TAMOXIFEN VERSUS PLACEBO IN THE TREATMENT OF PEYRONIE’S DISEASE

0022-5347/99/1626-2003/0 THE JOURNAL OF UROLOGY® Copyright © 1999 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 162, 2003–2005, December 1999 Printed in U.S.A.

TAMOXIFEN VERSUS PLACEBO IN THE TREATMENT OF PEYRONIE’S DISEASE ´ LIO MEYER GRAZZIOTIN, CLAUDIO TELOKEN, ERNANI LUIS RHODEN, TU CARLOS TEODÓSIO DA ROS, PAULO ROBERTO SOGARI AND CARLOS ARY VARGAS SOUTO From the Department of Urology, Andrology Section, Santa Casa Hospital and Fundac¸a˜o Faculdade Federal de Cieˆncias Me´dicas, Porto Alegre, Brazil

ABSTRACT

Purpose: We evaluated the effects of oral tamoxifen and placebo in patients with Peyronie’s disease. Materials and Methods: We selected 25 patients with Peyronie’s disease who did not have calcified plaque for treatment in the andrology outpatient clinic. A medical history was obtained, and physical examination, penile x-ray, penile ultrasound and pharmacologically induced erection with prostaglandin E1 were performed. Patients were randomly divided into group 1—those who received 20 mg. tamoxifen twice daily for 3 months and group 2—those who received placebo for the same period. The same evaluations were done 4 months later and results were compared. Qualitative (chi-square test) and quantitative (Student’s t test) results were analyzed using the Yates correction factor with p ,0.05 considered significant. Results: Pain subsided in 66.6 and 75% of the patients treated with tamoxifen and placebo, respectively (p .0.05). In groups 1 and 2 a reduction in the penile deformity was noticed by 46.1 and 41.7% of the patients (p .0.05), and a decrease in plaque size was noticed by 30.7 and 25%, respectively. On the other hand, objective measurements did not reveal any difference in plaque area or curvature angle. Conclusions: This study did not show significant improvement in pain, curvature or plaque size in patients with Peyronie’s disease who were treated with tamoxifen compared with those treated with placebo. KEY WORDS: disease, Peyronie; penis; tamoxifen; placebo

Peyronie’s disease is a fibrotic and multifocal structural degeneration of the penile tunica albuginea, and a common cause of pathological penile bending during erection.1 To our knowledge the etiology of Peyronie’s disease remains unknown, which explains the limited success of the numerous therapies used. Recent research on the pathogenesis of Peyronie’s disease has focused on the involvement of transforming growth factor-b (TGF-b).2, 3 TGF-b has been shown to participate in the initiation of complex sequences of monocyte chemo-attraction, induction of angiogenesis. and control of production of cytokine and other inflammatory mediators. Moreover, TGF-b stimulates the synthesis of individual matrix components while simultaneously blocking matrix degradation by decreasing the synthesis of proteases and increasing the levels of protease inhibitors. However, the deposition of extracellular matrix at the site of tissue injury may lead to scarring and fibrosis. Furthermore, the ability of TGF-b to induce its own production may be the key to the development of scarring and fibrosis.4 The effects of tamoxifen on the production of TGF-b and its interference with the inflammatory response were the reasons that led us to test it in Peyronie’s disease. PATIENTS AND METHODS

This study was approved by the ethics committee at our hospital. Patients were previously informed of the research details and possible side effects of the drug, and they agreed to participate in the study. The study included 25 consecutive men 46 to 75 years old (mean age 59.6) who presented from March to December 1997 with Peyronie’s disease. The reported duration of disease ranged from 4 to 72 months (mean Accepted for publication July 23, 1999.

20). Patients had received no previous treatment. In all patients a medical history was obtained. Evaluations included physical examination involving the measurement of the longitudinal and transverse dimensions of plaque size with a ruler, x-ray, penile ultrasound and pharmacologically induced erection with 20 mg. prostaglandin E1 with determination of the degree of bending during a full erection using angle measurement equipment. A repeat dose was not necessary in any patient. Men with calcified plaque on x-ray and those who had been previously treated were excluded from study. Patients were randomly divided into group 1—13 who received 20 mg. tamoxifen orally twice daily for 3 months and group 2—12 who received a similar regimen of placebo. There were no statistical differences in plaque size, penile curvature and disease onset in the 2 groups. All determinations were repeated 1 month after cessation of treatment. The placebo tablet was a starch compound equal in color and size to the tamoxifen tablet. Each medication was prepared in the hospital pharmacy and offered to the patients gratuitously. Patients were evaluated by the same interviewers after each treatment period. The chi-square test for qualitative and Student’s t test for quantitative data were used with the Yates correction factor for statistical analysis of the qualitative results of the differences in this study with p ,0.05 considered significant. RESULTS

All patients with Peyronie’s disease presented with a palpable plaque but none had an hourglass deformity. Table 1 lists the results of symptomatic improvement. Penile pain subsided in 66% of the patients who received tamoxifen and

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2004

TAMOXIFEN VERSUS PLACEBO FOR PEYRONIE’S DISEASE TABLE 1. Symptomatic effects of tamoxifen and placebo No. Pts. (%) No. Pts.

Painful erection: Tamoxifen Placebo Deformity: Tamoxifen Placebo Patient perception of plaque size Tamoxifen Placebo Chi-square test p .0.05.

Pretreatment Status

Posttreatment Improvement

12 12

6 (46.1) 4 (33.3)

4 (66.6) 3 (75)

13 12

13 (100) 12 (100)

6 (46.1) 4 (41.7)

13 12

13 (100) 12 (100)

4 (30.7) 3 (25)

in 75% who received placebo (p .0.05). A reduction in penile deformity was noticed by 46.1 and 41.7% of the patients who received tamoxifen and placebo, respectively (p .0.05). Plaque size decreased in 30.7% of the men who received tamoxifen and in 25% of those who received placebo (p .0.05). Table 2 shows objective evaluation results. After treatment calcifications were noted in 7.7% of the patients who had received tamoxifen and in 16.6% of those who received placebo (p .0.05). The plaque area and curvature angle measurements determined after treatment did not reveal any difference in the 2 groups (p .0.05). In the tamoxifen and placebo groups 1 patient each reported an episode of gastritis (p .0.05). DISCUSSION

Fibrosis of the tunica albuginea is a major contributor to morbidity in patients with Peyronie’s disease. Many clinical factors define those at increased risk for this devastating condition but none of these clinical factors definitively explains the pathogenesis of this entity. The true pathogenesis of Peyronie’s disease remains unknown. Some have described an association with penile trauma, diabetes, hypertension and nonspecific connective tissue disorders, such as retroperitoneal fibrosis, arthrosis and Dupuytren’s contracture, as well as with the histocompatibility factor HLA-B27 and other autoimmune markers.4 – 8 More recently interference in the inflammatory process has been noted. According to this theory Peyronie’s disease has 2 phases. The acute inflammatory phase usually lasts between 6 and 18 months, and is characterized by pain, penile curvature and nodule formation, often with a self-limiting course. The chronic phase is usually marked by minimal or no pain and stable nodule size but residual penile curvature may be present.4 The sequence of events leading to penile fibrosis in Peyronie’s disease involves injury or ischemia processes with inflammation and disruption of the normal tissue architecture followed by tissue repair and an accumulation of mesenchymal cells in the area of derangement. The role of TGF-b in this process remains controversial. Ralph et al reported that the cytokine TGF-b, which is re-

TABLE 2. Objective effects of tamoxifen and placebo on plaque area and curvature angle No. Pts.

Median 6 SD Before Treatment

After Treatment

3.65 6 3.43 3.18 6 3.30

4.36 6 4.69 3.14 6 2.20

33.07 6 19.30 33.75 6 17.85

28.07 6 21.17 29.16 6 11.84

2

Plaque area (cm. ): Tamoxifen 13 Placebo 12 Curvature angle (degrees): Tamoxifen 13 Placebo 12 Unpaired Student’s t test p .0.05.

leased by platelets and activated macrophages, appears to have a central role in the inflammatory response and in wound healing.3 In normal healing TGF-b promotes matrix synthesis by fibroblasts and it is self-regulated in an autocrine manner. However, high concentrations of TGF-b in the cellular environment inhibit the inflammatory response, causing macrophage deactivation and T lymphocyte suppression, preventing further fibrogenesis. On the other hand, El-Sakka et al studied plaque in patients with Peyronie’s disease and noted that TGF-b is strongly associated with tunica albuginea fibrosis .4 This association may be responsible for the induction of extracellular matrix synthesis and the concomitant inhibition of extracellular matrix degradation. Medical management of Peyronie’s disease has generally been unsuccessful, although many agents have been tried.9 –13 Recently tamoxifen has been suggested as a medical alternative due to its effects on the overproduction of TGF-b by human fibroblasts. Ralph et al reported an overall response rate of 55% with improvement in pain in 80% of patients, improvement in deformity in 35% and plaque shrinkage in 34%.14 The greatest response occurred in patients in whom the disease was less than 4 months in duration. In this group pain improved in 100% of cases, deformity in 56% and plaque in 64%. However, the beneficial effects of tamoxifen were not reproduced in our study, although we selected patients without any calcified plaque. None of our analyses showed a significant subjective or objective response. However, it is necessary to consider that our population of patients was different, especially with respect to disease duration. In 1 series the mean duration of disease was 20 months, which is higher than that in other published series. Four months after the preliminary investigation calcifications appeared in the same proportion in each group of patients, which may characterize disease progression despite the mean duration of disease.

CONCLUSIONS

We did not observe any beneficial effect of 3 months of therapy with 40 mg. tamoxifen daily in patients with Peyronie’s disease. However, we do not know whether longterm followup of such treatment would demonstrate any benefit. We agree that further studies must be done on this drug to define the true role of tamoxifen in Peyronie’s disease. The various factors involved in the pathogenesis of this entity also require more detailed analysis.

REFERENCES

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TAMOXIFEN VERSUS PLACEBO FOR PEYRONIE’S DISEASE 8. Montorsi, F., Guazzoni, G., Bergamaschi, F., Consonni, P., Rigatti, P., Pizzini, G. and Miani, A.: Vascular abnormalities in Peyronie’s disease: the role of color Doppler sonography. J. Urol., 151: 373, 1994. 9. Gelbard, M. K.: Relaxing incisions in the correction of penile deformity due to Peyronie’s disease. J. Urol., 154: 1457, 1995. 10. Levine, L. A., Merrick, P. F. and Lee, R. C.: Intralesional verapamil injection for the treatment of Peyronie’s disease. J. Urol., 151: 1522, 1994. 11. Gelbard, M. K., James, K., Riach, P. and Dorey, F.: Collagenase

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