Factors Affecting the Degree of Penile Deformity ... - Wiley Online Library

Journal of Andrology, Vol. 32, No. 5, September/October 2011 Copyright E American Society of Andrology

Factors Affecting the Degree of Penile Deformity in Peyronie Disease: An Analysis of 1001 Patients ATES KADIOGLU,* ONER SANLI,* TOLGA AKMAN,{ ONDER CANGUVEN,{ MEMDUH AYDIN,§ FATIH AKBULUT,* AND FARUK KUCUKDURMAZ* From the *Department of Urology, Medical Faculty of Istanbul, Istanbul University, Istanbul, Turkey; the Department of Urology, Haseki Teaching and Research Hospital, Istanbul, Turkey; the `Urology II Clinics, Kartal Training and Research Hospital, Istanbul, Turkey; and the §Department of Urology, Taksim Teaching and Research Hospital, Istanbul, Turkey.

ABSTRACT: Only a few studies have investigated the association between the severity of Peyronie disease (PD) and clinical parameters such as age and associated comorbidities. The aim of this study was to report the relationship between the degree of curvature of the penis and the clinical parameters among patients with PD. A total of 1001 patients with PD were evaluated retrospectively in terms of penile deformity, erectile status, and risk factors for systemic vascular diseases. The degree of curvature was assessed with a protractor during maximum erection in response to a combined injection and stimulation test and/or vacuum device. A modified Kelami classification was used to categorize penile deformities as follows: patients with deformities without curvature (notching, hourglass, and swan neck deformity, group 1), with mild curvature (#30 degrees, group 2), with moderate curvature (31–60

degrees, group 3), or with severe curvature (.60 degrees, group 4). Chi-square tests, 1-way analysis of variance, and univariate and multiple ordinal regression analyses were used for statistical analysis. Penile deformity without curvature was detected in 12.3% of the patients, whereas the curvature was less than 30 degrees in 39.5%, 30 to 60 degrees in 34.5%, and more than 60 degrees in 13.5% of the patients. Multiple ordinal regression analysis identified age (P 5 .013), side of deformity (P 5 .007), erectile dysfunction (P , .0001), and diabetes mellitus (P 5 .001) as significant independent predictors of the severity of penile curvature. In conclusion, patients’ age, side of deformity, erectile function, and diabetes were significantly associated with the degree of curvature. Key words: Erectile dysfunction, risk factors, curvature. J Androl 2011;32:502–508

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and ischemic heart disease, have been hypothesized to play a role in the pathogenesis of PD (Pryor et al, 2004). Thus, the aim of this study was to evaluate the relationship between the degree of penis curvature and the clinical features of PD and to determine the predictive factors of the type of deformity using data from 1001 patients with PD, which is the largest sample of patients with PD evaluated in a study, to our knowledge.

eyronie disease (PD) is an acquired benign pathologic condition characterized by exaggerated inflammation and changes in the collagen composition, leading to fibrosis within the tunica albuginea (TA) of the corpora cavernosum of the penis. PD occurs in 3.7% to 7.1% of men. It is clinically characterized by varying degrees of penile deformity, pain on erection, penile nodule, difficulty in vaginal penetration, and erectile dysfunction (ED) (La Pera et al, 2001; Schwarzer et al, 2001). Although the exact pathogenesis is not understood, the most widely accepted theory is that PD is a wound-healing disorder, initiated by repetitive microtraumas to the penis, with subsequent scar formation. Moreover, systemic vascular risk factors, such as diabetes mellitus (DM), hyperlipidemia, hypertension,

Materials and Methods During an 18-year period, 1001 consecutive patients with PD were presented for evaluation at our institution. At the initial visit, all patients completed a specific questionnaire for PD that asked for information on the duration of the disease, presenting symptoms, and comorbidities such as DM, hypercholesterolemia, hypertriglyceridemia, hypertension, and ischemic heart disease. In addition, a comprehensive medical history and sexual history as well as serial serum analyses for glucose, creatinine, total cholesterol, and triglycerides were obtained for the identified comorbid conditions. All patients signed an informed consent before recruitment to the study.

Correspondence to: Dr Ates Kadioglu, Department of Urology, Section of Andrology, Istanbul Faculty of Medicine, Istanbul University, 34390 Capa, Istanbul, Turkey (e-mail: kadiogluates@ ttmail.com). Received for publication June 17, 2010; accepted for publication January 7, 2011. Presented at the American Urological Association Annual Meeting; May 17–22, 2008; Orlando, Florida. DOI: 10.2164/jandrol.110.011031

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Predictive Factors of Penile Curvature Severity in PD

The acute phase of PD is recognized by pain on erection and/or pain that lasted less than 12 months. It is then followed by the chronic or stable phase, which is characterized by minimal pain and stable penile deformity. The erectile status of patients was investigated using questionnaires and a combined injection and stimulation (CIS) test. Between 1992 and 2001, a questionnaire addressing sexual issues such as the effect of PD on ED and pain on erection was used. Since 2001, the International Index of Erectile Function (IIEF) questionnaire has been used to evaluate erectile function. A total of 402 patients were evaluated with the IIEF questionnaire. The sum of the scores relating to questions 1 to 5 and 15 of the IIEF domain was calculated, with a maximum score of 30. Patients who had a total erectile score of less than 26 were identified as having ED. All patients were given an intracavernous injection of a vasoactive agent (papaverine 30–60 mg), which was combined with manual genital self-stimulation and audio-visual assistance for the assessment of the location and degree of the curvature and tumescence. Repeated dosing was used as necessary to achieve optimal erectile response. Additionally, a vacuum erection device (VED) was used to achieve full erection in patients with a negative CIS test to determine the exact angle of the curvature after the constrictor ring was placed over the VED to the base of the penis. The criteria for positive and negative erectile response to the CIS test have been described elsewhere (Akkus et al, 1994). The degree of the curvature was measured with a protractor during maximum erection in response to the CIS test and/or use of the VED, when the patients described that the erection they achieved was similar to what they had accomplished at home. All deformities were also documented by photographs or drawings by a single author (A.K.). A modified Kelami classification was used to categorize the penile deformities as follows: group 1: patients with deformities without any curvature (notching, hourglass, and swan neck deformities); group 2: mild curvature (deformity angle #30 degrees); group 3: moderate curvature (deformity angle 31–60 degrees); or group 4: severe curvature (.60 degrees). In addition, a penile color Doppler ultrasound (ATL Ultramark 9/7.5 MHz probe; Philips, Best, The Netherlands) was performed in 224 patients. Peak systolic blood flow velocity values of $35 cm/s were considered normal for the penile arterial system. End-diastolic values of .5 cm/s and resistive index of ,0.9 were considered diagnostic for cavernosal disease.

Statistical Analysis With the NCSS 2000 statistical package (NCSS Inc, Kaysville, Utah), it was determined that the present study had a statistical power of 100% to detect an effect size (w) of 0.20 using 2 degrees of freedom (a 5 .05). All other data were analyzed using SPSS version 11.5 (SPSS Inc, Chicago, Illinois). The clinical parameters of patients in the 4 groups were compared with each other using x2, KruskalWallis, or 1-way analysis of variance tests. When significant differences were observed, analysis of variance results were confirmed using posthoc Tukey tests. Multivariate ordinal

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logistic regression analysis was performed for the effect of independent variables on the degree of deformity (categorized as 4 groups according to Kelami classification). In addition, the other variables were entered as continuous variables except for age, response to CIS test, and side of deformity, which were categorized as present or absent. Age, response to CIS test, and side of deformity were categorized as follows: #54 years vs .54 years (based on median age), negative vs positive, and lateral vs other types of deformities, respectively. In all analyses, 2-sided hypothesis testing was carried out. P , .05 was deemed significant.

Results Overall, the mean age of the patients and duration of the disease were 53.3 6 10.6 years (range, 21–79 years) and 20.0 6 30.1 months (range, 1–144 months), respectively. Of these patients, 58.8% (589) were in the acute phase and 41.2% (412) were in the chronic phase. By Kelami classification, the number of patients in each group was as follows: group 1: 124 (12.3%) patients; group 2: 396 (39.5%) patients; group 3: 346 (34.5%) patients; and group 4: 135 (13.5%) patients. The most frequently noted penile abnormality was the dorsal curvature observed in 29.9% of patients (Figure). According to the potency data from the patient history and IIEF, 582 men (58.1%) reported ED. The frequency of ED evaluated with the IIEF (n 5 402) was 60.1% (n 5 242), whereas this frequency was 67.3% (37 of 55), 66.2% (110 of 166), 56.7% (76 of 134), and 40.4% (19 of 47) for groups 1, 2, 3, and 4, respectively (P 5 .009). According to the outcomes of the penile color Doppler ultrasound, penile vascular disease was diagnosed in 76.8% of the patients. Among these patients, mixed vascular disease was detected in 41.1%, cavernosal disease in 23.2%, and arterial disease in 12.5% of the patients. In subgroup analyses, the mean age of the patients and the mean duration of the disease were 52.0 6 10.5 years (range, 26–77 years) and 21.7 6 41.9 months (range, 1–240 months), respectively, in group 1; 52.8 6 11.4 years (range, 21–79 years) and 18.6 6 26.3 months (range, 1–150 months), respectively, in group 2; 53.1 6 9.3 years (range, 24–76 years) and 22.3 6 33.2 months (range, 2–240 months), respectively, for group 3; and 56.2 6 10.9 years (range, 23–76 years) and 16.7 6 18.2 months (range, 1–20 months), respectively, for group 4. Of note, the mean age of the patients in group 4 was significantly higher compared with that in the other groups (P 5 .004). However, the difference in terms of the mean duration of the disease was not statistically different across the groups (P 5 .19). Table 1 presents the clinical parameters for each group. Deformity of the penis was the most common

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Figure. Side of the deformity. Color figure available online at www.andrologyjournal.org.

complaint in group 4 (89.6%), whereas smaller percentages were detected in groups 1 (52.4%), 2 (67.5%), and 3 (85.8%) (P , .0001). Furthermore, ED by history was more frequent in groups 1 and 2 compared with groups 3 and 4 (P 5 .0001). However, this frequency did not differ significantly between groups 3 and 4. A negative response to the CIS test was more frequent in group 1 (46.7%) relative to other groups (group 2, 33.4%; group 3, 32.7%; and group 4, 30.4%) (P 5 .026). In addition,

there was no difference in the sensation of pain upon erection across the groups. Penile curvature was not the presenting symptom in 14 of the 135 patients in group 4. These 14 patients had severe ED and negative responses to the CIS test. Specifically, 9 patients had DM, 1 patient had ischemic heart disease, 2 patients had a history of radical prostatectomy, and the remaining 2 patients were found to have no health problems that led to ED.

Table 1. Comparison of clinical parameters for each group Parameter Age, y Duration of disease, mo

Group 1 52.0 6 10.5 21.7 6 41.9 (range, 1–240; median, 8)




P .004a .19b

Symptoms, n (%) Erectile dysfunction Penile curvature Pain on erection

65.8 (81) 52.4 (65) 22.6 (28)

67.3 (267) 67.5 (268) 13.6 (54)

50.9 (176) 85.8 (297) 12.1 (42)

43 (58) 89.6 (121) 13.3 (18)

,.0001c ,.0001c .2c

53.2 (66) 46.7 (58)

66.6 (264) 33.4 (132)

67.3 (233) 32.7 (113)

69.6 (94) 30.4 (41)

.026c

45.4 29.5 7.3 13.6 4.3

37.5 27.5 16.2 13.6 5.2

20.8 37.0 14.8 20.7 6.7

CIS test, n (%) (+) (2) Side of the deformity, n (%) Lateral Dorsal Dorsolateral Ventral Ventrolateral

... ... ... ... ...

Abbreviation: CIS, combined injection and stimulation. a

One-way analysis of variance. Kruskal-Wallis test. c Chi-square test. b

(180) (117) (29) (54) (17)

(130) (95) (56) (47) (18)

(28) (50) (20) (28) (9)

, .0001c .11c .00c .09c .53c

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Table 2. Systemic vascular risk factors for each group Risk Factor Diabetes mellitus Hypertension Hypercholesterolemia Ischemic heart disease Hypertriglyceridemia a

Group 1, n (%) 28 28 19 13 8

Group 2, n (%)

(22.6) (22.6) (15.3) (10.5) (6.5)

89 71 99 35 50

(22.4) (17.9) (24.9) (8.8) (12.6)

Group 3, n (%) 106 62 88 21 49

(30.6) (17.9) (25.4) (6.1) (14.2)

Pa

Group 4, n (%) 38 18 34 16 14

(28.1) (13.3) (25.2) (11.9) (10.4)

.056 .3 .12 .15 .13

Chi-square test.

The frequency of lateral curvature was significantly lower in patients in group 4 compared with that of patients in groups 2 and 3 (P , .0001). In addition, dorsal and ventral curvatures were found to be more frequent in patients in group 4, although this difference was not significant. In the study cohort, the most commonly associated comorbidities were DM (n 5 261 [26%]), hypercholesterolemia (n 5 240 [24%]), hypertension (n 5 179 [17.9%]), hyperlipidemia (n 5 121 [12.1%]), and ischemic heart disease (n 5 85 [8.5%]). Of the patients with PD, 53.7% had at least 1 of these comorbidities. The relationship between comorbidities of the patients and the degree of penile curvature in each group is shown in Table 2. The most commonly associated comorbidities were DM (22.6%) and hypertension (22.6%) in group 1; in groups 2, 3, and 4, the most common were DM and hypercholesterolemia, and the frequencies of DM (22.4%, 30.6%, and 28.1%, respectively) and hypercholesterolemia (24.9%, 25.4%, and 25.2%, respectively) were similar across the groups. Statistical analyses did not reveal any correlations between individual non–DM comorbidities across the groups (P . .05). In addition, DM was more frequent in groups 3 and 4 compared with groups 1 and 2, although the differences were not statistically significant (P 5 .056). The present study showed that systemic vascular risk factors were more commonly observed in patients with PD and ED in comparison with patients with PD and no ED. The frequencies of DM, hypertension, and hypertriglyceridemia were significantly higher in patients with PD and ED (Table 3). Based on the multiple ordinal regression analyses, the factors affecting the degree of deformity were patient’s

age (P 5 .013), side of deformity (P 5 .007), ED by history (P , .0001), and DM (P 5 .001). However, multivariate regression models did not demonstrate any significant predictive factors that affected the duration of disease, pain on erection, response to CIS test, and systemic non-DM vascular risk factors (Table 4).

Discussion PD is generally found in men in their fifth decade of life, and correlations have been detected between PD and age in previous studies (Lindsay et al, 2001; Rhoden et al, 2001). However, a wide age range (19–80 years) among patients with PD has been reported, and nearly one-tenth of men with PD are younger than 40 years (Deveci et al, 2007). Recently, Deveci et al (2007) evaluated the relationship with age among a total of 296 consecutive patients with PD. Although a statistically significant difference was not observed, 24% of the patients older than 40 years had more than 60 degrees of penile curvature, whereas this rate was 17% in those under 40 years. In another study, Levine et al (2003) investigated the characteristic features of young men with PD and reported that only 7% of the patients had severe deformities. Similarly, the present study provided strong evidence that aging was a positive predictive factor on the severity of the penile deformity. This outcome may be attributed to the increased vulnerability of the TA owing to its decreased rigidity and elasticity as well as physiologic problems in the wound-healing process with aging. Similar to the results from other series reports (Kadioglu et al, 2002; Levine et al, 2003; Kendirci et

Table 3. Disruption of the comorbidities in patients with PD according to erectile status Comorbidity Diabetes mellitus Hypertension Ischemic heart disease Hypercholesterolemia Hypertriglyceridemia

PD Without ED, n (%) 65 59 32 95 38

(15.5) (14.1) (7.7) (22.7) (9.1)

Abbreviations: ED, erectile dysfunction; PD, Peyronie disease. a

Chi-square test.

PD With ED, n (%) 196 120 53 145 83

(33.7) (20.7) (9.1) (25.0) (14.3)

Pa ,.0001 .008 .41 .42 .01

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Table 4. Multivariate ordinal logistic regression analysis to predict the severity of penile deformity Estimate

SE

Wald

Significance

20.28 0.001 20.84 0.03 20.41 20.55 20.24 20.21 0.09 0.17

0.14 0.00 0.13 0.14 0.15 0.16 0.16 0.22 0.15 0.20

3.9 0.44 36.69 0.06 7.2 11.90 2.18 0.94 0.42 0.77

.013 .506 ,.0001 .797 .007 .001 .139 .330 .516 .378

Age (,54 y vs $54 y) Duration of disease (#12 y vs .12 y) Erectile dysfunction (present vs absent) CIS test (positive vs negative) Side of deformity (lateral vs other type of deformity) Diabetes mellitus (present vs absent) Hypertension (present vs absent) Ischemic heart disease (present vs absent) Hypercholesterolemia (present vs absent) Hypertriglyceridemia (present vs absent) Abbreviation: CIS, combined injection and stimulation.

al, 2005), the most common type of penile deformities were dorsal and lateral curvatures in the present study. However, we observed that patients with lateral curvature had milder deformities, whereas patients with dorsal curvature generally presented with more severe curvature. The cause of these changes may be due to the anatomic properties of the TA. The TA is thicker on the dorsal aspect because of the increased numbers of collagen bundles, whereas it is thinner at the 3 and 9 o’clock positions (Brock et al, 1997). In addition, the outer layer of the TA, which is a ligament-like structure, exists at the 4 to 5, 7 to 8, and 11 to 1 o’clock positions. A more exaggerated wound-healing process may occur in the thickest side (at the 11 to 1 o’clock position) than in the thinner sides (at the 3, 6, and 9 o’clock positions). Because the TA is not an avascular structure, the entrapment of inflammatory cells and deposition of the extracellular matrix may be more prominent at the dorsal side. Removal of fibrosis-stimulating products such as transforming growth factor b1 (TGF-b1) may not be sufficiently effective because of the abnormal tunical thickness leading to severe curvature (El-Sakka et al, 1997, 1998; Moreland and Nehra, 2002). However, experimental studies are needed to test this theory. Left-sided curvatures were 3-fold higher in frequency than the right-sided curvatures in the present study. Similarly, Usta et al (2004) reported that left-sided lateral curvatures were more frequent than right-sided curvatures. This frequently may be associated with 2 factors: 1) the vasoactive injection could be delivered uniformly to 1 side and 2) although the supportive data are lacking, the influence of masturbatory behaviors such as the patient’s handedness may affect the side of deformity. The impact of these factors on the side of the penile curvature remains to be determined in future studies. As a presenting symptom of PD, ED has been reported to occur in 4% to 80% of the patients in different series studies, and ED is significantly higher in patients with PD compared with patients without PD (Kadioglu et al, 2006). Despite the higher frequency of ED in PD, its

pathophysiology has not yet been elucidated (Weidner et al, 1997; Bella et al, 2007). The pathophysiology might be due to the deformity preventing penetrative intercourse, the effect of plaque formation and fibrotic tissue reactions on both the cavernosal blood in-flow and the TA (causing corporal veno-occlusive dysfunction), or performance anxiety (El-Sakka et al, 1997). Another proposed mechanism is the negative effects of coexisting vascular risk factors, such as DM on erectile function. The present report revealed that ED by history was a negative predictive factor for the severity of the curvature. This outcome may be attributed to the patients with ED having less frequent sexual intercourse owing to the limited rigidity of the penis, which lessens the cumulative effect of the repetitive trauma. In contrast to the results of the present study, Deveci et al (2006) reported that between patients with PD with and without ED, the differences in the frequency of patients with curvature and the degree of the curvature were not statistically significant. It is difficult to interpret this discrepancy between the 2 studies, but it may be associated with the positional type and frequency of sexual intercourse between the study populations. Furthermore, in the present study, the prevalence of ED was higher in group 1 and group 2 compared with that in group 4 (Table 1). For group 1, the prevalence may be explained by the greater plaque volume and consequent compression of the arterial system, especially for the hourglass or notching deformities. In support of this explanation, Kendirci et al (2005) reported that in patients with the hourglass deformity, arterial blood flow was reported to be the poorest in both cavernous arteries compared with that in other deformity groups. However, for milder deformities such as those in group 2, it is likely that the frequency of sexual intercourse is lower because of concomitant ED, and this probably does not lead to repetitive minor trauma that can cause more severe curvature. There are a limited number of published reports regarding the relationship between systemic vascular risk factors and the severity of PD. In one of these

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reports, Usta et al (2004) noted that the majority (68%) of the patients with PD had at least 1 of these comorbidities and that hypertension (27.2%) and smoking (25.5%) were the most frequently documented comorbid conditions. In the present study, at least 1 risk factor for systemic vascular disease was noted in 53.7% of the patients, and the 2 most commonly encountered risk factors were DM (26%) and hypercholesterolemia (25.8%). However, in contrast to the study by Usta et al (2004), we found a significant relationship between DM and the severity of the penile deformity. In the present study, the mean degree of penile curvature was significantly higher (45.2 vs 30.2 degrees), and severe degrees of penile curvature were encountered more frequently (27.1% vs 5.5%) in patients with PD and DM rather than those without risk factors. Similarly, Kendirci et al (2007) reported that patients with DM and PD had more severe mean degrees of curvature than men without any risk factors (45.1 vs 30.2 degrees). However, the authors noted that penile curvatures of more than 60 degrees were more prevalent in the former group. The effect of DM on the severity of penile deformity may be attributed to systemic changes in the extracellular matrix metabolism and increased TGF-b production in patients with DM and PD, which exacerbate fibrotic changes in the penis (Tefekli et al, 2006). Moreover, in a PD-like model, an increase in the level of inducible nitric oxide synthase (iNOS) after TGF-b1 injection was detected. Under normal conditions, iNOS is not expressed in the penis; however, after administration of inflammatory mediators, its release is stimulated, and the amount of NO generated by iNOS is found to be relatively above the physiologic limits (Bivalacqua et al, 2001). At these supraphysiologic levels, NO causes the formation of peroxynitrite, which is associated with the emergence of free oxygen radicals. Subsequently, cellular damage mechanisms are induced, which eventually lead to fibrosis. In association with DM, the increase in TGF-b1 expression stimulates the production of collagen 1, fibronectin, and plasminogen activator inhibitor type 1 and causes fibrosis and accumulation of matrices (Davila et al, 2005; Seo et al, 2009). In support of this finding, in some experimental studies, significant increases in iNOS levels have been detected in the cochleas and aortic segments of diabetic rats (Nangle et al, 2006; Liu et al, 2008). Consequently, the observed relationship between DM and fibrotic cytokines may explain the important correlation between the severity of PD and DM. The present study has some limitations that merit mentioning. First, the present study lacked demographic data of the control group such as obesity, smoking, marital status, and serum testosterone levels. Recently ElSakka (2006) reported significant associations between

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PD and obesity, smoking, and duration and number of cigarettes smoked per day. However, there is no evidence in the literature regarding the relationship between the previously mentioned parameters and severity of PD. Second, Moreno and Morgentaler (2009) reported in a study of patients with PD that the severity of the curvature was greater for men with testosterone deficiency compared with men with normal serum testosterone levels. Again, our study did not include this parameter, which may influence wound healing. Last, the present study did not include data on penile trauma. There is some evidence in the literature that PD results from repetitive minor traumas to the TA of the penis, with subsequent abnormal wound healing and scar formation. It has been reported that approximately 8.5% to 40% of patients with PD had a history of penile trauma during sexual intercourse or masturbation (Jarow and Lowe, 1997; Usta et al, 2004). The major strengths of this study are that it was conducted in a large number of patients, and it used an objective tool (CIS test) for the assessment of the curvature, which was implemented by a single operator.

Conclusions We observed that patient’s age, side of deformity, erectile function, and presence of DM were predictive factors for the degree of penile deformity. However, there were no predictive factors for systemic non-DM vascular risk factors, pain on erection, response to CIS test, and duration of disease.

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