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Address correspondence to: Ege C. Serefoglu, M.D., F.E.C.S.M., Department of Urology, Bagcilar Training & Research Hospital, Cinnah Caddesi No. 47, 06680 Cankaya-Ankara, Turkey.
To elucidate patient characteristics that impact symptom-related bother and erectile function in patients with Peyronie disease (PD).
Methods
A post hoc analysis used data from patients with PD (ie, had PD symptoms ≥12 months and penile curvature deformity of 30-90 degrees) who received ≥1 injection of study medication in 2 phase 3 trials of collagenase clostridium histolyticum (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Study I [n = 417] and Investigation for Maximal Peyronie's Reduction Efficacy and Safety Study II [n = 415]). The Covariance Analysis of Linear Structural Equations procedure was used to estimate the potential relationship of specified variables on the level of distress and erectile dysfunction associated with PD as measured by the Peyronie's Disease Questionnaire and the International Index of Erectile Function, erectile function domain.
Results
Pain during intercourse (P = .02) and PD bother (P <.0001) had a significant impact on International Index of Erectile Function, erectile function scores. The Peyronie's Disease Questionnaire bother domain score was significantly affected by penile curvature deformity, penile shortening, pain during intercourse, and the presence of plaques (P ≤.0005 for all), with pain during intercourse having the greatest impact (maximum likelihood estimation ± standard error = .496 ± .030; P <.0001). Erectile function did not appear to be directly influenced by the presence of plaques, penile curvature deformity, or penile shortening but was associated with PD bother and penile pain.
Conclusion
This post hoc analysis provides a conceptual framework through which disease characteristics may impact PD-related bother and erectile function in patients with PD.
Peyronie disease (PD) is a penile condition that is characterized by focal fibrosis of the tunica albuginea that results in the formation of plaque(s), curvature or deformation of the penis, and, in some cases, pain.
penile curvature or deformity persists and may impact patients' psychological health, relationships with their sexual partners, and emotional well-being.
For example, a single-center, cross-sectional study demonstrated that more than half of patients with PD experienced relationship problems because of the condition, and 81% reported emotional problems.
Furthermore, an observational study of 92 men with PD demonstrated that almost half (48%) indicated that they were depressed and that the depression had not resolved over time.
Penile duplex ultrasonography in men with Peyronie's disease: is it veno-occlusive dysfunction or poor cavernosal arterial inflow that contributes to erectile dysfunction?.
A systematic review of the psychosocial outcomes associated with erectile dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex?.
Penile duplex ultrasonography in men with Peyronie's disease: is it veno-occlusive dysfunction or poor cavernosal arterial inflow that contributes to erectile dysfunction?.
A systematic review of the psychosocial outcomes associated with erectile dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex?.
Given the overlap of the physical and psychological symptoms associated with PD and ED, it is important for health-care providers to understand how baseline demographic and clinical factors may contribute to comorbid ED.
The Peyronie's Disease Questionnaire (PDQ) was developed to quantify the psychosexual influence of PD, which, along with objective measures, was intended to provide a more thorough assessment of the impact of PD.
The conceptual framework and subscale structure of the PDQ was validated using baseline data from 2 phase 3 trials that examined the efficacy and safety of collagenase clostridium histolyticum (CCH) in patients with PD (ie, Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies [IMPRESS]-I and IMPRESS-II).
The results of these trials demonstrated correlation with clinical measures of PD and sexual function (as assessed by the International Index of Erectile Function [IIEF] questionnaire
Thus, the PDQ may facilitate an understanding of the impact of various factors on PD and ED. The objective of this post hoc analysis was to examine the potential relationship among baseline factors that may impact PD-related bother and erectile function in patients with PD.
Methods
This post hoc analysis included data from 2 published clinical trials
Clinical efficacy, safety and tolerability of collagenase Clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies.
that evaluated the safety and efficacy of CCH injection in patients with PD (ClinicalTrials.gov identifiers: IMPRESS-I, NCT01221597; IMPRESS-II, NCT01221623). Data were included from patients in a predefined modified intention-to-treat (mITT) population of IMPRESS-I and IMPRESS-II (ie, mITT defined as patients with both a curvature deformity measurement and a PD symptom bother score at screening who received ≥1 injection of study drug and ≥1 postinjection measurement).
Study designs for IMPRESS-I and IMPRESS-II have been published.
Clinical efficacy, safety and tolerability of collagenase Clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies.
Briefly, both were double-blind, placebo-controlled, multicenter, 52-week, phase 3 trials that recruited patients from Australia and the United States starting in September 2010 for both studies and ending in March 2012 (IMPRESS II) and April 2012 (IMPRESS I). Eligible patients were men ≥18 years of age with stable PD (diagnosis of PD for ≥12 months) and a penile curvature of 30-90 degrees who were in a heterosexual relationship and participated in vaginal intercourse. Patients were excluded if they had calcified plaques that interfered with injections, had penile hourglass deformity, received treatment for PD in the past or planned to receive treatment, had undergone surgery for the correction of PD, or had ED that was unresponsive to phosphodiesterase type 5 inhibitors. In both studies, 2 doses of either CCH .58 mg or placebo were injected into a plaque located at the point of maximal penile curvature within each cycle. The 2 injections were separated by 24-72 hours, with investigator penile plaque modeling approximately 24-72 hours after the second injection. Each cycle was separated by 6 weeks, and up to 4 cycles (8 injections) were permitted.
Main Outcome Measures
At baseline, patients were asked to rate the severity of multiple PD symptoms (ie, penile curvature, penile shape, penile rigidity, erection pain, presence of plaques or lesions) as none, mild, moderate, or severe. Patients also reported the severity of penile shortening (no shortening, >0-0.5 inches, >0.5-1 inch, >1-2 inches, or >2 inches). Penile curvature was measured at baseline using a goniometer.
All patients who had vaginal intercourse during the previous 3 months were asked to complete the PDQ and the IIEF at baseline; if patients did not meet the vaginal intercourse requirement, they did not complete the PDQ.
It consists of 3 domains: psychological and physical symptoms (6 items; score range, 0-24), penile pain (3 items; score range, 0-30), and symptom bother (4 scored items and 2 yes or no unscored questions; score range, 0-16). In general, higher scores within each domain indicate greater severity.
The IIEF is a validated, 15-question survey designed to assess ED symptoms.
Questions are divided into 5 domains: erectile function (6 items; maximum score, 30), orgasmic function (2 items; maximum score, 10), sexual desire (2 items; maximum score, 10), intercourse satisfaction (3 items; maximum score, 15), and overall satisfaction (2 items; maximum score, 10). Each question is rated from 0 to 5 (questions 1-10) or from 1 to 5 (questions 11-15), where higher values indicate less difficulty, greater frequency, more satisfaction, confidence, or enjoyment. For questions that focus on intercourse (ie, questions 1-10), “0” indicated that sexual intercourse had not taken place or was not attempted.
Individual domains of the PDQ and IIEF (eg, erectile function, sexual desire) were prospectively evaluated as secondary end points in both IMPRESS studies. In the current post hoc analysis, various relationships between baseline demographics and disease characteristics, PD symptoms, and ED symptoms were analyzed (Table 1).
Table 1Characteristics and symptom parameters evaluated in analyses
Duration of PD (y) Stratum of baseline penile curvature Direction of penile curvature Stratum of baseline penile curvature Distress over PD symptoms Decreased erection or rigidity Pain in erect penis Severity of penile curvature Change in penile shape Presence of plaque or lesion Penile shortening Consistency of primary plaque Trauma to the penis Penile curvature (degrees)
PDQ PD symptoms total score PDQ penile pain total score PDQ PD bother total score PDQ Q7: pain at rest PDQ Q8: pain with erection PDQ Q9: pain during intercourse
Self-reported history of ED ED IIEF-EF score <22 IIEF-EF total score
ED, erectile dysfunction; IIEF-EF, International Index of Erectile Dysfunction, erectile function domain; PD, Peyronie disease; PDQ, Peyronie's Disease Questionnaire.
Variables that were highly correlated after the preliminary correlation analysis of all baseline variables were included in subsequent modeling. The relationships between selected variables were analyzed using a Covariance Analysis of Linear Structural Equations (CALIS) procedure. The standardized root mean square residual, adjusted goodness of fit index, and Bentler comparative fit index were used to evaluate the goodness of fit. The estimated maximum likelihood of the relationships between PDQ-reported bother and IIEF-EF domain score was evaluated using covariance structure analysis.
Results
In IMPRESS-I and IMPRESS-II, 832 patients (IMPRESS-I, n = 417; IMPRESS-II, n = 415) were randomly assigned to treatment (CCH or placebo) and received ≥1 injection of study medication. Of these, 612 patients (73.6%) were included in the mITT population. Because 4 patients did not have a baseline IIEF-EF domain score, only 608 patients (99.3%) were included in the current post hoc analysis. Mean (± standard deviation) age for the 608 patients was 57.3 (8.3) years and mean penile curvature was 49.8° (14.2°; Supplementary Table S1). The majority of patients (61.0%) reported some degree of pain during vaginal intercourse. More than half (53.1%) experienced pain upon erection, although few (22.6%) reported pain when the penis was flaccid.
Initial Spearman correlation analysis showed significant relationships among a variety of demographic and baseline penile symptoms (Table S2, Table S3). Age correlated with ethnicity (P = .0534), distress over PD (P = .0360), change in penile shape (P = .0066), presence of a plaque or lesion (P = .0054), duration of PD (P = .0002), direction of penile curvature (P = .0260), trauma to the penis (P = .0090), pain in the erect penis (P <.0001), and a history of self-reported ED (P = .0167). Distress over PD was associated with age (P = .0360; Supplementary Table S2), duration of PD (P = .0003; Supplementary Table S2), and a variety of penile symptoms (eg, penile curvature severity, degree of curvature, decreased erection or rigidity, penile shortening [P <.0001 for each], and pain in the erect penis [P = .0002]; Supplementary Table S3), suggesting that patients with a longer duration of PD and those with more penile symptoms may experience greater distress. Distress over PD, pain in the erect penis, presence of a plaque or lesion, penile shortening, and IIEF total score correlated with all PDQ variables examined, including PDQ question 9 (pain during intercourse; Supplementary Table S4). The degree of penile curvature was significantly associated with PDQ symptom total score (P <.0001) and PD bother total score (P = .0003), but not PDQ penile pain total score (P = .2823). The presence of a plaque or lesion was significantly correlated with several disease parameters (eg, pain in the erect penis; P = .0042; Supplementary Table S2) and all individual PDQ parameters examined (P ≤.0111; Supplementary Table S4). IIEF-EF total score was associated with distress over PD (P <.0001; Table S4, Table S5), decreased erection or rigidity (P <.0001; Supplementary Table S5), severity of penile curvature (P = .0228; Supplementary Table S3), self-reported history of ED (P <.0001; Supplementary Table S5), and all PDQ parameters (P <.05 for all; Table S4, Table S5). The relationships between penile curvature deformity, perceived penile shortening, pain during intercourse, presence of plaques, PD bother score, and IIEF-EF score shown in Figure 1 were confirmed using the CALIS procedure. Using the structural equation model, items measured by the PDQ (ie, pain during intercourse and PD bother) had a significant impact on IIEF-EF scores (Fig. 1). Pooled patient data from IMPRESS-I and IMPRESS-II fit the proposed model well, as indicated by model fit and threshold parameters from multiple goodness of fit analyses (Table 2). As expected, penile curvature deformity, penile shortening, pain during intercourse, and the presence of plaques significantly affected the PDQ bother domain (P ≤.0005; Table 3). Among these 4 factors, pain during intercourse had the most impact on the PDQ bother domain and the presence of plaques had the least effect. In turn, PD bother and pain during intercourse significantly impacted erectile function (Table 3).
Figure 1Proposed relationships between baseline characteristics and PD and ED that were confirmed using the CALIS procedure. Data are presented as standardized coefficients (statistical P values). CALIS, Covariance Analysis of Linear Structural Equations; ED, erectile dysfunction; IIEF-EF, International Index of Erectile Function, erectile function domain; PD, Peyronie disease; PDQ, Peyronie's Disease Questionnaire; Q9, question 9.
Standard root mean square residual values close to 0 indicate a good fit; good fit is represented as values closest to 1 in the adjusted goodness of fit index and Bentler comparator fit index.
Note that the following model fit threshold values indicate that the model fits the collected data well: standardized root mean square residual, <.05; adjusted goodness of fit index, >.90; Bentler comparator fit index, >.9.
Standardized root mean square residual
.034
<.05
Adjusted goodness of fit index
.969
>.90
Bentler comparator fit index
.967
>.90
* Standard root mean square residual values close to 0 indicate a good fit; good fit is represented as values closest to 1 in the adjusted goodness of fit index and Bentler comparator fit index.
† Note that the following model fit threshold values indicate that the model fits the collected data well: standardized root mean square residual, <.05; adjusted goodness of fit index, >.90; Bentler comparator fit index, >.9.
This post hoc analysis of data from 2 phase 3 trials of patients with PD demonstrated significant relationships between baseline factors and PD bother and erectile function. Penile curvature deformity, penile shortening, and pain during intercourse all affected PD-related bother. Erectile function was associated with only PD bother and pain during intercourse, whereas pain during intercourse affected both PD bother and erectile function. These data suggest that alleviating pain during intercourse could improve both erectile function and PD bother, and that treatment that alleviates pain during intercourse may be particularly beneficial in patients with PD and ED.
Patients with PD often present with multiple physical (eg, penile curvature deformity, penile shortening) and psychosocial difficulties (eg, painful intercourse, apprehension about physical appearance, sexual self-image, loss of sexual confidence and feelings of attractiveness, performance anxiety, partner satisfaction, social isolation), which may impact their overall quality of life.
In a cross-sectional study of 245 men with PD, the inability to have sex was associated with relationship difficulties, which itself was predictive of emotional problems.
The current post hoc analysis supports the association of sexual difficulties with psychological complications through the confirmed relationships of pain during intercourse, penile curvature deformity, and penile shortening (all of which may prevent sexual intercourse) with PD bother, and between PD bother and the IIEF-EF domain scores.
ED is common in patients with PD (up to 54% of patients with PD report ED
For example, a prospective prevalence study (n = 1440) demonstrated that comorbid PD significantly increased the duration (P <.05) and severity of symptoms (P <.05) in patients with ED.
A systematic review of the psychosocial outcomes associated with erectile dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex?.
The direction and severity of penile curvature does not have an impact on concomitant vasculogenic erectile dysfunction in patients with Peyronie's disease.
which are prevalent among patients with PD. However, in a retrospective study of men with complaints of penile curvature and shortening who underwent penile duplex Doppler ultrasonography, demographic and baseline disease characteristics (eg, age, diabetes, smoking, hyperlipidemia, hypertension) were similar in patients with PD alone and in those with PD and ED.
Penile duplex ultrasonography in men with Peyronie's disease: is it veno-occlusive dysfunction or poor cavernosal arterial inflow that contributes to erectile dysfunction?.
Furthermore, among reported medical comorbidities, history of presenting complaint, penile duplex Doppler characteristics (eg, tunical thickening, intracavernosal calcification, peak systolic velocity), and plaque size, only the size of PD plaque correlated with the development of ED.
Penile duplex ultrasonography in men with Peyronie's disease: is it veno-occlusive dysfunction or poor cavernosal arterial inflow that contributes to erectile dysfunction?.
Thus, the connection between ED and PD remains a topic of exploration.
Data in the current study support the interrelationship of PD and ED symptomatology, given that the PD bother domain influenced erectile function as measured by the IIEF-EF. The results of the CALIS procedure revealed that erectile function is not directly influenced by presence of plaques, penile curvature deformity, or penile shortening, whereas PD bother and penile pain have a stronger impact on erectile function. This influence suggests that improvement in bother and penile pain of the patient with PD may, in turn, improve ED and other factors associated with ED and PD (eg, sexual relationship). It remains to be determined which PD treatments improve PDQ bother domain scores; however, a separate analysis of the IMPRESS-I and IMPRESS-II trials showed significant improvement from baseline to week 52 in PD symptom bother domain and penile pain with injections of CCH.
Strengths of the current analysis include the use of data from 2 large, multinational, multicenter clinical trials that used uniform measurements. Indeed, most trials of patients with PD are less rigorous, and the diversity among the outcome measures makes comparisons difficult. Another advantage of the current analysis is that multiple statistical analyses were performed to confirm the goodness of fit of the proposed associations. However, the post hoc nature of the analysis and its inclusion of men with PD who met specific conditions for the 2 clinical trials potentially limit the generalizability of the results, particularly for patients with acute-phase PD and patients with ED that was unresponsive to phosphodiesterase type 5 inhibitors. In addition, the CALIS procedure only looks at first-order (linear) relationships between variables. In reality, the relationship between variables is much more complex and requires additional exploration.
In conclusion, this post hoc analysis offers unique insight into the potential psychosexual impact of baseline characteristics on PD-related bother and erectile function, and further supports the validity of the PDQ for the assessment of psychological PD symptoms.
Acknowledgment
The authors thank Mary Beth Moncrief, PhD, and Jillian Gee, PhD, Synchrony Medical Communications, LLC, West Chester, PA, for providing editorial and writing support under the direction of the authors; this support was funded by Endo Pharmaceuticals Inc., Malvern, PA, USA.
Appendix. Supplementary Data
The following are the supplementary data to this article:
Penile duplex ultrasonography in men with Peyronie's disease: is it veno-occlusive dysfunction or poor cavernosal arterial inflow that contributes to erectile dysfunction?.
A systematic review of the psychosocial outcomes associated with erectile dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex?.
Clinical efficacy, safety and tolerability of collagenase Clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies.
The direction and severity of penile curvature does not have an impact on concomitant vasculogenic erectile dysfunction in patients with Peyronie's disease.
Financial Disclosure:Wayne J.G. Hellstrom was a principal investigator on the phase III IMPRESS trial and is currently on the speakers' bureau and advisory board for Endo Pharmaceuticals Inc. Genzhou Liu is an employee of Endo Pharmaceuticals Inc. Gregory J. Kaufman and Ted M. Smith were employees of Endo Pharmaceuticals Inc when the manuscript was initiated. Ted M. Smith owns Endo stock. Ted M. Smith and Gregory J. Kaufman are former employees of Auxilium Pharmaceuticals, Inc. The remaining authors declare that they have no relevant financial interests.
Funding Support:The IMPRESS-I and IMPRESS-II trials were funded by Auxilium Pharmaceuticals, Malvern, PA, USA.
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