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A Case-Control Study on Risk Factors for Peyronie’s Disease
J Clin Epidemiol Vol. 51, No. 6, pp. 511–515, 1998 Copyright 1998 Elsevier Science Inc. All rights reserved.
0895-4356/98/$19.00 PII S0895-4356(98)00015-8
A Case-Control Study on Risk Factors for Peyronie’s Disease Maria Patrizia Carrieri,1 Diego Serraino,2,* Fabio Palmiotto,3 Giuseppe Nucci,3 and Francesco Sasso3 1
Servizio Elaborazione Dati, Istituto Superiore di Sanita`, Roma, Italy, 2Servizio di Epidemiologia, Centro di Riferimento Oncologico, Aviano, Italy, 3 Policlinico Gemelli, Cattedra di Urologia, Universita` Cattolica, Roma, Italy
ABSTRACT. The aim of this study was to investigate the relationship between history of selected diseases, genital traumas, and Peyronie’s disease. A hospital-based case-control study was conducted at the Andrologic and Surgical Outpatient Units of the Policlinico Gemelli, Rome, where 134 men with Peyronie’s disease and 134 male controls were interviewed. The association between Peyronie’s disease and selected characteristics was estimated by means of odds ratios (OR) and 95% confidence intervals (CI). Patients who underwent invasive procedures on the penis (i.e., urethral catheterization, cystoscopy, and transurethral prostatectomy) had a 16fold increased risk for Peyronie’s disease (OR 5 16.1, 95% CI: 1.8–142), while a nearly three-fold increase was observed among patients who had genital and/or perineal traumatisms (95% CI: 1.0–7.1). A history of urethritis, uricacidemia, and lipoma was also significantly associated with an increased risk for Peyronie’s disease. Twentyone percent of the cases and none of the controls were affected by Dupuytren’s contracture, and 4% of cases and none of the controls reported familial history for Peyronie’s disease. The frequency of inflammatory or fibromatous lesions of the genital tract of the partner was significantly higher in men with Peyronie’s disease than among controls. These results were consistent when performing a stratified analysis according to the type of controls (i.e., controls affected by urologic or by digestive conditions) to rule out the potential effect of recall bias. The findings of the study lend support to clinical reports stressing the importance of genital traumatisms and genetic conditions in the development of Peyronie’s disease. j clin epidemiol 51;6:511–515, 1998. 1998 Elsevier Science Inc. KEY WORDS. Peyronie’s disease, penis, risk factors
INTRODUCTION Peyronie’s disease is a disorder of the penis characterized by the formation of irregular dense plaques of fibrous tissue, generally located in the tunica albuginea of the corpora cavernosa, which causes abnormal curvature of the penis. Most patients report painful intercourse, whereas in certain individuals such deformity may be severe enough to prevent vaginal penetration [1]. Although the disease was first described more than two centuries ago [2], its epidemiology remains largely obscure. Neither prevalence nor incidence data are available, and etiologic factors have never been investigated by formal analytical studies. An etiologic role in the occurrence of Peyronie’s disease was attributed, by few reports, to two main groups of risk factors (i.e., a propen-
*
Address for correspondence: Dr. Diego Serraino, Servizio di Epidemiologia, Centro di Riferimento Oncologico, via Pedemontana Occ, 12, 33081 Aviano (PN), Italy. Phone: 39434659231; fax: 39434659222. Accepted for publication on 30 January 1998.
sity to abnormal production of collagenous tissue and penile traumatisms) [1,3–7]. To clarify the etiology of Peyronie’s disease, the present study evaluated the relationship between history of selected diseases, genital traumatisms, and the occurrence of Peyronie’s disease. METHODS A hospital-based case-control study was conducted at the Andrologic and Surgical Outpatient Units of the Policlinico Gemelli, Universita` Cattolica, Rome. The study was based on 134 cases aged 25 to 76 years (median age: 60 years), consecutively diagnosed with Peyronie’s disease between February 1992 and October 1994, and 134 male controls, aged 19 to 71 years (median age: 58 years). At diagnosis, the fibrotic plaques were palpable among 87 of the 134 cases (65%), whereas in the remaining cases the plaques were not palpable, and thus diagnosed by means of ultrasound scan or nuclear magnetic resonance. All cases had
M. P. Carrieri et al.
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penile deviation, varying from 30 to 90 degrees. The controls were admitted to the before mentioned units for a wide spectrum of diseases requiring minor surgical interventions: 62 (46%) for conditions related to the urogenital apparatus, 53 (40%) for digestive conditions, and 19 (14%) for various other conditions. Controls were interviewed within the same time period of cases, and consecutively enrolled into the study according to the age distribution of cases. A diagnosis of Peyronie’s disease among controls was excluded by clinical and anamnestic evaluation. After the informed consent was obtained, a standardized questionnaire, specifically designed for the present study, was administered by two of the authors (F.P. and G.N.) to both cases and controls. Information was elicited on sociodemographic characteristics (age, education, and residence), smoking habits, and on personal history, among others, of urologic and non-urologic conditions and familial history for Peyronie’s disease. Information was also collected regarding two main groups of traumatisms: genital and/or perineal injuries caused by recreational activities (e.g., football, tennis, skiing, biking, or climbing) and penile injuries caused by invasive, iatrogenic, procedures such as urethral catheterization, diagnostical or interventional cystoscopies, and transurethral prostatectomy. In addition, previous diseases of the genital tract of the female partner were also investigated. Histories of uricacidemia (i.e., $7 mg/dl, or documented history of specific pharmacological treatment with drugs like probenecid or sulfinpyrazone), diabetes, and high blood pressure were thoroughly ascertained by pooling information based on patient’s self-referral of disease, use of disease-specific drugs, and of laboratory tests. For both cases and controls, the diagnosis of all the investigated diseases referred to at least a 6-month period prior to the onset of the disease that led to enrollment. The associations between potential risk factors and Peyronie’s disease was statistically evaluated using odds ratios (OR) and their 95% confidence intervals (CI) [8]. Adjusted ORs were computed by a multiple logistic regression model, in order to select, among the characteristics associated with Peyronie’s disease at univariate analysis, a restricted set most likely to predict the occurrence of the disease [8]. To rule out the potential role of recall bias, variables significantly associated with the risk of Peyronie’s disease were further analyzed using two separate subgroups of controls (i.e., those affected by urologic or by digestive conditions). RESULTS Cases of Peyronie’s disease and controls were comparable as concerns age, education, and area of residence. More controls than cases had ever smoked (76% and 63%, respectively), but such a difference was not statistically significant (Table 1). The distribution of cases and controls according to history of selected diseases with corresponding ORs and 95% CI for Peyronie’s disease is shown in Table 2.
TABLE 1. Distribution of 134 cases of Peyronie’s disease and
134 controls,a according to selected characteristics (Rome, 1992–1994) Cases (n 5 134) No. (%) Age (years) #39 40–54 55–64 $65
14 35 49 36
Years of education #5 6–8 9–13 $14
21 38 58 9
Area of residence Rome Lazio region Other regions
87 (65) 18 (13) 29 (22)
(10) (26) (37) (27)
Controls (n 5 134) No. (%) 11 45 57 21
P values
(8) (34) (43) (16) 0.20 b
(17) (30) (46) (7)
27 41 47 19
(20) (31) (35) (14) 0.97 b
81 (60) 13 (10) 40 (30) 0.25 c
Smoking habit Never smoker Current smoker Ex-smoker
49 (37) 48 (36) 37 (28)
32 (24) 60 (45) 42 (31) 0.07 c
a
In some items, the sum does not add up to the total because of missing values. b 2 χ for trend test. c 2 χ test.
By univariate analysis, the strongest risk factor for Peyronie’s disease turned out to be a history of invasive procedures on the penis, reported by 13% of cases and 1% of controls (OR 5 19.3, 95% CI: 2.9–813). In addition, a significantly higher proportion of cases than controls reported history of genital and/or perineal injuries (OR 5 2.6), urethritis (OR 5 3.7), uricacidemia (OR 5 4.7), lipoma (OR 5 6.2), and dermoid (OR 5 5.3). Conversely, no associations with risk of Peyronie’s disease emerged for history of diabetes and arterial hypertension. Among cases, 20% were affected by Dupuytren’s contracture, while 4% reported a familial history for Peyronie’s disease: none of the controls reported such conditions (Table 2). Furthermore, a familial history of gout was more common among cases than among controls (OR 5 4.8). Both cases and controls were also interviewed on past diseases of the genital tract of the female partner. As shown in Table 2, inflammatory or fibromatous lesions, or surgical intervention in the genital tract of the partner were more frequently reported by the cases. Among the factors significantly associated with Peyronie’s disease in the univariate analysis, a subset of them was identified, by multiple logistic regression analysis, as the best minimum set of predictors of Peyronie’s disease risk. The corresponding adjusted ORs are listed in Table 2. Men who
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513
TABLE 2. Odds ratios (OR) and 95% confidence intervals (CI) for Peyronie’s disease (Rome, 1992–1994)
History of Urethritis No Yes Uricacidemia No Yes Diabetes No Yes High blood pressure No Yes Lipoma No Yes Dermoid No Yes Dupuytren’s contracture No Yes Familiarity for Peyronie’s disease No Yes History of Familiarity for gut No Yes Genital and/or perineal injuries No Yes Invasive procedures on the penis No Yes Inflammatory diseases of the genital tract of the partner No Yes Fibromautos lesions of the genital tract of the partner No Yes Surgical intervention on the genital tract of the partner No Yes a
Cases (n 5 134) No. (%)
Controls (n 5 134) No. (%)
Crude-OR (95% CI)
MLR-OR a (95% CI)
87 (65) 47 (35)
117 (87) 17 (13)
1 3.7 (1.9–7.3)
1 3.1 (1.4–6.7)
47 (35) 87 (65)
96 (72) 38 (28)
1 4.7 (2.7–8.1)
1 5.4 (2.9–10.3)
113 (84) 21 (16)
120 (90) 14 (10)
1 1.6 (0.9–2.8)
—
92 (69) 42 (31)
104 (78) 30 (22)
1 1.6 (0.9–2.8)
—
96 (72) 38 (28)
126 (94) 8 (6)
1 6.2 (2.7–15.2)
1 5.2 (2.0–13.3)
90 (70) 40 (30)
124 (93) 10 (7)
1 5.3 (2.4–11.9)
—
106 (79) 28 (21)
134 (100) 0 (0)
1 NC b (10.8–∞)b
—
128 (96) 6 (4)
134 (100) 0 (0)
1 NC c (1.6–∞)
—
113 (84) 21 (96)
129 (96) 5 (4)
1 4.8 (1.7–16.7)
—
111 (83) 23 (17)
123 (93) 10 (7)
1 2.6 (1.1–6.1)
1 2.7 (1.0–7.1)
117 (87) 17 (13)
133 (99) 1 (1)
1 19.3 (2.9–813)
1 16.1 (1.8–142)
97 (72) 37 (28)
125 (93) 9 (7)
1 5.3 (2.3–12.4)
1 3.7 (1.5–9.1)
103 (77) 31 (23)
125 (93) 9 (7)
1 4.1 (1.8–9.9)
1 2.5 (1.0–6.5)
86 (64) 48 (36)
121 (90) 13 (10)
1 5.2 (2.5–10.8)
—
Multiple logistic regression odds ratio (MLR-OR): only factors significantly associated with Peyronie’s disease at univariate analysis, and whose statistical significance persisted after allowance for their mutual confounding effect, were retained in the final model. b Fisher’s exact test: P 5 0.25. c Fisher’s exact test: P 5 0.03.
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TABLE 3. Odds ratios (OR) and 95% confidence intervals (CI) for Peyronie’s disease according to the type of controls (Rome, 1992–1994)
Controls affected by Urologic conditions
Digestive conditions
History of
OR
(95% CI)
OR
(95% CI)
Urethritis Uricacidemia Lipoma Genital and/or perineal injuries Invasive procedures on the penis Inflammatory diseases of the genital tract of partner Fibromautos lesions of the genital tract of the partner
5.2 3.8 3.8 3.1
(2.3–15.8) (1.9–7.5) (1.5–11.7) (1.0–12.9)
2.4 11.1 19.0 1.8
(1.0–5.8) (4.4–29.5) (3.0–786) (0.6–6.5)
9.2
(1.4–388)
NC a
(2.1–∞)
5.7
(1.9–23.0)
3.4
(1.2–11.6)
4.5
(1.5–18.4)
2.6
(0.9–9.3)
a
Odds ratio not calculable. Fisher’s exact test: P 5 0.007.
underwent invasive procedures on the penis still showed a high risk of Peyronie’s disease (OR 5 16.1, 95% CI: 1.8– 142), followed by history of uricacidemia (OR 5 5.4), lipoma (OR 5 5.2), and urethritis (OR 5 3.1). For diseases of partner’s genital tract, a significantly increased risk for Peyronie’s disease was still present among patients whose partners had inflammatory or fibromatous conditions (OR 5 3.7 and OR 5 2.5, respectively), but not among those whose partners underwent surgical interventions (Table 2). Overall, these associations did not change substantially when considering two subsets of controls affected either by urologic or digestive conditions. A decrease in the OR was noted as concerns history of invasive procedures on the penis, from 16.1 in the totality of controls to 9.2 among controls affected by urologic conditions (Table 3). However, since only one control reported a history of invasive procedures, the 95% CIs of the two OR estimates widely overlapped (1.8–142 and 1.4–388, respectively). DISCUSSION The present case-control study identified three main groups of potential risk factors for Peyronie’s disease; penile traumatisms, genetic and familial conditions, and history of diseases of the genital tract of the female partner. The role of trauma in the development of Peyronie’s disease was hypothesized for the first time by Peyronie himself in 1743 [2]. Since then, it has been supposed that rupture of small vessels may favor the deposition of fibrous plaques in the tunica albuginea, so that repeated minor trauma has been considered among the causes of this disorder [3]. Some studies have reported a relationship between Peyronie’s disease and trauma to the erect [9,10] or to the flaccid penis [10], and with the use of the vacuum erection device [11,12]. Others have reported the occurrence of Peyronie’s disease following radical pelvic surgery [13]. In the present investigation, a history of invasive proce-
dures on the penis was reported by 13% of cases and 1% of the controls. The proportion of cases exposed to trauma was in agreement with those reported in case series of Peyronie’s disease [3,4], and they were attributable to cystoscopy, urethral catheterization, and prostatectomy. Since only one control reported a history of invasive procedures on the penis (he underwent urethral catheterization) it was not possible to analyze separately the risks associated with each single invasive procedure. The 16-fold increased risk was independent from other risk factors, and, in agreement with Chilton [4], a higher prevalence of iatrogenic penile traumatisms was observed in men aged 40–54 years. To limit the possible role of recall bias, a further analysis was carried out, taking into consideration the subset of controls affected by other urologic conditions. Although to a lower extent, the risk of Peyronie’s disease was still significantly higher in cases who reported invasive procedures on the penis. In addition, a significantly increased risk for Peyronie’s disease was also noted among men who reported genital and/or perineal injuries, thus confirming the importance of traumatic events in the development of Peyronie’s disease. In 1943, Wesson [14] hypothesized that changes in the mucosal genital tract of female sexual partners approaching menopause made penetration more difficult, thus fostering injuries of the penis. The findings of the present case-control study appear to agree with such a hypothesis. The risk of Peyronie’s disease was higher in patients whose female partners had inflammatory or fibromatous lesions of the genital tract, and it was consistent across age groups. The evidence supporting the role of genetic and familial conditions in the etiology of Peyronie’s disease arose, in the present study, from the increased risk associated with Dupuytren’s contracture and familiarity for Peyronie’s disease. Although the small number of exposed cases and the lack of exposure among controls limit their generalizability, these results are consistent with previous studies. The association between Peyronie’s disease and Dupuytren’s contracture was
Risk Factors for Peyronie’s Disease
first noted in 1879 by Paget, and it seems that Dupuytren’s contracture may be inherited as dominant gene which manifests itself in middle age [15,16]. Moreover, the relationship between some histocompatibility antigens such as HLA-A1, B8, Cw7, DR3 and DQw2 [6] and HLA-B7 [17] and the occurrence of Peyronie’s disease strongly supports the hypothesis of a genetic predisposition to the disease. In addition to such main risk factors, history of urethritis, uricacidemia, and lipoma also appeared to enhance the risk of developing Peyronie’s disease. Whereas history of uricacidemia and lipoma may be assimilated to the genetic predisposition and were not previously reported, case series reports already mentioned the presence of urethritis among men with Peyronie’s disease, although its role is not clear [3,4]. For the correct interpretation of the study findings some drawbacks are worth noticing. First, detailed information was not collected for each of the investigated risk factors. Due to the lack of previous analytical studies reported in literature, etiologic hypotheses were based on clinical reports. Such a limitation applies in particular to the information regarding genital and/or perineal injuries and invasive procedure on the penis. Second, the effect of recall bias (i.e., the potential misclassification that can result if cases are more likely than controls to recall past medical events [18]) should be considered. Since, in the present study, OR estimates did not show wide variations among controls with urologic or digestive conditions, it is likely that recall bias has not substantially affected the results. Third, we are aware of the limitation of using hospital controls [19]. However, in the present study, cases and controls were drawn from the same catchment area, therefore we can assume that controls would have been diagnosed as cases at the hospital where the present study has been conducted had they developed Peyronie’s disease [19]. Two points should be kept in mind concerning the low prevalence of invasive procedures on the penis and familial predispositions. First, the quality of life of patients with Peyronie’s disease may be heavily affected by this condition, and the prevention of an albeit small fraction of the affected population is undoubtedly worthwhile. Secondly, familial predisposition is a wellknown risk factor for many diseases, although it not always accounts for a large attributable fraction (e.g., cancer). In conclusion, the findings of the study highlighted some potential risk factors that increase the risk of developing Peyronie’s disease. The genetic predisposition to the laying down of fibrous tissue may be enhanced by other factors, first of all trauma. Due to the potential positive role of preventive measures in controlling penile injuries, particularly the iatrogenic ones, the etiology of Peyronie’s disease de-
515
serves more epidemiological attention than it has received until now. References 1. Chesney J. Peyronie’s disease. Br J Urol 1975; 47: 209–218. 2. Peyronie F de la. Sur quelques obstacle qui s’opposent a` l’e´jaculation naturelle de la semence. Me´m Acad r Chir 1743; 425. 3. Hinman F. Etiology factors in Peyronie’s disease. Urol Int 1980; 35: 407–413. 4. Chilton CP, Castle WM, Westwood CA, Pryor JP. Factors associated in the etiology of Peyronie’s disease. Br J Urol 1982; 54: 748–750. 5. Llopis-Cartagena M, Allona-Almagro A, Navio-Nino S, Jimenez-Cidre M, Romero-Aguirre C. Aspects e´tiologiques et diagnostiques de la maladie de La Peyronie. A propos de 42 cas. J Urol 1989; 95: 221–224. 6. Rompel R, Weidner W, Mueller-Eckhardt G. HLA association of idiopathic Peyronie’s disease: An indication of autoimmune phenomena in etiopathogenesis? Tissue Antigens 1991; 38: 104–106. 7. Mantovani F, Meroni PL, Austoni E, Bellofronte C, Patelli E. La malattia di La Peyronie come collagenopatia autoimmune. Urologia 1983; 1: 174–178. 8. Breslow NE, Day NE. The analysis of case-control studies. In: Statistical Methods in Cancer Research, Vol. 1. IARC Sci Publ No. 32, Lyon: IARC; 1980. 9. Penson Df, Seftel AD, Krane RJ, Frohrib D, Goldstein I. The hemodynamic pathophysiology of impotence following blunt trauma to the erect penis. J Urol 1992; 148: 1171–1180. 10. Jarow JP, Lowe FC. Penile trauma: An etiologic factor in Peyronie’s disease and erectile dysfunction. J Urol 1997; 158: 1388–1390. 11. Kim JH, Carson CC, Development of Peyronie’s disease with the use of a vacuum constriction device. J Urol 1993; 149: 1314–1315. 12. Hakim LS, Munarriz RM, Kulaksizoglu H, Nehra A, Udelson D, Goldstein I. Vacuum erection associated impotence and Peyronie’s disease. J Urol 1996; 155: 534–535. 13. Grossfeld GD, Ginsburg DA, Boyd SD. Ventral penile curvature following pelvic surgery: A variant of urethral manipulation syndrome. Urology 1995; 46: 707–709. 14. Wesson MB. Peyronie’s disease (plastic induratio), cause and treatment. J Urol 1943; 49: 350. 15. Murphy LJT. History of Urology, Part II. Springfield, IL: Thomas; 1972: 486. 16. Ling RSM. The genetic factors in Dupuytren’s disease. J Bone Joint Sur Br 1963; 45: 709–718. 17. Willscher MK, Cwazka WF, Novicki DE. The association of histocompatibility antigens of the B7 cross-reacting group with Peyronie’s disease. J Urol 1979; 122: 34–35. 18. Schlesselman JJ, Stolley PD. Sources of bias. In: Schlesselman JJ, Ed. Case-Control Studies. Design, Conduct, Analysis. Oxford: Oxford University Press; 1981: 124–143. 19. Wacholder S, McLauglin JK, Silverman DT, Mandel JS. Selection of controls in case-control studies. I Principles. Am J Epidemiol 1992; 135: 1019–1028.
0895-4356/98/$19.00 PII S0895-4356(98)00015-8
A Case-Control Study on Risk Factors for Peyronie’s Disease Maria Patrizia Carrieri,1 Diego Serraino,2,* Fabio Palmiotto,3 Giuseppe Nucci,3 and Francesco Sasso3 1
Servizio Elaborazione Dati, Istituto Superiore di Sanita`, Roma, Italy, 2Servizio di Epidemiologia, Centro di Riferimento Oncologico, Aviano, Italy, 3 Policlinico Gemelli, Cattedra di Urologia, Universita` Cattolica, Roma, Italy
ABSTRACT. The aim of this study was to investigate the relationship between history of selected diseases, genital traumas, and Peyronie’s disease. A hospital-based case-control study was conducted at the Andrologic and Surgical Outpatient Units of the Policlinico Gemelli, Rome, where 134 men with Peyronie’s disease and 134 male controls were interviewed. The association between Peyronie’s disease and selected characteristics was estimated by means of odds ratios (OR) and 95% confidence intervals (CI). Patients who underwent invasive procedures on the penis (i.e., urethral catheterization, cystoscopy, and transurethral prostatectomy) had a 16fold increased risk for Peyronie’s disease (OR 5 16.1, 95% CI: 1.8–142), while a nearly three-fold increase was observed among patients who had genital and/or perineal traumatisms (95% CI: 1.0–7.1). A history of urethritis, uricacidemia, and lipoma was also significantly associated with an increased risk for Peyronie’s disease. Twentyone percent of the cases and none of the controls were affected by Dupuytren’s contracture, and 4% of cases and none of the controls reported familial history for Peyronie’s disease. The frequency of inflammatory or fibromatous lesions of the genital tract of the partner was significantly higher in men with Peyronie’s disease than among controls. These results were consistent when performing a stratified analysis according to the type of controls (i.e., controls affected by urologic or by digestive conditions) to rule out the potential effect of recall bias. The findings of the study lend support to clinical reports stressing the importance of genital traumatisms and genetic conditions in the development of Peyronie’s disease. j clin epidemiol 51;6:511–515, 1998. 1998 Elsevier Science Inc. KEY WORDS. Peyronie’s disease, penis, risk factors
INTRODUCTION Peyronie’s disease is a disorder of the penis characterized by the formation of irregular dense plaques of fibrous tissue, generally located in the tunica albuginea of the corpora cavernosa, which causes abnormal curvature of the penis. Most patients report painful intercourse, whereas in certain individuals such deformity may be severe enough to prevent vaginal penetration [1]. Although the disease was first described more than two centuries ago [2], its epidemiology remains largely obscure. Neither prevalence nor incidence data are available, and etiologic factors have never been investigated by formal analytical studies. An etiologic role in the occurrence of Peyronie’s disease was attributed, by few reports, to two main groups of risk factors (i.e., a propen-
*
Address for correspondence: Dr. Diego Serraino, Servizio di Epidemiologia, Centro di Riferimento Oncologico, via Pedemontana Occ, 12, 33081 Aviano (PN), Italy. Phone: 39434659231; fax: 39434659222. Accepted for publication on 30 January 1998.
sity to abnormal production of collagenous tissue and penile traumatisms) [1,3–7]. To clarify the etiology of Peyronie’s disease, the present study evaluated the relationship between history of selected diseases, genital traumatisms, and the occurrence of Peyronie’s disease. METHODS A hospital-based case-control study was conducted at the Andrologic and Surgical Outpatient Units of the Policlinico Gemelli, Universita` Cattolica, Rome. The study was based on 134 cases aged 25 to 76 years (median age: 60 years), consecutively diagnosed with Peyronie’s disease between February 1992 and October 1994, and 134 male controls, aged 19 to 71 years (median age: 58 years). At diagnosis, the fibrotic plaques were palpable among 87 of the 134 cases (65%), whereas in the remaining cases the plaques were not palpable, and thus diagnosed by means of ultrasound scan or nuclear magnetic resonance. All cases had
M. P. Carrieri et al.
512
penile deviation, varying from 30 to 90 degrees. The controls were admitted to the before mentioned units for a wide spectrum of diseases requiring minor surgical interventions: 62 (46%) for conditions related to the urogenital apparatus, 53 (40%) for digestive conditions, and 19 (14%) for various other conditions. Controls were interviewed within the same time period of cases, and consecutively enrolled into the study according to the age distribution of cases. A diagnosis of Peyronie’s disease among controls was excluded by clinical and anamnestic evaluation. After the informed consent was obtained, a standardized questionnaire, specifically designed for the present study, was administered by two of the authors (F.P. and G.N.) to both cases and controls. Information was elicited on sociodemographic characteristics (age, education, and residence), smoking habits, and on personal history, among others, of urologic and non-urologic conditions and familial history for Peyronie’s disease. Information was also collected regarding two main groups of traumatisms: genital and/or perineal injuries caused by recreational activities (e.g., football, tennis, skiing, biking, or climbing) and penile injuries caused by invasive, iatrogenic, procedures such as urethral catheterization, diagnostical or interventional cystoscopies, and transurethral prostatectomy. In addition, previous diseases of the genital tract of the female partner were also investigated. Histories of uricacidemia (i.e., $7 mg/dl, or documented history of specific pharmacological treatment with drugs like probenecid or sulfinpyrazone), diabetes, and high blood pressure were thoroughly ascertained by pooling information based on patient’s self-referral of disease, use of disease-specific drugs, and of laboratory tests. For both cases and controls, the diagnosis of all the investigated diseases referred to at least a 6-month period prior to the onset of the disease that led to enrollment. The associations between potential risk factors and Peyronie’s disease was statistically evaluated using odds ratios (OR) and their 95% confidence intervals (CI) [8]. Adjusted ORs were computed by a multiple logistic regression model, in order to select, among the characteristics associated with Peyronie’s disease at univariate analysis, a restricted set most likely to predict the occurrence of the disease [8]. To rule out the potential role of recall bias, variables significantly associated with the risk of Peyronie’s disease were further analyzed using two separate subgroups of controls (i.e., those affected by urologic or by digestive conditions). RESULTS Cases of Peyronie’s disease and controls were comparable as concerns age, education, and area of residence. More controls than cases had ever smoked (76% and 63%, respectively), but such a difference was not statistically significant (Table 1). The distribution of cases and controls according to history of selected diseases with corresponding ORs and 95% CI for Peyronie’s disease is shown in Table 2.
TABLE 1. Distribution of 134 cases of Peyronie’s disease and
134 controls,a according to selected characteristics (Rome, 1992–1994) Cases (n 5 134) No. (%) Age (years) #39 40–54 55–64 $65
14 35 49 36
Years of education #5 6–8 9–13 $14
21 38 58 9
Area of residence Rome Lazio region Other regions
87 (65) 18 (13) 29 (22)
(10) (26) (37) (27)
Controls (n 5 134) No. (%) 11 45 57 21
P values
(8) (34) (43) (16) 0.20 b
(17) (30) (46) (7)
27 41 47 19
(20) (31) (35) (14) 0.97 b
81 (60) 13 (10) 40 (30) 0.25 c
Smoking habit Never smoker Current smoker Ex-smoker
49 (37) 48 (36) 37 (28)
32 (24) 60 (45) 42 (31) 0.07 c
a
In some items, the sum does not add up to the total because of missing values. b 2 χ for trend test. c 2 χ test.
By univariate analysis, the strongest risk factor for Peyronie’s disease turned out to be a history of invasive procedures on the penis, reported by 13% of cases and 1% of controls (OR 5 19.3, 95% CI: 2.9–813). In addition, a significantly higher proportion of cases than controls reported history of genital and/or perineal injuries (OR 5 2.6), urethritis (OR 5 3.7), uricacidemia (OR 5 4.7), lipoma (OR 5 6.2), and dermoid (OR 5 5.3). Conversely, no associations with risk of Peyronie’s disease emerged for history of diabetes and arterial hypertension. Among cases, 20% were affected by Dupuytren’s contracture, while 4% reported a familial history for Peyronie’s disease: none of the controls reported such conditions (Table 2). Furthermore, a familial history of gout was more common among cases than among controls (OR 5 4.8). Both cases and controls were also interviewed on past diseases of the genital tract of the female partner. As shown in Table 2, inflammatory or fibromatous lesions, or surgical intervention in the genital tract of the partner were more frequently reported by the cases. Among the factors significantly associated with Peyronie’s disease in the univariate analysis, a subset of them was identified, by multiple logistic regression analysis, as the best minimum set of predictors of Peyronie’s disease risk. The corresponding adjusted ORs are listed in Table 2. Men who
Risk Factors for Peyronie’s Disease
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TABLE 2. Odds ratios (OR) and 95% confidence intervals (CI) for Peyronie’s disease (Rome, 1992–1994)
History of Urethritis No Yes Uricacidemia No Yes Diabetes No Yes High blood pressure No Yes Lipoma No Yes Dermoid No Yes Dupuytren’s contracture No Yes Familiarity for Peyronie’s disease No Yes History of Familiarity for gut No Yes Genital and/or perineal injuries No Yes Invasive procedures on the penis No Yes Inflammatory diseases of the genital tract of the partner No Yes Fibromautos lesions of the genital tract of the partner No Yes Surgical intervention on the genital tract of the partner No Yes a
Cases (n 5 134) No. (%)
Controls (n 5 134) No. (%)
Crude-OR (95% CI)
MLR-OR a (95% CI)
87 (65) 47 (35)
117 (87) 17 (13)
1 3.7 (1.9–7.3)
1 3.1 (1.4–6.7)
47 (35) 87 (65)
96 (72) 38 (28)
1 4.7 (2.7–8.1)
1 5.4 (2.9–10.3)
113 (84) 21 (16)
120 (90) 14 (10)
1 1.6 (0.9–2.8)
—
92 (69) 42 (31)
104 (78) 30 (22)
1 1.6 (0.9–2.8)
—
96 (72) 38 (28)
126 (94) 8 (6)
1 6.2 (2.7–15.2)
1 5.2 (2.0–13.3)
90 (70) 40 (30)
124 (93) 10 (7)
1 5.3 (2.4–11.9)
—
106 (79) 28 (21)
134 (100) 0 (0)
1 NC b (10.8–∞)b
—
128 (96) 6 (4)
134 (100) 0 (0)
1 NC c (1.6–∞)
—
113 (84) 21 (96)
129 (96) 5 (4)
1 4.8 (1.7–16.7)
—
111 (83) 23 (17)
123 (93) 10 (7)
1 2.6 (1.1–6.1)
1 2.7 (1.0–7.1)
117 (87) 17 (13)
133 (99) 1 (1)
1 19.3 (2.9–813)
1 16.1 (1.8–142)
97 (72) 37 (28)
125 (93) 9 (7)
1 5.3 (2.3–12.4)
1 3.7 (1.5–9.1)
103 (77) 31 (23)
125 (93) 9 (7)
1 4.1 (1.8–9.9)
1 2.5 (1.0–6.5)
86 (64) 48 (36)
121 (90) 13 (10)
1 5.2 (2.5–10.8)
—
Multiple logistic regression odds ratio (MLR-OR): only factors significantly associated with Peyronie’s disease at univariate analysis, and whose statistical significance persisted after allowance for their mutual confounding effect, were retained in the final model. b Fisher’s exact test: P 5 0.25. c Fisher’s exact test: P 5 0.03.
M. P. Carrieri et al.
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TABLE 3. Odds ratios (OR) and 95% confidence intervals (CI) for Peyronie’s disease according to the type of controls (Rome, 1992–1994)
Controls affected by Urologic conditions
Digestive conditions
History of
OR
(95% CI)
OR
(95% CI)
Urethritis Uricacidemia Lipoma Genital and/or perineal injuries Invasive procedures on the penis Inflammatory diseases of the genital tract of partner Fibromautos lesions of the genital tract of the partner
5.2 3.8 3.8 3.1
(2.3–15.8) (1.9–7.5) (1.5–11.7) (1.0–12.9)
2.4 11.1 19.0 1.8
(1.0–5.8) (4.4–29.5) (3.0–786) (0.6–6.5)
9.2
(1.4–388)
NC a
(2.1–∞)
5.7
(1.9–23.0)
3.4
(1.2–11.6)
4.5
(1.5–18.4)
2.6
(0.9–9.3)
a
Odds ratio not calculable. Fisher’s exact test: P 5 0.007.
underwent invasive procedures on the penis still showed a high risk of Peyronie’s disease (OR 5 16.1, 95% CI: 1.8– 142), followed by history of uricacidemia (OR 5 5.4), lipoma (OR 5 5.2), and urethritis (OR 5 3.1). For diseases of partner’s genital tract, a significantly increased risk for Peyronie’s disease was still present among patients whose partners had inflammatory or fibromatous conditions (OR 5 3.7 and OR 5 2.5, respectively), but not among those whose partners underwent surgical interventions (Table 2). Overall, these associations did not change substantially when considering two subsets of controls affected either by urologic or digestive conditions. A decrease in the OR was noted as concerns history of invasive procedures on the penis, from 16.1 in the totality of controls to 9.2 among controls affected by urologic conditions (Table 3). However, since only one control reported a history of invasive procedures, the 95% CIs of the two OR estimates widely overlapped (1.8–142 and 1.4–388, respectively). DISCUSSION The present case-control study identified three main groups of potential risk factors for Peyronie’s disease; penile traumatisms, genetic and familial conditions, and history of diseases of the genital tract of the female partner. The role of trauma in the development of Peyronie’s disease was hypothesized for the first time by Peyronie himself in 1743 [2]. Since then, it has been supposed that rupture of small vessels may favor the deposition of fibrous plaques in the tunica albuginea, so that repeated minor trauma has been considered among the causes of this disorder [3]. Some studies have reported a relationship between Peyronie’s disease and trauma to the erect [9,10] or to the flaccid penis [10], and with the use of the vacuum erection device [11,12]. Others have reported the occurrence of Peyronie’s disease following radical pelvic surgery [13]. In the present investigation, a history of invasive proce-
dures on the penis was reported by 13% of cases and 1% of the controls. The proportion of cases exposed to trauma was in agreement with those reported in case series of Peyronie’s disease [3,4], and they were attributable to cystoscopy, urethral catheterization, and prostatectomy. Since only one control reported a history of invasive procedures on the penis (he underwent urethral catheterization) it was not possible to analyze separately the risks associated with each single invasive procedure. The 16-fold increased risk was independent from other risk factors, and, in agreement with Chilton [4], a higher prevalence of iatrogenic penile traumatisms was observed in men aged 40–54 years. To limit the possible role of recall bias, a further analysis was carried out, taking into consideration the subset of controls affected by other urologic conditions. Although to a lower extent, the risk of Peyronie’s disease was still significantly higher in cases who reported invasive procedures on the penis. In addition, a significantly increased risk for Peyronie’s disease was also noted among men who reported genital and/or perineal injuries, thus confirming the importance of traumatic events in the development of Peyronie’s disease. In 1943, Wesson [14] hypothesized that changes in the mucosal genital tract of female sexual partners approaching menopause made penetration more difficult, thus fostering injuries of the penis. The findings of the present case-control study appear to agree with such a hypothesis. The risk of Peyronie’s disease was higher in patients whose female partners had inflammatory or fibromatous lesions of the genital tract, and it was consistent across age groups. The evidence supporting the role of genetic and familial conditions in the etiology of Peyronie’s disease arose, in the present study, from the increased risk associated with Dupuytren’s contracture and familiarity for Peyronie’s disease. Although the small number of exposed cases and the lack of exposure among controls limit their generalizability, these results are consistent with previous studies. The association between Peyronie’s disease and Dupuytren’s contracture was
Risk Factors for Peyronie’s Disease
first noted in 1879 by Paget, and it seems that Dupuytren’s contracture may be inherited as dominant gene which manifests itself in middle age [15,16]. Moreover, the relationship between some histocompatibility antigens such as HLA-A1, B8, Cw7, DR3 and DQw2 [6] and HLA-B7 [17] and the occurrence of Peyronie’s disease strongly supports the hypothesis of a genetic predisposition to the disease. In addition to such main risk factors, history of urethritis, uricacidemia, and lipoma also appeared to enhance the risk of developing Peyronie’s disease. Whereas history of uricacidemia and lipoma may be assimilated to the genetic predisposition and were not previously reported, case series reports already mentioned the presence of urethritis among men with Peyronie’s disease, although its role is not clear [3,4]. For the correct interpretation of the study findings some drawbacks are worth noticing. First, detailed information was not collected for each of the investigated risk factors. Due to the lack of previous analytical studies reported in literature, etiologic hypotheses were based on clinical reports. Such a limitation applies in particular to the information regarding genital and/or perineal injuries and invasive procedure on the penis. Second, the effect of recall bias (i.e., the potential misclassification that can result if cases are more likely than controls to recall past medical events [18]) should be considered. Since, in the present study, OR estimates did not show wide variations among controls with urologic or digestive conditions, it is likely that recall bias has not substantially affected the results. Third, we are aware of the limitation of using hospital controls [19]. However, in the present study, cases and controls were drawn from the same catchment area, therefore we can assume that controls would have been diagnosed as cases at the hospital where the present study has been conducted had they developed Peyronie’s disease [19]. Two points should be kept in mind concerning the low prevalence of invasive procedures on the penis and familial predispositions. First, the quality of life of patients with Peyronie’s disease may be heavily affected by this condition, and the prevention of an albeit small fraction of the affected population is undoubtedly worthwhile. Secondly, familial predisposition is a wellknown risk factor for many diseases, although it not always accounts for a large attributable fraction (e.g., cancer). In conclusion, the findings of the study highlighted some potential risk factors that increase the risk of developing Peyronie’s disease. The genetic predisposition to the laying down of fibrous tissue may be enhanced by other factors, first of all trauma. Due to the potential positive role of preventive measures in controlling penile injuries, particularly the iatrogenic ones, the etiology of Peyronie’s disease de-
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serves more epidemiological attention than it has received until now. References 1. Chesney J. Peyronie’s disease. Br J Urol 1975; 47: 209–218. 2. Peyronie F de la. Sur quelques obstacle qui s’opposent a` l’e´jaculation naturelle de la semence. Me´m Acad r Chir 1743; 425. 3. Hinman F. Etiology factors in Peyronie’s disease. Urol Int 1980; 35: 407–413. 4. Chilton CP, Castle WM, Westwood CA, Pryor JP. Factors associated in the etiology of Peyronie’s disease. Br J Urol 1982; 54: 748–750. 5. Llopis-Cartagena M, Allona-Almagro A, Navio-Nino S, Jimenez-Cidre M, Romero-Aguirre C. Aspects e´tiologiques et diagnostiques de la maladie de La Peyronie. A propos de 42 cas. J Urol 1989; 95: 221–224. 6. Rompel R, Weidner W, Mueller-Eckhardt G. HLA association of idiopathic Peyronie’s disease: An indication of autoimmune phenomena in etiopathogenesis? Tissue Antigens 1991; 38: 104–106. 7. Mantovani F, Meroni PL, Austoni E, Bellofronte C, Patelli E. La malattia di La Peyronie come collagenopatia autoimmune. Urologia 1983; 1: 174–178. 8. Breslow NE, Day NE. The analysis of case-control studies. In: Statistical Methods in Cancer Research, Vol. 1. IARC Sci Publ No. 32, Lyon: IARC; 1980. 9. Penson Df, Seftel AD, Krane RJ, Frohrib D, Goldstein I. The hemodynamic pathophysiology of impotence following blunt trauma to the erect penis. J Urol 1992; 148: 1171–1180. 10. Jarow JP, Lowe FC. Penile trauma: An etiologic factor in Peyronie’s disease and erectile dysfunction. J Urol 1997; 158: 1388–1390. 11. Kim JH, Carson CC, Development of Peyronie’s disease with the use of a vacuum constriction device. J Urol 1993; 149: 1314–1315. 12. Hakim LS, Munarriz RM, Kulaksizoglu H, Nehra A, Udelson D, Goldstein I. Vacuum erection associated impotence and Peyronie’s disease. J Urol 1996; 155: 534–535. 13. Grossfeld GD, Ginsburg DA, Boyd SD. Ventral penile curvature following pelvic surgery: A variant of urethral manipulation syndrome. Urology 1995; 46: 707–709. 14. Wesson MB. Peyronie’s disease (plastic induratio), cause and treatment. J Urol 1943; 49: 350. 15. Murphy LJT. History of Urology, Part II. Springfield, IL: Thomas; 1972: 486. 16. Ling RSM. The genetic factors in Dupuytren’s disease. J Bone Joint Sur Br 1963; 45: 709–718. 17. Willscher MK, Cwazka WF, Novicki DE. The association of histocompatibility antigens of the B7 cross-reacting group with Peyronie’s disease. J Urol 1979; 122: 34–35. 18. Schlesselman JJ, Stolley PD. Sources of bias. In: Schlesselman JJ, Ed. Case-Control Studies. Design, Conduct, Analysis. Oxford: Oxford University Press; 1981: 124–143. 19. Wacholder S, McLauglin JK, Silverman DT, Mandel JS. Selection of controls in case-control studies. I Principles. Am J Epidemiol 1992; 135: 1019–1028.