Ir J Med Sci DOI 10.1007/s11845-013-1036-5
ORIGINAL ARTICLE
Effects of sildenafil treatment on patients with Peyronie’s disease and erectile dysfunction U. Ozturk • S. Yesil • H. N. G. Goktug A. Gucuk • C. Tuygun • N. C. Sener • I. Nalbant • M. A. Imamoglu
•
Received: 21 February 2013 / Accepted: 28 October 2013 Ó Royal Academy of Medicine in Ireland 2013
Abstract Introduction It has been shown on experimental rat models that type 5-phosphodiesterase isoenzyme (PDE5) inhibitors have anti-fibrotic effects for Peyronie’s disease (PD); however, this issue has not been addressed clinically. The aim of this study was to document the effects of PDE5 inhibitors used for erectile dysfunction (ED) seen in PD patients on the main course of the PD clinically. Methods A total of 39 PD patients with ED were divided into two groups. Patients in Group 1 (n = 18) served as controls and received 400 IU vitamin E per day. Those in Group 2 (n = 21) received 50 mg sildenafil per day for 12 weeks. Penile plaque volume was assessed by palpation and by duplex ultrasound. Erectile capacity, penile deformity and plaque characteristics were assessed by the International Index of Erectile Function questionnaire form (IIEF-5) and penile duplex ultrasound. Results Statistically significant improvement in all parameters was observed within both groups except for IIEF score in Group 1 when compared with the initial values. Significant reduction in plaques and pain were observed in 7 (33.3 %) and 14 (66.6 %) patients in Group 2 and 6 (33.3 %) and 9 U. Ozturk H. N. G. Goktug C. Tuygun N. C. Sener I. Nalbant M. A. Imamoglu Department of Urology, Ministry of Health, Ankara Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey S. Yesil (&) Urology Department, Gazi University School of Medicine, Cevizlidere caddesi 143/26, 06520 Ankara, Turkey e-mail: [email protected] A. Gucuk Urology Department, Abant Izzet Baysal University School of Medicine, Bolu, Turkey
patients (42.8 %) in Group 1, respectively. At the end of the therapy, improvement in IIEF score and reduction in pain were statistically significant in Group 2 compared with Group 1 (p = 0.028 and p = 0.045, respectively). Conclusion We conclude that continuous administration of oral PDE5 inhibitors may be a candidate for medical treatment of PD; however, more controlled studies are needed. Keywords Peyronie’s disease Phosphodiesterase isoenzyme inhibitors Sildenafil Treatment
Introduction Peyronie’s disease (PD) is manifested by localized fibrous inelastic scars in the tunica albuginea and cause palpable penile plaque, abnormal penile curvature, painful erections and erectile dysfunction (ED) [1]. PD plaque affects 3–9 % of the male population [2, 3]. Although it was described nearly 250 years ago, and to date it has been treated with various drugs and techniques, currently there is no standard medical treatment [4]. In other words we do not exclude a standard surgical treatment. Over the last decade, it has been shown in both experimental rat PD models and radical post-prostatectomy that type-5 phosphodiesterase isoenzyme (PDE5) inhibitors display an anti-fibrotic effect [5]. We designed this study on the continuous use of PDE5 inhibitors to clinically document this anti-fibrotic effect in ED patients with PD.
Methods From September 2007 to October 2010 a total of 39 PD patients with ED were included into the study. Written
123
Ir J Med Sci
informed consent was obtained from all subjects before entering the study, which was conducted in accordance with the Declaration of Helsinki. The Human Ethics Committee approved the study. Patients were enrolled into the study if they had primary PD with a history of symptoms for no longer than 6 months and with noncalcified plaque, penile deviation and pain on erection and the initiation of ED at the beginning of other symptoms. Plaques were assessed by penile ultrasound whether to have calcification or not. Erection was induced by injecting 40 mg papaverine. The patients with previous treatment for PD or ED, hormonal abnormality, alcohol or tobacco abuse, hypertension, coronary artery disease and diabetes mellitus were excluded. All patients were evaluated by medical and sexual history, physical examination, subjective score scales, photographs, and penile USG, before and after therapy. To exclude organic sexual dysfunctions and other underlying diseases fasting blood glucose level, urinalysis, complete blood count, sex hormones and prolactin levels were measured. The evaluation of the penile plaque volume and was performed on the fully stretched penis during flaccidity by palpation and by measurement of the plaque length and width using a high-resolution penile ultrasonography and duplex ultrasound. A correction of 20 % or more in plaque volumes was considered significant. The International Index of Erectile Function questionnaire form (IIEF-5) [6] and penile duplex ultrasound were used to assess erectile capacity, penile deformity and plaque characteristics. Penile curvature was measured according to the Kelami’s criteria after taking a photograph during erection. Diagnostic procedures included a ten-scale pain score. Control group consisted of patients who were administered only vitamin E for treatment. The patients were randomized into two groups, Group 1 (n = 18) received 400 IU vitamin E (Vitamin E, Koc¸ak, Istanbul) per day and Group 2 (n = 21) received a standard dose of 50 mg sildenafil (sildenafil citrate, Pfizer, New York) per day for 12 weeks. At the end of the therapy, improvement in erectile status and pain on erection and the change of plaque volume and penile deviation were recorded. Statistical analysis was performed by Statistical Package for Social Sciences (SPSS) 13 software (SPSS Inc., Chicago, IL, USA). Whether the continuous variables were normally distributed or not was determined by using the Shapiro–Wilk test. All the data are presented as mean ± SD. In-group differences between before and after treatment were evaluated by Wilcoxon test. Data comparison between groups was evaluated by Mann– Whitney U test. A p value less than 0.05 was considered statistically significant.
123
Results All of the 39 patients completed the entire study. The mean age of the patients in Group 1 was 53.44 ± 5.98 (42–62) years and in Group 2 was 55.05 ± 4.87 (46–62) years. The etiology of ED was similar in both groups (Table 1). A peak systolic flow below 25 cm/s was considered as arterial insufficiency and end diastolic velocity [6 cm/s and resistive index \0.6 was considered diagnostic for venous leakage [7]. Remarkable reduction in palpable plaques and in pain were observed in 7 patients (33.3 %) and 14 (66.6 %) patients in Group 2 and 6 patients (33.3 %) and 9 patients (42.8 %) in Group 1, respectively. With respect to penile curvature, various correction degrees were observed in eight patients with 30° in one patient, 20° in three patients, and 10° in four patients, with no change in the remaining five patients (23.8 %) in Group 2. A total of eight patients (38.09 %) showed an increase in their IIEF-5 scores in Group 2. With respect to penile curvature, various correction degrees were observed in seven patients with 30° in one patient, 20° in three patients, and 10° in three patients, with no change in the remaining four patients (22.2 %). Six patients (28.5 %) showed an increase in their IIEF-5 scores in Group 1. A significant increase in IIEF-5 symptom scores was observed in one patient with severe ED, six patients with moderate ED and one patient with mild ED in Group 2. A significant increase in IIEF-5 symptom scores was observed in one patient with severe ED, four patients with moderate ED and one patient with mild ED in Group 1. The mean IIEF scores, penile curvature, plaque volume and pain reduction of each group were compared after the therapy, these results were significantly higher than initial scores (p \ 0.05, except Group 1 IIEF scores). There was no difference between the two groups in terms of age, penile curvature and plaque volume. At the end of the therapy, improvement in IIFF score and reduction in pain were statistically significant in Group 2 compared with Group 1 (p = 0.028 and p = 0.045, respectively) (Table 2). There were no side effects except for a single patient having mild headaches which was treated with analgesics in Group 2.
Table 1 Etiology of erectile dsyfunction ED etiology
Group 1 n (%)
Group 2 n (%)
Arterial abnormalities
3 (16.6 %)
3 (14.28 %)
Veno-occlusive dysfunction
7 (38.8 %)
8 (38.09 %)
Mixt arterial and venous pathology
3 (16.6 %)
2 (9.52 %)
Other (due to pain, curvature or anxiety)
7 (38.8 %)
8 (38.09 %)
Ir J Med Sci Table 2 The distrubition of IIEF, Penile curvature, plaque volume, pain and follow-up data by groups [median ± standard deviation (min max)] Group 1 (n = 18) IIEF pretreatment IIEF posttreatment Penile curvature pretreatment (°) Penile curvature posttreatment (°) Plaque volume pretreatment Plaque volume posttreatment Pain score pretreatment
9.78 ± 3.46
Follow-up (weeks)
p
10.10 ± 3.77
0.686
(3–15)
(2–16)
10.67 ± 3.27
13.90 ± 5.52*,
(5–16)
(4–22)
?
0.028
37.22 ± 13.64
38.57 ± 13.15
(20–60)
(20–60)
28.33 ± 15.81? (10–60)
29.05 ± 16.10? (10–60)
0.885 0.463
48.89 ± 18.33
54.14 ± 24.30 (16–96)
40.56 ± 15.10?
39.05 ± 14.24?
(14–62)
(14–62)
3.39 ± 1.42 2.61 ± 1.09?
P (Group 1)
P (Group 2)
0.055
0.001
0.017
0.007
0.0001
0.001
0.004
0.001
0.716
(16–84)
(0–5) Pain score posttreatment
Group 2 (n = 21)
3.24 ± 1.30
0.692 0.637
(0–5) 1.95 ± 0.97*,
(0–4)
(0–4)
12.94 ± 2.18
13.24 ± 1.70
(10–18)
(10–16)
?
0.045 0.528
* p \ 0.05 compared to the group1 p \ 0.05 compared with first measurement
?
Discussion Our study has demonstrated that the continuous administration of PDE5 inhibitors in PD patients with ED can be beneficial particularly in reducing pain and improving erectile function, and in some cases, also reducing plaque volume and curvature deviation. There is disagreement over the ideal management of PD [8]. Over time, PD has been treated with methods including oral pharmacotherapy (vitamin E, colchicine, tamoxifen, potassium para-aminobenzoate, L-carnitine, propoleum, pentoxifylline), intralesional drug therapy (verapamil, interferon a-2a or interferon a-2b, collagenase), iontophoresis, extracorporeal shock wave therapy and radiation therapy [9, 10]. However, today no consensus exists for the treatment of acute-phase PD [11]. PD can affect the sexual function and ED rates vary up to 80 % in previously reports [12, 13]. The proposed mechanisms for ED development are; difficulties in vaginal penetration due to pain or curvature, distress or performance anxiety, increased sympathetic tone and corporeal veno-occlusive dysfunction secondary to structural alteration in the fibroelastic trabeculae [14]. Primary reasons for ED in PD are vascular. A one study reported 70.6 % ED rate and 76.5 % vascular abnormalities in 136 patients with PD [15]. In another study the venoocclusive dysfunction was found to be the most common reason of ED in patients with PD [16]. The etiology of ED
patients in our study were similar to those found in the literature. The on-demand use of sildenafil is already recommended to PD patients with ED for ED treatment [17]. These observations led to the conclusion that an increase of cGMP or nitric oxide by a long-term continuous administration of PDE5 inhibitors should reduce the PD plaque. Two experiments in the literature stand out in this field: first, in a study by Valente et al. [18] that went beyond the classic on-demand use of PDE5 inhibitors, and administered long-term and continuously on experimental rat PD models, and observed anti-fibrotic effects. It reduced the sildenafil collagen deposits, profibrotic factor secretion, oxidative stress and myofibroblast counts. Second, in a similar study, Ferrini et al. [19] used verdenafil and observed a reversal in the formation of PD-like plaque. It has been shown that PDE5 inhibitors like sildenafil decrease fibrous plaque formed in rats with experimental PD [5]. The studies in humans on this topic are relatively limited. Only Valente et al. [18] stated that L-arginine and phosphodiesterase inhibitors counteract fibrosis in the Peyronie’s fibrotic plaque; however, this study was conducted in vitro with human fibroblast. On the other hand, Levine used PDE5 inhibitors only in the ED patients accompanied by PD; however, the ameliorating effects of PDE5 inhibitors on the features of PD were not studied [17]. For this reason, this clinical study, in which the effects of PDE5 inhibitors on PD were investigated is the first in related literature. In this study, statistically
123
Ir J Med Sci
significant improvements have been observed in PD patients using sildenafil at the end of the therapy compared with the initial parameters studied. In addition, improvement in IIEF score and reduction in pain were statistically significant in Group 2 compared with Group 1 (p = 0.028 and p = 0.045, respectively).Therapeutic effects of sildenafil on PD patients could be explained by following mechanisms. PD is assumed to result from an abnormal healing process subsequent to trauma to the erect penis that causes fibrin extravasation into the tunica albuginea. This leads to inflammation and release of fibrotic effectors, mainly transforming growth factor b1 and reactive oxygen species, which then trigger excessive deposition and disorganization of the collagen fibers [18–20]. Since many of the effects of NO are mediated via the stimulation of guanylyl cyclase to produce cGMP, it could be possible that part of the anti-fibrotic action of NO may occur through the elevation of cGMP levels in the PD plaque, and the subsequent activation of protein kinase G (PKG) [21, 22]. PDE5 is assumed to be present in the penile cavernosal smooth muscle cells, in analogy to their localization in vascular tissue. Inhibition of phosphodiesterase-5 (PDE5), the PDE isoenzyme that catalyzes cGMP breakdown, leads to elevation of cGMP levels and activation of PKG, while simultaneously causing apoptosis and reducing collagen synthesis [23, 24]. By these effects, decrease of penile curvature is expected after both sildenafil and vitamin E treatment. Because of the duration of our study, which is 12 weeks, only moderate alterations for penile curvature is expected. Therefore, both groups had encountered an improvement of about 10° of penile curvature (Group 1, 37.22 ± 13.64 to 28.33 ± 15.81; Group 2, 38.57 ± 13.15 to 29.05 ± 16.10). There is no statistical significant difference between treatment modalities after 12 weeks of treatment. IIEF scores, as well, have improved with the treatment. That is, as expected, is statistically significant for the patients taking sildenafil as a treatment for PD. For Groups 1 and 2, IIEF scores were 9.78 ± 3.46 and 10.10 ± 3.77, respectively, and after the treatment, the scores were improved to 10.67 ± 3.27 and 13.90 ± 5.52, respectively, (p \ 0.05 for Group 2). Our study is the first clinical study to evaluate the antifibrotic effect of PD. However, our study has many limitations, such as small patient population, the study not being double blind. Duration of the study is short (12 weeks). Also, only acute-phase patients were included, so possible resolution of the disease may be expected for this cohort.
Conclusion As a result of this along with the two experimental studies mentioned above, our study of continuous PDE5 inhibitors
123
we conducted on early-stage PD patients shows that administration of continuous PDE5 inhibitors may be beneficial in PD patients—particularly in correcting erectile capacity and reducing pain. We included patients with ED component in our study because of our expectations of the effects on their erectile capacities, if not more. We conclude that continuous administration of oral PDE5 inhibitors may be a candidate for medical treatment of PD. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Taylor FL, Levine LA (2007) Peyronie’s disease. Urol Clin North Am 34:517–534 2. Gholami SS, Gonzalez-Cadavid NF, Lin CS et al (2003) Peyronie’s disease: a review. J Urol 169:1234–1241 3. Mu¨ller A, Mulhall JP (2009) Peyronie’s disease intervention trials: methodological challenges and issues. J Sex Med 6:848–861 4. Gonzalez-Cadavid NF, Rajfer J (2009) Experimental models of Peyronie’s disease. Implications for new therapies. J Sex Med 6:303–313 5. Gonzalez-Cadavid NF, Rajfer J (2010) Treatment of Peyronie’s disease with PDE5 inhibitors: an anti-fibrotic strategy. Nat Rev Urol 7:215–221 6. Rosen RC, Cappelleri JC, Smith MD et al (1999) Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 11:319–326 7. Sikka SC, Hellstrom WJ, Brock G, Morales AM (2013) Standardization of vascular assessment of erectile dysfunction: standard operating procedures for duplex ultrasound. J Sex Med 10:120–129 8. Kumar R, Nehra A (2009) Surgical and minimally invasive treatments for Peyronie’s disease. Curr Opin Urol 19:589–594 9. Hauck EW, Diemer T, Schmelz HU et al (2009) A critical analysis of nonsurgical treatment of Peyronie’s disease. Eur Urol 49:987–997 10. Hellstrom WJ (2009) Medical management of Peyronie’s disease. J Androl 30:397–405 11. Vanni AJ, Bennett NE (2009) Current treatment and management of the acute phase of Peyronie’s disease. Arch Esp Urol 62:614–622 12. Erdogru T, Savas M, Yilmaz N et al (2002) Evaluation of penile hemodynamic status and adjustment of treatment alternatives in Peyronie’s disease. Asian J Androl 4(1):87–90 13. Lopez JA, Jarow JP (1993) Penile vascular evaluation of men with Peyronie’s disease. J Urol 149:53–55 14. Deveci S, Palese M, Parker M et al (2006) Erectile function profiles in men with Peyronie’s disease. J Urol 175:1807–1811 15. Kadiog˘lu A, Tefekli A, Erol H et al (2000) Color Doppler ultrasound assessment of penile vascular system in men with Peyronie’s disease. Int J Impot Res 12:263–267 16. Weidner W, Schroeder-Printzen I, Weiske WH et al (1997) Sexual dysfunction in Peyronie’s disease: an analysis of 222 patients without previous local plaque therapy. J Urol 157:325–328 17. Levine LA, Latchamsetty KC (2002) Treatment of erectile dysfunction in patients with Peyronie’s disease using sildenafil citrate. Int J Impot Res 14:478–482
Ir J Med Sci 18. El-Sakka AI, Hassoba HM, Chui RM et al (1997) An animal model of Peyronie’s-like condition associated with an increase of transforming growth factor beta mRNA and protein expression. J Urol 158:2284–2290 19. Ferrini MG, Vernet D, Magee TR et al (2002) Anti-fibrotic role of inducible nitric oxide synthase. Nitric Oxide 6:283–294 20. Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200:500–503 21. Nagayama T, Zhang M, Hsu S et al (2008) Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. J Pharmacol Exp Ther 326:380–387
22. Yildirim A, Ersoy Y, Ercan F et al (2010) Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycininduced lung fibrosis. Pulm Pharmacol Ther 23:215–221 23. Vernet D, Ferrini MG, Valente EGA et al (2002) Effect of nitric oxide on fibroblast differentiation in to myofibroblasts in cell cultures from the Peyronie’s fibrotic plaque and in its rat model in vivo. Nitric Oxide 7(262):276 24. Gonzalez-Cadavid NF, Ignarro L, Rajfer J (1999) Nitric oxide and cyclic GMP in the penis. Mol Urol 3:51–59
123
ORIGINAL ARTICLE
Effects of sildenafil treatment on patients with Peyronie’s disease and erectile dysfunction U. Ozturk • S. Yesil • H. N. G. Goktug A. Gucuk • C. Tuygun • N. C. Sener • I. Nalbant • M. A. Imamoglu
•
Received: 21 February 2013 / Accepted: 28 October 2013 Ó Royal Academy of Medicine in Ireland 2013
Abstract Introduction It has been shown on experimental rat models that type 5-phosphodiesterase isoenzyme (PDE5) inhibitors have anti-fibrotic effects for Peyronie’s disease (PD); however, this issue has not been addressed clinically. The aim of this study was to document the effects of PDE5 inhibitors used for erectile dysfunction (ED) seen in PD patients on the main course of the PD clinically. Methods A total of 39 PD patients with ED were divided into two groups. Patients in Group 1 (n = 18) served as controls and received 400 IU vitamin E per day. Those in Group 2 (n = 21) received 50 mg sildenafil per day for 12 weeks. Penile plaque volume was assessed by palpation and by duplex ultrasound. Erectile capacity, penile deformity and plaque characteristics were assessed by the International Index of Erectile Function questionnaire form (IIEF-5) and penile duplex ultrasound. Results Statistically significant improvement in all parameters was observed within both groups except for IIEF score in Group 1 when compared with the initial values. Significant reduction in plaques and pain were observed in 7 (33.3 %) and 14 (66.6 %) patients in Group 2 and 6 (33.3 %) and 9 U. Ozturk H. N. G. Goktug C. Tuygun N. C. Sener I. Nalbant M. A. Imamoglu Department of Urology, Ministry of Health, Ankara Diskapi Yildirim Beyazit Education and Research Hospital, Ankara, Turkey S. Yesil (&) Urology Department, Gazi University School of Medicine, Cevizlidere caddesi 143/26, 06520 Ankara, Turkey e-mail: [email protected] A. Gucuk Urology Department, Abant Izzet Baysal University School of Medicine, Bolu, Turkey
patients (42.8 %) in Group 1, respectively. At the end of the therapy, improvement in IIEF score and reduction in pain were statistically significant in Group 2 compared with Group 1 (p = 0.028 and p = 0.045, respectively). Conclusion We conclude that continuous administration of oral PDE5 inhibitors may be a candidate for medical treatment of PD; however, more controlled studies are needed. Keywords Peyronie’s disease Phosphodiesterase isoenzyme inhibitors Sildenafil Treatment
Introduction Peyronie’s disease (PD) is manifested by localized fibrous inelastic scars in the tunica albuginea and cause palpable penile plaque, abnormal penile curvature, painful erections and erectile dysfunction (ED) [1]. PD plaque affects 3–9 % of the male population [2, 3]. Although it was described nearly 250 years ago, and to date it has been treated with various drugs and techniques, currently there is no standard medical treatment [4]. In other words we do not exclude a standard surgical treatment. Over the last decade, it has been shown in both experimental rat PD models and radical post-prostatectomy that type-5 phosphodiesterase isoenzyme (PDE5) inhibitors display an anti-fibrotic effect [5]. We designed this study on the continuous use of PDE5 inhibitors to clinically document this anti-fibrotic effect in ED patients with PD.
Methods From September 2007 to October 2010 a total of 39 PD patients with ED were included into the study. Written
123
Ir J Med Sci
informed consent was obtained from all subjects before entering the study, which was conducted in accordance with the Declaration of Helsinki. The Human Ethics Committee approved the study. Patients were enrolled into the study if they had primary PD with a history of symptoms for no longer than 6 months and with noncalcified plaque, penile deviation and pain on erection and the initiation of ED at the beginning of other symptoms. Plaques were assessed by penile ultrasound whether to have calcification or not. Erection was induced by injecting 40 mg papaverine. The patients with previous treatment for PD or ED, hormonal abnormality, alcohol or tobacco abuse, hypertension, coronary artery disease and diabetes mellitus were excluded. All patients were evaluated by medical and sexual history, physical examination, subjective score scales, photographs, and penile USG, before and after therapy. To exclude organic sexual dysfunctions and other underlying diseases fasting blood glucose level, urinalysis, complete blood count, sex hormones and prolactin levels were measured. The evaluation of the penile plaque volume and was performed on the fully stretched penis during flaccidity by palpation and by measurement of the plaque length and width using a high-resolution penile ultrasonography and duplex ultrasound. A correction of 20 % or more in plaque volumes was considered significant. The International Index of Erectile Function questionnaire form (IIEF-5) [6] and penile duplex ultrasound were used to assess erectile capacity, penile deformity and plaque characteristics. Penile curvature was measured according to the Kelami’s criteria after taking a photograph during erection. Diagnostic procedures included a ten-scale pain score. Control group consisted of patients who were administered only vitamin E for treatment. The patients were randomized into two groups, Group 1 (n = 18) received 400 IU vitamin E (Vitamin E, Koc¸ak, Istanbul) per day and Group 2 (n = 21) received a standard dose of 50 mg sildenafil (sildenafil citrate, Pfizer, New York) per day for 12 weeks. At the end of the therapy, improvement in erectile status and pain on erection and the change of plaque volume and penile deviation were recorded. Statistical analysis was performed by Statistical Package for Social Sciences (SPSS) 13 software (SPSS Inc., Chicago, IL, USA). Whether the continuous variables were normally distributed or not was determined by using the Shapiro–Wilk test. All the data are presented as mean ± SD. In-group differences between before and after treatment were evaluated by Wilcoxon test. Data comparison between groups was evaluated by Mann– Whitney U test. A p value less than 0.05 was considered statistically significant.
123
Results All of the 39 patients completed the entire study. The mean age of the patients in Group 1 was 53.44 ± 5.98 (42–62) years and in Group 2 was 55.05 ± 4.87 (46–62) years. The etiology of ED was similar in both groups (Table 1). A peak systolic flow below 25 cm/s was considered as arterial insufficiency and end diastolic velocity [6 cm/s and resistive index \0.6 was considered diagnostic for venous leakage [7]. Remarkable reduction in palpable plaques and in pain were observed in 7 patients (33.3 %) and 14 (66.6 %) patients in Group 2 and 6 patients (33.3 %) and 9 patients (42.8 %) in Group 1, respectively. With respect to penile curvature, various correction degrees were observed in eight patients with 30° in one patient, 20° in three patients, and 10° in four patients, with no change in the remaining five patients (23.8 %) in Group 2. A total of eight patients (38.09 %) showed an increase in their IIEF-5 scores in Group 2. With respect to penile curvature, various correction degrees were observed in seven patients with 30° in one patient, 20° in three patients, and 10° in three patients, with no change in the remaining four patients (22.2 %). Six patients (28.5 %) showed an increase in their IIEF-5 scores in Group 1. A significant increase in IIEF-5 symptom scores was observed in one patient with severe ED, six patients with moderate ED and one patient with mild ED in Group 2. A significant increase in IIEF-5 symptom scores was observed in one patient with severe ED, four patients with moderate ED and one patient with mild ED in Group 1. The mean IIEF scores, penile curvature, plaque volume and pain reduction of each group were compared after the therapy, these results were significantly higher than initial scores (p \ 0.05, except Group 1 IIEF scores). There was no difference between the two groups in terms of age, penile curvature and plaque volume. At the end of the therapy, improvement in IIFF score and reduction in pain were statistically significant in Group 2 compared with Group 1 (p = 0.028 and p = 0.045, respectively) (Table 2). There were no side effects except for a single patient having mild headaches which was treated with analgesics in Group 2.
Table 1 Etiology of erectile dsyfunction ED etiology
Group 1 n (%)
Group 2 n (%)
Arterial abnormalities
3 (16.6 %)
3 (14.28 %)
Veno-occlusive dysfunction
7 (38.8 %)
8 (38.09 %)
Mixt arterial and venous pathology
3 (16.6 %)
2 (9.52 %)
Other (due to pain, curvature or anxiety)
7 (38.8 %)
8 (38.09 %)
Ir J Med Sci Table 2 The distrubition of IIEF, Penile curvature, plaque volume, pain and follow-up data by groups [median ± standard deviation (min max)] Group 1 (n = 18) IIEF pretreatment IIEF posttreatment Penile curvature pretreatment (°) Penile curvature posttreatment (°) Plaque volume pretreatment Plaque volume posttreatment Pain score pretreatment
9.78 ± 3.46
Follow-up (weeks)
p
10.10 ± 3.77
0.686
(3–15)
(2–16)
10.67 ± 3.27
13.90 ± 5.52*,
(5–16)
(4–22)
?
0.028
37.22 ± 13.64
38.57 ± 13.15
(20–60)
(20–60)
28.33 ± 15.81? (10–60)
29.05 ± 16.10? (10–60)
0.885 0.463
48.89 ± 18.33
54.14 ± 24.30 (16–96)
40.56 ± 15.10?
39.05 ± 14.24?
(14–62)
(14–62)
3.39 ± 1.42 2.61 ± 1.09?
P (Group 1)
P (Group 2)
0.055
0.001
0.017
0.007
0.0001
0.001
0.004
0.001
0.716
(16–84)
(0–5) Pain score posttreatment
Group 2 (n = 21)
3.24 ± 1.30
0.692 0.637
(0–5) 1.95 ± 0.97*,
(0–4)
(0–4)
12.94 ± 2.18
13.24 ± 1.70
(10–18)
(10–16)
?
0.045 0.528
* p \ 0.05 compared to the group1 p \ 0.05 compared with first measurement
?
Discussion Our study has demonstrated that the continuous administration of PDE5 inhibitors in PD patients with ED can be beneficial particularly in reducing pain and improving erectile function, and in some cases, also reducing plaque volume and curvature deviation. There is disagreement over the ideal management of PD [8]. Over time, PD has been treated with methods including oral pharmacotherapy (vitamin E, colchicine, tamoxifen, potassium para-aminobenzoate, L-carnitine, propoleum, pentoxifylline), intralesional drug therapy (verapamil, interferon a-2a or interferon a-2b, collagenase), iontophoresis, extracorporeal shock wave therapy and radiation therapy [9, 10]. However, today no consensus exists for the treatment of acute-phase PD [11]. PD can affect the sexual function and ED rates vary up to 80 % in previously reports [12, 13]. The proposed mechanisms for ED development are; difficulties in vaginal penetration due to pain or curvature, distress or performance anxiety, increased sympathetic tone and corporeal veno-occlusive dysfunction secondary to structural alteration in the fibroelastic trabeculae [14]. Primary reasons for ED in PD are vascular. A one study reported 70.6 % ED rate and 76.5 % vascular abnormalities in 136 patients with PD [15]. In another study the venoocclusive dysfunction was found to be the most common reason of ED in patients with PD [16]. The etiology of ED
patients in our study were similar to those found in the literature. The on-demand use of sildenafil is already recommended to PD patients with ED for ED treatment [17]. These observations led to the conclusion that an increase of cGMP or nitric oxide by a long-term continuous administration of PDE5 inhibitors should reduce the PD plaque. Two experiments in the literature stand out in this field: first, in a study by Valente et al. [18] that went beyond the classic on-demand use of PDE5 inhibitors, and administered long-term and continuously on experimental rat PD models, and observed anti-fibrotic effects. It reduced the sildenafil collagen deposits, profibrotic factor secretion, oxidative stress and myofibroblast counts. Second, in a similar study, Ferrini et al. [19] used verdenafil and observed a reversal in the formation of PD-like plaque. It has been shown that PDE5 inhibitors like sildenafil decrease fibrous plaque formed in rats with experimental PD [5]. The studies in humans on this topic are relatively limited. Only Valente et al. [18] stated that L-arginine and phosphodiesterase inhibitors counteract fibrosis in the Peyronie’s fibrotic plaque; however, this study was conducted in vitro with human fibroblast. On the other hand, Levine used PDE5 inhibitors only in the ED patients accompanied by PD; however, the ameliorating effects of PDE5 inhibitors on the features of PD were not studied [17]. For this reason, this clinical study, in which the effects of PDE5 inhibitors on PD were investigated is the first in related literature. In this study, statistically
123
Ir J Med Sci
significant improvements have been observed in PD patients using sildenafil at the end of the therapy compared with the initial parameters studied. In addition, improvement in IIEF score and reduction in pain were statistically significant in Group 2 compared with Group 1 (p = 0.028 and p = 0.045, respectively).Therapeutic effects of sildenafil on PD patients could be explained by following mechanisms. PD is assumed to result from an abnormal healing process subsequent to trauma to the erect penis that causes fibrin extravasation into the tunica albuginea. This leads to inflammation and release of fibrotic effectors, mainly transforming growth factor b1 and reactive oxygen species, which then trigger excessive deposition and disorganization of the collagen fibers [18–20]. Since many of the effects of NO are mediated via the stimulation of guanylyl cyclase to produce cGMP, it could be possible that part of the anti-fibrotic action of NO may occur through the elevation of cGMP levels in the PD plaque, and the subsequent activation of protein kinase G (PKG) [21, 22]. PDE5 is assumed to be present in the penile cavernosal smooth muscle cells, in analogy to their localization in vascular tissue. Inhibition of phosphodiesterase-5 (PDE5), the PDE isoenzyme that catalyzes cGMP breakdown, leads to elevation of cGMP levels and activation of PKG, while simultaneously causing apoptosis and reducing collagen synthesis [23, 24]. By these effects, decrease of penile curvature is expected after both sildenafil and vitamin E treatment. Because of the duration of our study, which is 12 weeks, only moderate alterations for penile curvature is expected. Therefore, both groups had encountered an improvement of about 10° of penile curvature (Group 1, 37.22 ± 13.64 to 28.33 ± 15.81; Group 2, 38.57 ± 13.15 to 29.05 ± 16.10). There is no statistical significant difference between treatment modalities after 12 weeks of treatment. IIEF scores, as well, have improved with the treatment. That is, as expected, is statistically significant for the patients taking sildenafil as a treatment for PD. For Groups 1 and 2, IIEF scores were 9.78 ± 3.46 and 10.10 ± 3.77, respectively, and after the treatment, the scores were improved to 10.67 ± 3.27 and 13.90 ± 5.52, respectively, (p \ 0.05 for Group 2). Our study is the first clinical study to evaluate the antifibrotic effect of PD. However, our study has many limitations, such as small patient population, the study not being double blind. Duration of the study is short (12 weeks). Also, only acute-phase patients were included, so possible resolution of the disease may be expected for this cohort.
Conclusion As a result of this along with the two experimental studies mentioned above, our study of continuous PDE5 inhibitors
123
we conducted on early-stage PD patients shows that administration of continuous PDE5 inhibitors may be beneficial in PD patients—particularly in correcting erectile capacity and reducing pain. We included patients with ED component in our study because of our expectations of the effects on their erectile capacities, if not more. We conclude that continuous administration of oral PDE5 inhibitors may be a candidate for medical treatment of PD. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Taylor FL, Levine LA (2007) Peyronie’s disease. Urol Clin North Am 34:517–534 2. Gholami SS, Gonzalez-Cadavid NF, Lin CS et al (2003) Peyronie’s disease: a review. J Urol 169:1234–1241 3. Mu¨ller A, Mulhall JP (2009) Peyronie’s disease intervention trials: methodological challenges and issues. J Sex Med 6:848–861 4. Gonzalez-Cadavid NF, Rajfer J (2009) Experimental models of Peyronie’s disease. Implications for new therapies. J Sex Med 6:303–313 5. Gonzalez-Cadavid NF, Rajfer J (2010) Treatment of Peyronie’s disease with PDE5 inhibitors: an anti-fibrotic strategy. Nat Rev Urol 7:215–221 6. Rosen RC, Cappelleri JC, Smith MD et al (1999) Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 11:319–326 7. Sikka SC, Hellstrom WJ, Brock G, Morales AM (2013) Standardization of vascular assessment of erectile dysfunction: standard operating procedures for duplex ultrasound. J Sex Med 10:120–129 8. Kumar R, Nehra A (2009) Surgical and minimally invasive treatments for Peyronie’s disease. Curr Opin Urol 19:589–594 9. Hauck EW, Diemer T, Schmelz HU et al (2009) A critical analysis of nonsurgical treatment of Peyronie’s disease. Eur Urol 49:987–997 10. Hellstrom WJ (2009) Medical management of Peyronie’s disease. J Androl 30:397–405 11. Vanni AJ, Bennett NE (2009) Current treatment and management of the acute phase of Peyronie’s disease. Arch Esp Urol 62:614–622 12. Erdogru T, Savas M, Yilmaz N et al (2002) Evaluation of penile hemodynamic status and adjustment of treatment alternatives in Peyronie’s disease. Asian J Androl 4(1):87–90 13. Lopez JA, Jarow JP (1993) Penile vascular evaluation of men with Peyronie’s disease. J Urol 149:53–55 14. Deveci S, Palese M, Parker M et al (2006) Erectile function profiles in men with Peyronie’s disease. J Urol 175:1807–1811 15. Kadiog˘lu A, Tefekli A, Erol H et al (2000) Color Doppler ultrasound assessment of penile vascular system in men with Peyronie’s disease. Int J Impot Res 12:263–267 16. Weidner W, Schroeder-Printzen I, Weiske WH et al (1997) Sexual dysfunction in Peyronie’s disease: an analysis of 222 patients without previous local plaque therapy. J Urol 157:325–328 17. Levine LA, Latchamsetty KC (2002) Treatment of erectile dysfunction in patients with Peyronie’s disease using sildenafil citrate. Int J Impot Res 14:478–482
Ir J Med Sci 18. El-Sakka AI, Hassoba HM, Chui RM et al (1997) An animal model of Peyronie’s-like condition associated with an increase of transforming growth factor beta mRNA and protein expression. J Urol 158:2284–2290 19. Ferrini MG, Vernet D, Magee TR et al (2002) Anti-fibrotic role of inducible nitric oxide synthase. Nitric Oxide 6:283–294 20. Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200:500–503 21. Nagayama T, Zhang M, Hsu S et al (2008) Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. J Pharmacol Exp Ther 326:380–387
22. Yildirim A, Ersoy Y, Ercan F et al (2010) Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycininduced lung fibrosis. Pulm Pharmacol Ther 23:215–221 23. Vernet D, Ferrini MG, Valente EGA et al (2002) Effect of nitric oxide on fibroblast differentiation in to myofibroblasts in cell cultures from the Peyronie’s fibrotic plaque and in its rat model in vivo. Nitric Oxide 7(262):276 24. Gonzalez-Cadavid NF, Ignarro L, Rajfer J (1999) Nitric oxide and cyclic GMP in the penis. Mol Urol 3:51–59
123
