comparison ofpapaverine injection with the penile-brachia! index and nocturnal penile tumescence monitoring. J. Urol., 135: 923, 1986. Talley, J. D. and Crawley, I. S.: Transdermal nitrate, penile erection, and spousal headache. Letter to the Editor. Ann. Intern. Med., 103: 804, 1985. Hedlund, H. and Andersson, K.-E.: Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J. Urol., 134: 1245, 1985. Lue, T. F ., Hricak, H., Schmidt, R. A. and Tanagho, E. A.: Functional evaluation of penile veins by cavernosography and papaverine-induced erection. J . Urol., 135: 479, 1986. Kuznar, W.: New technique in impotence shows hope. Urol. T imes, 14: 1, January 1987. Courtheoux, P., Maiza, D., Henriet, J .-P., Vaislic, C. D., Evrard, C. and Theron, J.: Erectile dysfunction caused by venous leakage: treatment with detachable balloons and coils. Radiology, 161: 807, 1986. Batten, W. H .: Patient and sexual partner performance and satisfaction with semi-rigid and inflatable penile prostheses. Read at annual meeting of Southeastern Section, American Urological Association, Dorado Beach, Puerto Rico, p. 34, March 16-19, 1986.
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THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
Review Article NONOPERATIVE MANAGEMENT OF IMPOTENCE ROBERT P. NELSON From the Department of Uro/,ogy, Medical University of South Carolina, Charleston, South Carolina
lI I
As more insight is gained into the etiology of the disease, many men who formerly were considered to suffer from purely psychological erectile dysfunction currently are being recognized as candidates for aggressive treatment of the organically caused problems. Subsequently, treatment modalities have become more varied, such that to treat sexual dysfunction adequately physicians must constantly keep abreast of new developments. The increasing popularity of nerve-sparing radical retropubic prostatectomy is an example of the importance that patients and physicians have placed on the preservation of potency. 1 • 2 In this article alternatives to the surgical option of implantation of the penile prosthesis in the treatment of erectile dysfunction are reviewed. These options, mostly medical in nature, should be discussed thoroughly with the patient before any surgical intervention is begun. Sexual counseling before and during nonoperative therapy remains a cornerstone for the multifactorial treatment of erectile difficulties. Oral medications, such as isoxsuprine hydrochloride and yohimbine, are inexpensive with extremely few side effects, and injectable testosterone also has proved to be useful in selected patients.3 • 4 Additionally, recognition of pharmacological side effects, such as those with antihypertensives and antidepressants, may lead to the selection of alternative medications with less erectile dysfunction. 5 Self-injection ofvasoactive drugs into the corpora is gaining popularity, especially in patients with nonvasculogenic erectile dysfunction. 6 Additionally, vascular intervention with hypogastric arterial dilation in patients with the Leriche syndrome and arterial revascularization in selected patients, such as those with arterial disruption from pelvic trauma and venous ligation for abnormal venous efflux, are becoming increasingly popular in this country.7 • 8 Additionally, the option of external vacuum devices has proved to be a safe, simple and inexpensive method in an increasing number of patients. 9 - 11 Although none of these treatments can surpass the greater than 90 per cent success rate with a penile prosthesis, implant surgeons must continue to evaluate erectile dysfunction patients critically as candidates for a prosthesis, since patient dissatisfaction is increasing and malpractice claims in sexual dysfunction comprise the third highest within the field of urology. 5 Thus, there is no substitute for extensive patient education and a thorough evaluation of all options available to patients before implantation of a penile prosthesis.
sician must evaluate patient motivation for surgery and outline the expectations of the patient and partner, particularly those of penile size and concealability. Patients must be identified who, although motivated for an operation, will not respond well, such as when the procedure might precipitate emotional problems, especially if complications arise. Finally, after patients .have been fully evaluated for surgical implantation, the patient and partner must be prepared for postoperative adjustments, such as routine postoperative care and emotional reactions to the device and its use. The most common causes of sexual dysfunction in men are vascular, endocrine, neurological and psychogenic in nature. Of necessity, there frequently is an overlap of the 4 etiologies, such as in diabetic patients who have vascular and neurological components. The physician also should be aware that even though a specific organic etiology for the sexual dysfunction can be identified, there frequently is much psychogenic overlay associated. Of secondary importance as etiologies are drug-induced sexual dysfunction, which is becoming increasingly more apparent, and end organ problems, such as Peyronie's disease, phimosis, microphallus and chordee. The recognition of pharmacological impairment of sexual function mandates a thorough medication and drug history. Recent evidence has associated tobacco smoking with erectile dysfunction, documenting a statistically significant history of smoking in patients with erectile dysfunction compared to the general population. The adverse effects appear to emerge primarily in the small peripheral vasculature as documented by statistically significant abnormal penile brachia! index values compared to patients who did not smoke. 12 Cigarette smoking also appears to cause penile venous channels to open, resulting in decreased numbers of erections and decreased erectile time.13 Obvious drugs of abuse potential, such as marijuana and alcohol, can decrease libido and testosterone levels, cause gynecomastia and interfere with sperm production. Cimetidene and clofibrate are antiandrogens and along with metoclopramide hydrochloride they can cause increased prolactin secretion.5 Central nervous system depressants and anticholinergic agents have been associated with sexual dysfunction. The phenothiazine anti-psychotic agents, such as chlorpromazine and thioridazine, are particularly strong sedatives with side effects. These and the anticholinergic tricyclic antidepressants can block dilation of the arterial supply to the corpus cavernosum and corpus spongiosum. Thioridazine, tricyclic antidepressants, haloperidol and meprobamate have been associated with increased prolactin secretion. Changing from one of the older tricyclic antidepressants, such as amitriptyline or imipramine, to a new drug, such as trazodone, which has little anticholinergic affect, can be of significant benefit in improving erectile function. 5 Drugs used to treat hypertension also are a significant cause of sexual dysfunction. Spironolactone is an antiandrogen that lowers testosterone and increases testosterone clearance, causing gynecomastia and decreased libido. Central sympatholytic
GOALS OF THERAPY
The primary task for the physician caring for patients with sexual dysfunction is to identify the treatment goals of therapy. The initial goal should be to determine the primary complaint and the cause of the sexual dysfunction. This goal also implies identifying factors that initially may have caused and then maintained the dysfunction, in addition to the reaction of the spouse to the problem and the over-all relationship of the patient and his sexual partner. Another goal is to identify which patient will benefit from nonoperative treatment. Also, assuming that organic causes have been documented, the phy2
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.---,_·---1
NONOPERATIVE MANAGEM ENT OF IMPOTENCE
agents, through peripheral or central adrenergic blockade, interfere with dilation of the arterial supply to the corpora and, possibly, block autonomic transmission needed for emission and antegrade ejaculation. Additionally, reserpine and methyldopa elevate serum prolactin levels and further interfere with sexual function. 5 • 14 JJ-Blockers, especially propranolol, are a significant cause of sexual dysfunction. Their ability to penetrate the central nervous system causing central sympatholytic effects depends on their lipophilic nature. Some of the newer JJ-blockers, such as atenolol, are water soluble and have less potential for these serious effects. 5 JJ-Agonists, such as the angiotensin converting enzyme inhibitor captopril and calcium channel blockers have not been associated with sexual dysfunction to a significant degree. It must be remembered that some of the dysfunction from antihypertensives is owing to the primary disease of atherosclerosis and its changes in the ·pelvic vasculature, resulting in some degree of pelvic vascular insufficiency. Also, some of these antihypertensive agents, such as guanethidine and methyldopa, have a-blocking activity and _are associated with ejaculatory incompetence, increasing the possibility of a psychological basis for the erectile dysfunction. 5 MEDICAL TREATMENT OF ERECTILE DYSFUNCTION
Low or low normal serum testosterone levels may suggest 3 endocrinologic syndromes. If luteinizing hormone secretion is low, hypogonadotropic hypogonadism from primary pituitary failure is entirely possible. Normal or elevated luteinizing hormone levels may suggest hypergonadotropic hypogonadism resulting from primary testicular failure. Also, hyperprolactinemia resulting in decreased libido and, possibly, gynecomastia is seen with depressed testosterone levels. In this instance bromocriptine or surgical ablation of a localized pituitary tumor is indicated. 14 Some patients with low or low normal serum testosterone levels after pituitary dysfunction has been ruled out will benefit from injection of 200 mg. testosterone enanthate every 2 to 3 weeks. If this is the etiology of the dysfunction the patient should have a rather dramatic and immediate response. He then can be started on oral methyl testosterone, since other forms of testosterone are not absorbed well from the gastrointestinal tract, with the knowledge that it may increase the incidence of prostatic carcinoma. Isoxsuprine is a JJ-adrenergic receptor stimulant that in some studies has been effective in patients who have been heavy smokers. The side effects are rare and the dosage is 10 to 20 mg. orally 3 times daily.3 Yohimbine is a presynaptic a-2 receptor blocker that decreases outflow of blood from the corporeal tissue. It also probably works on upper levels in the brain to increase libido. Yohimbine has rare side effects, including anxiety and a possible mild antidiuretic action through a release of antidiuretic hormone. It is contraindicated in cases of renal dysfunction. Patients on antihypertension medication should be watched closely, since blood pressure changes may occur. A dose of 5.4 to 6 mg. orally 3 times daily has been effective in many patients.4 The physiology of erection indicates the necessity of JJ-adrenergic stimulation and a-receptor blockade, so that the ·combination of isoxsuprine and yohimbine sometimes is effective in patients refractory to one or the other. Psychological factors, either primary or secondary, frequently have a major role in the multifactorial etiology of erectile dysfunction. Frequently, these patients manifest a significant amount of depression and they may not be maintained on oral antidepressants. Trazodone has little anticholinergic effect, and has demonstrated efficacy in patients who are switched from other antidepressants and shown to have vasoactive potential when injected directly into the corpus cavernosum resulting in erections. 15 Therefore, I have found it useful to consider patients for maintenance on this medication after the initial visit. Indeed, in my experience this medication has
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,., - l
3
proved to be useful sometimes in conjunction with other oral medications. Patients with diabetic neuropathy sometimes present with significant amounts of pain in conjunction with the erectile dysfunction. This pain usually is owing to the neuropathic state that results from sorbitol deposition on Schwann's cells owing to aldose reductase enzyme activity. Previous authors have shown that aldose reductase inhibitors can be useful in reversing the neuropathy that causes the neurological component of diabetic impotence, so as to to improve erections in a select group of diabetic patients. 16 Although pure aldose reductase inhibitors currently are not available to the practicing physician, other agents with partial activity, such as amitryptyline, diphenhydramine, phenytoin, imipramine and carbamazepine, have demonstrated partial activity as aldose reductase inhibitors and may be considered in diabetic impotent patients who present with a significant degree of pain. 17 If the patient has failed medical therapy and penile tumescence studies demonstrate excellent erectile function, then psychogenic options and sexual counseling should be discussed. For some of these patients and also for those with documented organic dysfunction, the physician should discuss with the patient and partner the desire for other options, such as no sex whatsoever. Many women and some men are in need of close attention, such as hugging and caressing, and direct sexual activity is not mandatory. Additionally, some men initially seek consultation for the erectile dysfunction to make sure that they do not have a more serious condition, such as cancer or some other systemic illness that will directly affect the over-all quality of life. The patient and partner also may choose manual stimulation to orgasm without actual vaginal penetration. SELF-INJECTION WITH VASOACTIVE DRUGS
Papaverine (60 mg. injected intracorporeally) can be a useful clinical diagnostic tool. In a normal patient this drug causes arterial dilation, venous constriction and sinusoidal relaxation by bypassing the normal cavernosal nerve stimulation mechanism, and an erection will occur in 3 minutes or less. Patients with hormonal or neurological impotence also will have an excellent response to the injection, with initiation less than 5 minutes and duration longer than 60 minutes. Patients with mild psychogenic disturbances generally will have a good response to this test and subsequent treatment may build self confidence markedly, such that they may be cured with several injections. However, patients with moderate or severe psychogenic problems may have a poor response to the papaverine, possibly owing to increased adrenaline outflow. Patients with vasculogenic impotence will have a markedly delayed onset of erection with markedly reduced quality, length, circumference and duration.15' 18 A good erection but markedly reduced duration indicates a possible steal syndrome or venous incompetence. 6 • 7 • 15• 18 The addition of phentolamine further increases arterial flow and has little or no effect on venous compression. This a-blocking agent allows for lower doses of papaverine, while possibly reducing the most severe side effects of priapism and corporeal fibrosis. Sexual stimulation also enhances papaverine by releasing neurotransmitters. The combination of these 2 agents in a therapeutic protocol should be successful in greater than 70 per cent of all patients. This effect is age-dependent and related directly to the presence of vascular disease, such that the best candidates for these self-injections are those with neurological disease. 6 • 18 Patients must sign an informed consent, and undergo a selfinjection training period, liver function tests and an electrocardiogram. At monthly intervals they receive new supplies of these agents and undergo repeat liver function studies. The general recommended dose is 30 mg. papaverine per mg. phentolamine such that 1 cc will result in the delivery of about 25 and 0.86 mg., respectively. Vascular impotence will require higher doses of these agents. In more than 50 of my patients
4
NELSON
this dosage schedule has resulted in erection satisfactory for intercourse in 84 per cent. Several of these patients subsequently have received a penile prosthesis. For young patients and especially those with neurological disease, much lower doses of the combination agents can be used, initially as low as 1/10 to 3/10 cc increased in increments until adequate erections are obtained. 5 • 15 The most significant short-term complication is that of a prolonged erection, which if nonpulsatile should be aspirated. If this prolonged erection develops into a pulsatile priapismtype state, then epinephrine (1 mg. in 1 l. saline, or possibly dopamine or norepinephrine) at a dose of 0.001 mg./cc (1 µ,g./ cc) can be injected intracorporeally as 10 to 20 cc irrigant, which then is aspirated. Prolonged erections of more than 4 hours if treated do not result in priapism. Actual cases of priapism are uncommon if physicians and patients are careful to treat prolonged erections. Some cases of subclinical Peyronie's disease (cavernosal fibrosis), 15 approximately 4 per cent in 1 series,6 have been reported. Vasovagal reaction, bradycardia, hypotension, dizziness and facial flushing also are uncommon events and can be treated easily with atropine. Subcutaneous hematoma is an easily treated problem. Possible other complications include liver toxicity and heart rhythm changes, and they are rarely if ever reported. Liver function problems appear to be reversible when the drugs are stopped. 5, 6. 1s Most likely during a long treatment period corporeal fibrosis, which may result in a Peyronie's disease state, will be the limiting factor with any combination of papaverine, since the pH of about 3 to 4 with this agent will cause sclerosis. 5 Thus, it is important that doses of papaverine be kept minimal and that other agents be found that also may cause smooth muscle relaxation. A patient also may develop tolerance to these particular drugs. I believe that this condition could be secondary to depletion of the neurotransmitters available in the corporeal tissue, which may be an acceleration of the over-all erectile dysfunction state. Therefore, other agents must be investigated continually. Lue and Tanagho documented 6 groups of medications that possess smooth muscle relaxing properties and are capable of inducing penile erections when injected intracorporeally. 15 One group includes the smooth muscle relaxants, papaverine and nitroglycerin. It is noteworthy that nitroglycerin paste has been reported to be associated with erections and severe spousal headache in at least 1 instance in the recent literature. 19 Another group of agents are the a-blockers, which include phenoxybenzamine and phentolamine. Calcium channel blockers, such as verapamil, and polypeptides, such as vasoactive intestinal polypeptides, are 2 other groups. The /3-agonist isoproterenol and antidepressants, such as trazodone, or antipsychotic agents, such as thorazine, also induce penile erection when injected intracorporeally. The latter 2 agents possibly may be associated with significant priapism events. Prostaglandin El also has been implicated in the induction of penile erection. 20 Histological studies reveal that the framework of the sinusoids is made of smooth muscle in addition to the walls of the arteries and veins. These pharmacological agents release neurotransmitters and relax the smooth muscles, resulting in decreased peripheral resistance and sinusoidal space enlargement. 15, 1s VASCULAR INTERVENTION
Normal erection depends on a 6-fold increase in arterial inflow. 15 Obviously, patients with significant systemic or local arterial disease will not be able to provide an adequate increase in arterial inflow after appropriate nervous stimuli. Those with the Leriche syndrome have been considered candidates for percutaneous hypogastric arterial dilation. In carefully selected patients direct vascular intervention has been associated with long-term success. If young patients with local disease second-
ary to pelvic trauma or perineal straddle injuries, documented by internal pudendal arteriography, can be selected good results can be expected by anastomosis of the inferior epigastric artery to the dorsal penile artery on the side of the best flow. In this group of highly selected patients satisfactory results can be obtained in more than 70 per cent. 8 Patients with significant risk factors, such as myocardial infarction, hypertension, prolonged cigarette smoking, claudication and so forth, who have evidence of systemic vascular disease are poor candidates for arterial revascularization. Bennett and associates have popularized the procedure by Virag, termed the V-5 in this country, in which the epigastric artery is anastomosed to the dorsal vein, which then is sutured to the corpora in a side-to-side fashion after ligation of the vein proximally and removal of a segment. 7• 8 Initial results in selected patients have shown some benefit but, generally, success can be expected in less than 50 per cent over-all. A select number of patients initially have good erections that disappear during a short period. When studied with papaverine and infusion cavernosography, abnormal venous drainage can be documented. Ligation of the deep dorsal vein at the base of the penis has been effective in greater than 75 per cent of these patients. It is possible that long-term followup may reveal progressive erectile deterioration if collateral venous circulation develops. 7 • 21 Although revascularization procedures cannot boast the greater than 90 per cent patient-partner satisfaction statistics for penile implants, new patients continue to desire restoration of erection naturally if possible and this will continue to stimulate revascularization research. Radiologists also have become active in the diagnosis and treatment of patients with arterial and venous disease. Transluminal angioplasty has been shown to be at least temporarily effective in patients who have demonstrated lesions either in the hypergastric or pudendal arterial system. Bookstein demonstrated some minimal and transient improvement in blood flow through the internal pudendal artery with percutaneous balloon angioplasty. 22 Others have had partial success in treating erectile dysfunction caused by venous leakage with detachable balloons and coils. 23 These methods obviously are in their infancy and further clinical trials are indicated to prove the efficacy on a long-term basis. TREATMENT WITH EXTERNAL DEVICES
Some patients have become candidates for treatment with external devices, such as the Osbon Erec Aid system, which has been used in several thousand patients to date with great success. This is a vacuum-type device that essentially suctions blood into the penis. 9 Recently, 2 other devices were introduced: the vacuum constriction device 10 and a new glass clear silicone rubber device that sheathes the penis and holds it erect, permitting sexual intercourse as long as the device is worn. The latter device was used in 240 cases demonstrating its safety, efficacy and reliability. 11 These devices should be presented additionally to patients before consideration for a penile prosthesis. CONCLUSION
The diagnosis and treatment of erectile dysfunction require a multidisciplinary approach, since the etiology of this problem almost always is multifactorial. Some studies have shown that almost 10 per cent of the men who undergo penile prosthetic implantation ultimately never use the device 24 and, coupled with the increasing malpractice claims regarding urological prosthetic surgery, it is imperative that physicians who treat these patients become more aware of other options before they implant a penile prosthesis, which really is a last resort. I have developed an approach to these patients that I believe is pragmatic, starting with the most easily tolerated and least expensive forms of therapy initially, and proceeding up to more complicated and somewhat invasive treatments if the former
NONOPERATIVE MANAGEMENT OF IMPOTENCE
do not improve erection. Oral medications have proved to be of immense benefit in a significant number of patients and, frequently, they result in some improvement in function that also may improve the psychological status. Awareness of pharmacological side effects on erectile dysfunction should lead to alternative medications with less interference. Self-injection of the penis with vasoactive drugs is becoming increasingly popular and when new agents become available to reduce some of the potential side effects this form of treatment may result in unlimited success. As discussed, some highly selected patients may be candidates for either arterial revascularization or venous ligation if appropriate studies reveal these to be the etiologies of the impotence. External devices should be presented to patients, since they are particularly inexpensive and simple. Only if the patient rejects these forms of therapy or, indeed, fails any or all of them should a penile prosthesis be considered. It is gratifying that the penile prosthesis can produce a greater than 90 per cent satisfaction rate. With this in mind the patient always should have an optimistic outlook as to the ultimate solution for the erectile dysfunction.
10. 11. 12. 13. 14.
15. 16.
REFERENCES 1. Walsh, P . C. and Mostwin, J . C.: Radical prostatectomy and cystoprostatectomy with preservation of potency. Results using a new nerve-sparing technique. Brit. J. Urol., 56: 694, 1984. 2. Walsh, P. C. and Donker, P. J.: Impotence following radical prostatectomy: insight into etiology and prevention. J . Urol., 128: 492, 1982. 3. Elist, J ., Jarman, W. D. and Edson, M.: Evaluating medical treatment of impotence. Urology, 23: 374, 1984. 4. Morales, A., Surridge, D . H. C., Marshall, P . G. and Fenemore, J .: Nonhormonal pharmacological treatment of organic impotence. J. Urol., 128: 45, 1982. 5. Nelson, R. P.: Pathophysiology, diagnosis, and management of erectile dysfunction. In: Urology Annual, 1987. Edited by S. Rous. Norwalk, Connecticut: Appleton & Lange, vol. 1, pp. 139169, 1987. 6. Zorgniotti, A. W . and Lefleur, R. S.: Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133: 39, 1985. 7. Bennett, A. H., Rivard, D. J ., Blanc, R. P. and Moran, M .: Reconstructive surgery for vasculogenic impotence. J . Urol., 136: 599, 1986. 8. Virag, R.: Revascularization of the penis. In: Management of Male Impotence. Edited by A. H. Bennett. Baltimore: The Williams & Wilkins Co., chapt. 17, pp. 219-233, 1982. 9. Witherington, R.: The Osbon Erecaid System in the management
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of erectile impotence. Read at annual meeting of Southeastern Section, American Urological Association, Marco Island, Florida, p. 46, March 17-20, 1985. Nadig, P .: Utility of the vacuum-constriction device for men who have failed penile prostheses. J . Urol., part 2, 135: 232A, abstract 512, 1986. Gerow, F. J.: The erectaid tumescence assistance device. J . Urol., part 2, 135: 232A, abstract 513, 1986. Condra, M., Morales, A., Owen, J ., Surridge, D. H . and Fenemore, J .: The effect of tobacco smoking on erectile function: initial results. J. Urol., part 2, 131: 234A, abstract 524, 1984. Juenemann, K.-P., Lue, T . F., Luo, J.-A., Benowitz, N. L., Abozeid, M. and Tanagho, E. A.: The effect of cigarette smoking on penile erection. J . Urol., 138: 438, 1987. Krane, R. J .: Sexual function and dysfunction. In: Campbell's Urology, 5th ed. Edited by P. C. Walsh, R. F . Gittes, A. D. Perlmutter and T . A. Stamey. Philadelphia; W. B. Saunders Co., vol. 1, sect. VI, chapt. 13, p. 700, 1986. Lue, T. F. and Tanagho, E. A.: Physiology of erection and pharmacological management of impotence. J. Urol., 137: 829, 1987. Carson, C. C., III, Porretta, T., Bertram, R. A., Herman, S. H . and Feinglos, M . N .: The aldose reductase inhibitor in the treatment of diabetic impotence. Read at annual meeting of Southeastern Section, American Urological Association, Marco Island, Florida, p. 46, March 17-20, 1985. Buse, J .: Personal communication. Abber, J.C., Lue, T. F., Orvis, B. R., McClure, R. D. and Williams, R. D.: Diagnostic tests for impotence: a comparison ofpapaverine injection with the penile-brachia! index and nocturnal penile tumescence monitoring. J. Urol., 135: 923, 1986. Talley, J. D. and Crawley, I. S.: Transdermal nitrate, penile erection, and spousal headache. Letter to the Editor. Ann. Intern. Med., 103: 804, 1985. Hedlund, H. and Andersson, K.-E.: Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J. Urol., 134: 1245, 1985. Lue, T. F ., Hricak, H., Schmidt, R. A. and Tanagho, E. A.: Functional evaluation of penile veins by cavernosography and papaverine-induced erection. J . Urol., 135: 479, 1986. Kuznar, W.: New technique in impotence shows hope. Urol. T imes, 14: 1, January 1987. Courtheoux, P., Maiza, D., Henriet, J .-P., Vaislic, C. D., Evrard, C. and Theron, J.: Erectile dysfunction caused by venous leakage: treatment with detachable balloons and coils. Radiology, 161: 807, 1986. Batten, W. H .: Patient and sexual partner performance and satisfaction with semi-rigid and inflatable penile prostheses. Read at annual meeting of Southeastern Section, American Urological Association, Dorado Beach, Puerto Rico, p. 34, March 16-19, 1986.
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