Intracavernous Injection of Prostaglandin E1 for the Treatment of Erectile Impotence

0022-5347 /89/1412-0323$02.00/0 THE JOURNAL OF UROLOGY

Vol. 141, February

Copyright© 1989 by The Williams & Wilkins Co.

Printed in U.S.A.

INTRACAVERNOUS INJECTION OF PROSTAGLANDIN El FOR THE TREATMENT OF ERECTILE IMPOTENCE NOBUHISA ISHII, HIROYUKI WATANABE, CHIAKI IRISAWA, YOSHIHIRO KIKUCHI, YOKO KUBOTA, SHUNZO KAWAMURA, KIICHI SUZUKI, RHUICHI CHIBA, MICHIO TOKIWA AND MASAFUMI SHIRAI From the Department of Urology, University of Yamagata, Yamagata, Fukushima Rosai Hospital, Iwaki and University of Toho, Tokyo, Japan

ABSTRACT

We administered intracavernous injections of 20 µg. prostaglandin El to 135 patients with impotence, and evaluated the effects and side effects. Among 135 patients who underwent intracavernous injection of prostaglandin El complete erection was observed in 83 (62 per cent), while incomplete erection was noted in 33 (24 per cent). In both groups the erection was sufficient for sexual intercourse. Tumescence without rigidity was noted in 12 patients and no response was obtained in 7. Poor response was seen frequently in patients with disorders of the vascular system and/or damage to the cavernous body of the penis. Priapism after the injection was not observed. Moreover, we never observed any other severe side effects. Intracavernous injection of prostaglandin El could be applicable to the therapy of impotence, especially that due to neurogenic disturbance. Since prostaglandin El acts quickly and loses its validity rapidly it is considered to be a more suitable agent than other vasoactive drugs. (J. Urol., 141:323-325, 1989) We previously treated impotence by insertion of a double rod silicone penile prosthesis (semirigid type), which was suitable for Japanese patients. 1 However, the attitude of impotent Japanese patients was so conservative that few desired insertion of a penile prosthesis. Therefore, it was necessary to develop a nonoperative treatment for impotent patients. Virag2 and Brindley3 reported that intracavernous injection of vasoactive drugs produced a fully rigid erection. Recently, however, some cases ofpriapism after intracavernous injection of papaverine have been reported. Since we observed that erectile dysfunction was improved in some impotent patients who were under intravenous prostaglandin El treatment for vascular occlusive disease (fig. 1), prostaglandin El was presumed to be an effective agent for intracavernous injection. Therefore, we began intracavernous injection of prostaglandin El in 135 impotent patients, and we evaluated the effects and side effects of therapy. MATERIALS AND METHODS

All 135 patients with erectile dysfunction were treated on an outpatient basis at the departments of urology of our hospitals (table 1). To determine the etiology of impotence, the history was evaluated precisely in each patient. All patients underwent extensive laboratory studies that included blood counts, tests related to hepatic function, blood sugar levels, and serum testosterone and prolactin levels. Penile skin temperature was monitored during and after a visual sexual stimulation test, 4 and a nocturnal penile tumescence test was performed in some patients. 5 Patients with a normal response to these tests were diagnosed as having psychogenic impotence. Other patients were divided into 5 groups according to known most probable disorders that produce impotence. In the psychogenic impotence group 4 patients were diagnosed as having schizophrenia and 1 as having depression. In the intrapelvic surgery group 10 patients had undergone total cystectomy, 5 radical prostatectomy, 8 abdominoperineal resection of the rectum and 9 transurethral resection of the prostate. Of the patients with cerebrospinal Accepted for publication June 24, 1988.

disorders 14 had suffered spinal cord injury, 3 head injury, 1 cerebello- spinal atrophy, 1 myelitis and 1 intervertebral hernia, while 1 had postoperative extradural hemorrhage. Of the 9 patients with urethral injury 4 were complicated with pelvic fracture. Four of the 8 patients with diabetes mellitus had been receiving insulin treatment. Among the 6 patients with endocrine disturbances 4 had undergone bilateral orchiectomy, 1 had undergone hypophysectomy and 1 had the Werner syndrome. In all of these patients 20 µ.g. prostaglandin El dissolved into 1 to 20 ml. physiological saline were injected through a fine needle (26 gauge) according to the method of Zorgniotti and Lefleur. 6 Because patients with arteriosclerosis obliterans had been treated by 20 µ.g. prostaglandin El injection we decided to use this dose for our therapy. Since some reports had documented that a few patients complained of vascular pain during intravenous injection of prostaglandin El we first dissolved 20 µ.g. prostaglandin El into 20 ml. saline. However, no patient complained of local pain and we gradually decreased the dose of saline. To date we dissolve 20 µ.g. prostaglandin El in 5 ml. saline. The prostaglandin El concentration made no difference in the erectile response. The needle was inserted into the base of the penile cavernous body and completely through the albuginea. The drug could be infused easily without resistance and no patient complained of penile pain. We did not load patients with sexual stimulation. The effects were observed and graded as complete erection, incomplete erection but with rigidity sufficient for sexual intercourse, tumescence (penile circumference enlarged) without sufficient hardness for sexual intercourse and no reaction.

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ISHII AND ASSOCIATES TABLE 1.

Materials No. Pts.

Psychogenic (include psychosis) Intrapelvic surgery Cerebrospinal disorders Urethral injury Diabetes mellitus Endocrine disorders Totals

60 32 21 9 8 5

135

2. Results of intracavernous injection of prostaglandin El

TABLE

Mean Age (range) 42.5 64.2 36.1 50.4 47.0 52.2 47.7

(17-77) (49-78) (23-59) (19-60) (30-56) (44-71) (17-78)

Complete erection Incomplete erection Tumescence Nonreaction Totals

No. Pts. (%)

Mean Age (yrs.)

83 (62) 33 (24) 12 (9)

46.9 54.2 52.4 58.6 47.7

7 (5) 135 (100)

~30 RESULTS

In the patients who achieved complete erection the penile circumference was enlarged within 2 to 3 minutes after injection of prostaglandin El. At that time the erection lasted for 1 to 3 hours. There were no episodes of priapism. Table 2 shows the 'results of intracavernous injection of prostaglandin El. Of the 135 patients 83 (62 per cent) were able to obtain complete erection and 33 (24 per cent) achieved incomplete erection. All 116 patients had penile rigidity sufficient for sexual intercourse. Thus, the efficiency of prostaglandin El amounted to 86 per cent (116 of 135 patients) over-all. Also, there were 12 patients (10 per cent) in whom penile circumference was enlarged by the prostaglandin El injection but rigidity was insufficient for sexual intercourse, while 7 (5 per cent) showed no reaction. All patients were classified by age as shown in figure 2. Poor response (tumescence or nonreaction) often was noted in 40 to 60-year-old patients. The result could be attributed possibly to the fact that many patients at this age have organic disturbances that would cause impotence. The patients were classified by factors leading to impotence (fig. 3). Complete erection could be observed most often in the group with psychogenic impotence and the efficiency in this group amounted to 88 per cent. Seven patients in this group could not obtain enough rigidity for sexual intercourse: 1 had a history of extraction of a penile prosthesis but the other 6 had no appreciable record of illness in the past. The reasons for nonresponse to prostaglandin El are under study. Complete or incomplete erection was noted in 97 per cent of the intrapelvic surgery group and 95 per cent of the cerebrospinal disorders group. However, the erection rates were low in the pelvic fracture, diabetes mellitus and endocrine disorders groups (56, 63 and 40 per cent, respectively). DISCUSSION

Recently, self-injection of papaverine into the corpus cavernosum has been reported_ However, prolongation of the effect of papaverine leads to priapism in some patients. For this reason we applied prostaglandin El, which has the strongest vasodilating effect of all prostaglandins. Prostaglandin El reacts directly upon the smooth muscles in the corpus cavernosum and most of the injected prostaglandin El is metabolized during a single passage through the lungs. Therefore, the injected prostaglandin El acts quickly and loses its validity rapidly. In fact, from our experience with 135 patients erection began within 2 to 3 minutes after injection and lasted for a maximum of 3 hours. None of our patients had priapism. The mechanism of how prostaglandin El induces erection has not yet been clarified. However, it is obvious that papaverine reacts directly upon the smooth muscle of the corpus cavernosum and blood vessels without the aid of nerves. We performed direct infusion of prostaglandin El into the internal pudendal artery to achieve vascular dilatation in patients with vasculogenic impotence due to diabetes mellitus. 7 The results revealed that the penile arteries could be dilated fully down to the peripherals and the amount of intrapenile blood flow was increased. This finding could be observed also from the penile

31~40 41~50 51~60 61~70

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Complete

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Fm. 2. Results of intracavernous injection of prostaglandin El by age.

Psychogenic

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Fm. 3. Results of intracavernous injection of prostaglandin El by factors leading to impotence.

skin temperature. However, by injecting prostaglandin El into the pudendal artery no erection occurred. Jueneman and associates stated that papaverine induced erection when injected into the corpus cavernosum. 8 Thus, to induce an erection vasoactive drugs should make direct contact with the smooth muscle of corpus cavernosum or blood vessels. The patients in whom erection could not be obtained were closely examined to determine the causes of failure. In the 4 patients with urethral rupture complicated by pelvic fracture the corpus cavernosum and/or penile vascular system certainly was damaged. None of these 4 patients could achieve complete or incomplete erection. This finding suggests that vascular damage is a main cause of the poor response to prostaglandin El injection therapy. Moreover, vascular disturbance was clinically doubted in 3 patients with diabetes mellitus and none of them could obtain an erection. In the group more than 70 years old or with endocrine disorders the rate of cavernous atrophy

325

INTRACAVERNOUS iNJECTWN G:F PROSTAGLb,NDIN El

or sclerotic changes of the arteries was supposedly Vascular disturbances would be a major cause for the poor efficiency in these groups. Furthermore, giving consideration to the fact that the patients after extraction of a penile prosthesis had a poor response to prostaglandin El, it can be assumed that some factors in the corpus cavernosum are closely related to the responses to prostaglandin El. Abber and associates compared the result of intracavernous injection of papaverine with the penile brachial index and nocturnal penile tumescence tests, and reported that patients with a poor response to intracavernous injection of papaverine could be diagnosed as organically impotent." We performed the nocturnal penile tumescence test in patients who did not have any response to visual sexual stimulation and diagnosed them as organically impotent. 4 However, we made it a rule currently to perform intracavernous injection of prostaglandin El first to diagnose vasculogenic impotence. Then, in patients who showed a poor response we perform internal pudendal arteriography or cavernosography to confirm the vascular disorders. In vasculogenically impotent patients who are not candidates for a vascular operation we recommend intrapenile insertion of a prosthesis. We also have used papaverine and have observed poorer erection with it than with prostaglandin El in patients, such as those with spinal cord injury. For this reason if vasoactive drugs are to be used for therapy we adopt intracavernous injection of papaverine first and then apply prostaglandin El to those with a poor response. Some patients who received intracavernous injections of prostaglandin El several times had restoration of spontaneous erections. Moreover, some patients with psychogenic impotence could easily restore their confidence in the erection after therapy. Thus, this therapy could be of psychic or behavioral benefit. Finally, in regard to side effects ofprostaglandin El, we have experienced a limited number of patients who complained of dull penile pain. No patient had prolonged erection for more than 3 hours and none had hypotension. REFERENCES 1. Ishii, N., Fujioka, T., Shindoh, M., Koguchi, M., Majima, H., Suzuki, N., Kanetoh, H., Chiba, R., Tokiwa, M. and Shirai, M.: Studies on male sexual impotence. Report 15. Treatment of erectile impotence by implantation of Shirai's silicone penile prosthesis. Jap. J. Urol., 74: 2131, 1983.

2. 't/i:tag R.: Intracavernous injection of papaverine for erection failure. Letter to the Editor. Lancet, 2: 938, 1982. 3. Brindley, G. S.: Cavernosal alpha-blockade: a new technique for investigating and treating erectile impotence. Brit. J. Psychiat., 143: 332, 1983. 4. Ishii, N., Fujioka, T., Chiba, R., Tokiwa, M. and Shirai, M.: Studies on male sexual impotence. Report 12. A screening method of organic impotence for penothermocurve. Jap. J. Urol., 74: 640, 1983. 5. Karacan, I., Hursch, C. J., Williams, R. L. and Thornby, J. I.: Some characteristics of nocturnal penile tumescence in young adults. Arch. Gen. Psychiat., 26: 351, 1972. 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. Ishii, N., Watanabe, H., Irisawa, C., Kikuchi, Y., Kawamura, S., Suzuki, K., Chiba, R., Tokiwa, M. and Shirai, M.: Studies on male sexual impotence. Report 18. Therapeutic trial with prostaglandin El for organic impotence. Jap. J. Urol., 77: 954, 1986. 8. Juenemann, K.-P., Lue, T. F., Fournier, G. R., Jr. and Tanago, E. A.: Hemodynamics of papaverine- and phentolamine-induced penile erection. J. Urol., 136: 158, 1986. 9. Abber, J. C., Leu, 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. 1

EDITORIAL COMMENT The authors, who are the pioneers in the use of prostaglandin El for intracavernous injection, present an attractive alternative to papaverine alone or with phentolamine for intracavernous injection therapy. Prostaglandin El has been reported to be superior to other agents and to result in almost no complications. In my own experience with approximately 150 patients (dose l to 15 mg. in 0.1 to 1 ml. saline) several complications have occurred, including prolonged erection greater than 7 hours requiring epinephrine solution for reversal in 2 patients, mild discomfort to aching during erection in approximately 25 per cent of the patients, severe aching in 7 patients and skin rash in 1 patient. No other systemic reactions have occurred and no fibrosis has developed. In animal experiments the tissue reaction to prostaglandin El is minimal compared to that after papaverine. However, the readers should use caution in treating patients with this new agent. At our institution a consent form is obtained and the same precautions are taken as for papaverine when patients are treated with prostaglandin EL

TomF. Lue Department of Urology University of California San Francisco, California