International Journal of Impotence Research (2012) 24, 191 -- 195 & 2012 Macmillan Publishers Limited All rights reserved 0955-9930/12 www.nature.com/ijir
ORIGINAL ARTICLE Pharmaco-induced erections for penile color-duplex ultrasound: oral PDE5 inhibitors or intracavernosal injection?
Y Yang1,2, J-l Hu1,2,4,YMa1,2, H-x Wang1,2, Z Chen3, J-g Xia3, Y-x Wang1,2, Y-r Huang1,2 and B Chen1,2
To prospectively compare the clinical responses and penile color-duplex ultrasound (PCDU) results of oral PDE5 inhibitors (PDE5-Is) with papaverine intracavernosal injection (ICI) and to evaluate whether PDE5-Is could be used as alternatives to vasoactive agent injections, 25 ED patients underwent PCDU three times with an interval of at least 1 week, using different pharmacological induction: ICI mode (30--60 mg papaverine), sildenafil mode (100 mg sildenafil) and tadalafil mode (20 mg tadalafil). The preference of the patients was collected when all tests were completed. No significant differences were found in peak systolic velocity and acceleration time among all three modes. However for the ICI mode, end diastolic velocity of the right cavernosal artery was significantly higher than those of the sildenafil and tadalafil modes 5 min after erection induction, and at 15 min it became lower than those of two PDE5-I modes. Consequently, resistance index of the right cavernosal artery in ICI mode was reversed at 5 and 15 min. In all, 60.0 and 56.0% patients managed to reach full erection in PDE5-Is modes, which was significantly lower than in ICI mode (80.0%). Therefore, although PDE5-Is and papaverine ICI showed similar effects on PCDU parameters in detecting arterial ED, more patients had better clinical responses to ICI, and oral PDE5-Is administration still showed some pitfalls in practical use.
International Journal of Impotence Research (2012) 24, 191--195; doi:10.1038/ijir.2012.15; published online 17 May 2012 Keywords: erectile dysfunction; penile color-duplex ultrasound; sildenafil; tadalafil; intracavernosal injection
INTRODUCTION Therefore, the purpose of our study was to prospectively ED has been defined as the persistent inability to attain and evaluate and compare the clinical responses and PCDU results of maintain an erection sufficient to permit satisfactory sexual oral administration of sildenafil (100 mg) and tadalafil (20 mg) with performance.1 It has been suggested that ED may be considered papaverine ICI and to evaluate whether these PDE5-Is could be as a clinical manifestation of a generalized vascular disease used as alternatives to vasoactive agent injections. Also, the also affecting the penile arteries.2 Among all the etiological differences between these two PDE5-Is were elaborated. factors, it was reported that around 30--50% of ED cases are vasculogenic in origin.3,4 Intracavernosal injection (ICI) of vasoac- tive agents plus penile color-duplex ultrasound (PCDU) have been regarded as the most reliable and least invasive evidence-based PATIENTS AND METHODS assessment of ED5 since Lue introduced this method in 1985.6 Patients Although ICI is an important method for assessing penile A total of 25 consecutive patients (age range from 27 to 61 years old, mean hemodynamics, patients’ fear of injection often produces a 37.3±10.1) were randomly selected from our andrological outpatient heightened sympathetic response, which inhibits the response department. All the patients enrolled were naive about both the PDE5-I and of the cavernous smooth muscle to intracavernous agents. This the ICI approach. All the patients had at least a 3-month history of ED and may produce a false-positive result.7 In addition, erection were excluded from the study if their International Index of Erectile induction with vasoactive agents results in several complications, Function-5 (IIEF-5) scores were 421 or if they had any ICI and PDE5-I from the common (pain, ecchymosis and penile hematoma) to the contraindications such as poor cardiac performance, severe ischemia, most serious (priapism) in up to 7% of cases.5 On the other hand, coagulation defects, recent myocardial infarction and nitrates or nitric oxide PDE5 inhibitors (PDE5-Is), including sildenafil, tadalafil and donors taken in any form either regularly or intermittently. The patients vardenafil, have become the first-line drug therapies for the underwent complete diagnostic evaluations, including detailed medical treatment of ED.8 As PDE5-Is are safe, noninvasive and effective in and sexual history, physical examination, biochemical (fasting glucose, 70--80% cases of ED from various causes, there have been studies serum cholesterol, triglycerides, low- and high-density lipoprotein) and concerning the application of PDE-Is in PCDU tests, more hormonal testings (prolactin and total testosterone). Psychological tests specifically, using PDE5-Is as alternatives to vasoactive agent (self-rating anxiety scale (SAS) and self-rating depression scale (SDS)) injections. However, the results remain controversial.9,10 Moreover, and nocturnal penile tumescence assessment were also performed to studies have focused on sildenafil11 and vardenafil.12 determine the psychological status of patients and etiology of ED. The
1Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, 2Shanghai Institute of Andrology, Shanghai Jiaotong University School of Medicine, Shanghai, China and 3Department of Ultrasonography, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Correspondence: Professor B Chen, Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine. 7th Floor, No. 1 building, No. 145, Middle Shandong Road, Shanghai 200001, China. E-mail: [email protected] 4Current address: Department of Anaesthesiology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Received 27 May 2011; revised 24 February 2012; accepted 10 April 2012; published online 17 May 2012 For penile color-duplex ultrasound: oral PDE5 inhibitor or ICI? Y Yang et al 192 Institutional Review Board of Renji hospital approved the study, and written Table 1. Characteristics of participants informed consents were obtained from all the study patients. Age (years) 37.3±10.1 Under 30 24% (6/25) Erection induction and ultrasonography 30--50 60% (15/25) Above 50 16% (4/25) A MyLab 90 Doppler ultrasound diagnostic apparatus (Esaote, Genoa, Italy) and a 10-MHz linear array transducer were used for obtaining real-time Morbidities (%) images of the corpora cavernosa and for visualization and Doppler Hypertension 12% (3/25) calculations of the blood flow in the cavernous arteries. Patients were Diabetes mellitus 16% (4/25) examined in a quiet, dim room in supine position, with the penis slightly Current smokers 32% (8/25) stretched to the abdomen. The transducer was placed on the ventral Cardiovascular diseases 0% (0/25) penile surface and the cavernous arteries were examined at the Genital malformation 0% (0/25) penoscrotal junction. The Doppler angle was maintained at 601.Peak Low testicular volume 0% (0/25) systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI) IIEF-5 score 10.0±4.1 and acceleration time (AT) of bilateral cavernous arteries were recorded. SAS-scaled score 40.8±10.2 Clinical responses of pharmaco-induced erections were also assessed Anxiety 24.0% (6/25) and recorded. SDS-scaled score 0.45±0.12 All the patients underwent clinical response and PCDU tests before and Depression 28.0% (7/25) after three modes of pharmacologic stimulus, which are described in detail Total testosterone (ng mlÀ1) 4.81±1.72 as follows: Hypogonadism 8.0% (2/25) À1 ICI mode: Patients underwent an ICI treatment with papaverine Fasting glucose (mmol l ) 5.86±1.71 30--60 mg. An audiovisual sexual stimulus (AVSS) was given to promote Glycemia 28.0% (7/25) À1 ± penile erection as soon as the injection was given. Total cholesterol (mmol l ) 4.79 0.88 Triglycerides (mmol lÀ1) 1.41±0.72 Sildenafil mode: Patients were asked to take sildenafil 100 mg 1 h before 1 HDL (mmol lÀ ) 1.42±0.30 PCDU. An AVSS was given 15 min before the test, accompanied by self- LDL (mmol lÀ1) 2.97±0.71 genital stimulation. Hyperlipoidemia 44.0% (11/25) Tadalafil mode: Patients were asked to take tadalafil 20 mg 2 h before PCDU. Also, an AVSS and self-genital stimulation were performed 15 min Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; before the test. SAS, self-rating anxiety scale; SDS, self-rating depression scale. Data are expressed as mean±s.d. Hyperlipoidemia refers to total PCDU tests were performed at 5 and 15 min after the injection (ICI cholesterol, triglycerides or LDL higher than normal value. Hypogonadism mode) or AVSS (sildenafil and tadalafil modes). refers to serum total testosterone lower than normal value. Anxiety refers to Every patient underwent these three different modes with a washout SAS-scaled score over 50 and depression refers to SDS-scaled score over 0.5. period of at least 1 week between each mode. The sequence of the modes was determined by a random number table generated by a Visual Basic program (version 8.0, Microsoft, Redmond, WA, USA). Upon completion, patients were asked to fill in a self-made questionnaire about their Table 2. PCDU parameters measured 5 min after erection induction preferences of these modes. The questionnaire contained the following with three modes single-choice questions and options: (1) Which mode do you like the best before the ultrasound test? (a) Blue pills only; (b) Injection only; (c) Yellow ICI mode Sildenafil mode Tadalafil mode pills only. (2) The reasons why you choose this mode are: (a) Adequate hardness; (b) Painless; (c) Quick response; (d) Naturalness; (e) Others PSV (cm sÀ1) specify here. Right side 48.5±16.0 50.5±14.2 47.0±18.0 All the PCDU tests were done by the same experienced sonographer, Left side 43.8±12.4 48.3±14.3 44.1±13.9 and the same experienced urologist performed all ICIs and clinical EDV (cm sÀ1) assessments. Right side À2.8±5.5* À4.4±3.1 À4.4±3.1 Left side À1.3±4.3 À4.4±3.5 À3.7±2.3 RI Main outcome measures Right side 1.04±0.11* 1.09±0.07 1.09±0.07 The PCDU criteria for defining a normal erection response included either Left side 1.03±0.11 1.10±0.08 1.09±0.04 À1 À1 6 À1 cavernosal artery PSV X25 cm s or an EDV of o5cms . PSV o25 cm s AT as well as EDV 45cmsÀ1 (or/and RI o0.8) were considered as arterial inflow Right side 59.8±12.2 52.7±13.2 55.1±13.2 insufficiency; EDV 45cmsÀ1 (or with RI o0.8) were considered as veno- Left side 57.0±12.5 54.2±12.1 50.2±17.4 occlusive dysfunction. Clinical responses were assessed using the erection 13 Abbreviations: AT, acceleration time; EDV, end diastolic velocity; PSV, peak hardness score. Response options for erections on erection hardness score systolic velocity; RI, resistance index. were as follows: (1) increase in size but not hard, (2) hard but not hard *Po0.05. enough for penetration, (3) hard enough for penetration (but not completely hard) and (4) completely hard. RESULTS In all the 25 patients, nocturnal penile tumescence assessment Statistical analysis showed normal results in 8 (32.0%) and abnormal result in 17 Data were expressed as mean±s.d. when normally distributed, and as (68.0%), suggesting psychogenic and organic ED, respectively. The median (quartiles) for parameters with non-normal distribution, unless characteristics of the sample are summarized in Table 1. One otherwise specified. Comparison of the PCDU parameters and clinical patient (4.0%) was diagnosed with arterial inflow insufficiency and responses among the three modes was performed by using the one-way one patient (4.0%) showed evident signs of veno-occlusive analysis of variance and Chi-square test, respectively. Differences were dysfunction. All the remaining 23 patients showed normal considered significant when the P-value was o0.05. Statistical analysis hemodynamics, comprising 92.0%. was performed with SAS statistical software (version 8.0, SAS Institute, Cary, Table 2 shows the PCDU results measured 5 min after erection NC, USA). induction with each of the three modes. EDV of the right cavernosal
International Journal of Impotence Research (2012), 191 -- 195 & 2012 Macmillan Publishers Limited For penile color-duplex ultrasound: oral PDE5 inhibitor or ICI? Y Yang et al 193 Table 3. PCDU parameters measured 15 min after erection induction Table 4. Complications due to papaverine, sildenafil and tadalafil with three modes administration
ICI mode Sildenafil mode Tadalafil mode No. of ICI No. of sildenafil No. of tadalafil Complications modes (%) modes (%) modes (%) PSV (cm sÀ1) Right side 39.4±19.3 31.5±18.1 24.7±14.8 Priapism 2 (8.0) 0 0 Left side 38.0±14.9 29.4±16.3 24.3±11.9 Pain 19 (76.0) 0 0 EDV (cm sÀ1) Urethrorrhagia 1 (4.0) 0 0 Right side À2.3±4.5* À1.3±2.5 À0.1±2.6 Dizziness 0 3 (12.0) 4 (16.0) Left side À1.8±4.0 À1.5±3.2 À1.3±2.6 Flushing 0 3 (12.0) 2 (8.0) Muscle 0 1 (4.0) 1 (4.0) RI soreness Right side 1.04±0.15* 1.04±0.07 0.99±0.09 Left side 1.03±0.11 1.06±0.10 1.04±0.01 AT Right side 57.6±15.5 47.8±14.0 53.2±15.2 DISCUSSION Left side 57.0±10.2 50.6±16.3 47.5±16.9 ICI combined with PCDU provides reliable and detailed informa- Abbreviations: AT, acceleration time; EDV, end diastolic velocity; PSV, peak tion on penile hemodynamics and vascular anatomy and is recommended as a first-line test to evaluate penile arterial and systolic velocity; RI, resistance index. 14,15 *Po0.05. veno-occlusive function. Although most patients with ED can be managed within the primary care setting, some circumstances, such as failure of initial treatment, Peyronie’s disease, primary ED artery measured in ICI mode was significantly higher than that of and history of pelvic/perineal trauma, require specific diagnostic sildenafil and tadalafil modes (Po0.05 for both modes). Conse- testings including PCDU. Intracavernous vasodilators and the quently, RI of the right cavernosal artery measured in ICI mode was invasive nature of ICI, however, are known to cause several significantly lower than that of the sildenafil and tadalafil mode complications, from common (pain, ecchymosis and penile (Po0.05 for both modes). No significant differences were observed hematoma) to the most serious (priapism) in up to 7% of cases. in PSV and AT among the three modes in both sides, nor were they In our study, most patients (76.0%) complained of moderate to found in EDV and RI of the left cavernosal artery. severe pain and 8.0% had priapism during the ICI mode. Moreover, Table 3 shows the PCDU results measured 15 min after erection fears of injections may have caused further anxiety and stress. The induction with the three modes. The EDV of the right cavernosal increased sympathetic stimulation may result in a false-positive artery measured in ICI mode was significantly lower than that of response to pharmacological stimulation and subsequent PCDU 16 the sildenafil and tadalafil mode (Po0.05 for both modes). results. Shamloul in his study showed that the PSV may be falsely Consequently, RI of the right cavernosal artery measured in ICI lowered in young ED patients after the first ICI treatment. It was mode was significantly higher than those of the sildenafil and suggested that a repetition of ICI plus a PCDU test should be 17 tadalafil modes (Po0.05 for both modes). No significant performed to avoid the influence of these physiological factors. differences were observed in PSV and AT among the three modes However, it was rarely accepted by the patients in clinics. in both neither sides, nor were any found in EDV and RI of the left Therefore, we tried to investigate the potential of oral sildenafil cavernosal artery. and tadalafil administration, which has been proven with high Clinical response assessment using erection hardness score effectiveness in promoting erectile responses across a wide showed that 20 patients (80.0%) achieved a full erection (grade 4) spectrum of severity and causes of ED, as the alternative solutions in the ICI mode, whereas in the sildenafil and tadalafil modes, the for ICI. Indeed, PDE5-Is differ from papaverine both in molecular rates of full erection induction were 15 (60.0%) and 14 (56.0%), structures and mechanism of action. Papaverine increases the respectively. Therefore, the clinical responses to papaverine were production of cyclic adenosine monophosphate and cyclic significantly better than those to oral sildenafil and tadalafil guanosine monophosphate by an inhibitory action on PDE, administration (Po0.05). although papaverine acts at many levels, leading to a very Table 4 shows the adverse effects secondary to the study drugs. complex mode of action in the smooth muscle.18 On the other No significant side effect was observed after oral administration of hand, PDE5-Is maintain an erection by inhibiting the catabolism of sildenafil and tadalafil. However, two patients (8.0%) in ICI mode cyclic guanosine monophosphate, resulting in increased cyclic required pharmacological detumescence by ICIs due to priapism guanosine monophosphate. So, the activation of the nitric oxide-- and 76.0% complained of pain. Also, we have to mention that cyclic guanosine monophosphate pathway by sexual stimulation eight patients (32.0%) had a prolonged erection in ICI mode that is required. Thus, in the absence of sexual stimulation in humans, lasted 2--3 h after the injection but detumesce without pharma- PDE5-Is has little effect on cavernosal smooth muscle relaxation cological treatments. and does not cause a rigid penile erection.19 Therefore, we Concerning patients’ preferences of these modes, 12 patients employed an AVSS in our study to facilitate PDE5-Is and make the (48.0%) preferred the sildenafil mode and 11 patients (44.0%) effects of papaverine and PDE5-Is comparable. preferred the tadalafil mode, which was significantly higher than For PSV, the major parameter for diagnosing arterial ED, no the ICI mode (2/25, 8.0%). As to their mode preference choices, significant difference was observed among the three modes in patients who liked the sildenafil mode or the tadalafil mode both 5 and 15 min after erection induction. These results indicated mainly reported enough hardness (25% and 18.2%, respectively), that although PCDU with papaverine ICI was accepted as the gold painless (50% and 45.5%, respectively) and naturalness (25% and standard, PCDU facilitated with sildenafil or tadalafil could provide 36.4%, respectively), whereas patients who liked the ICI mode similar effects in detecting potential arterial ED. chose enough hardness (50%) and quick response (50%). No other Secondly, from the aspect of AT, no significant difference was reasons were specified. observed among the three modes in both 5 and 15 min after Concerning the comparison between sildenafil and tadalafil, no erection induction. ATs of penile arteries have been proposed as significant differences were found in any of the PCDU parameters. an indicator for arterial ED recently. Speel et al.20 showed a In the clinical response and patients’ preferences, no statistical thickened intima media of cavernosal arteries when AT reached differences were observed. X100 ms, which could cause further atherosclerotic ED. Sensitivity
& 2012 Macmillan Publishers Limited International Journal of Impotence Research (2012), 191 -- 195 For penile color-duplex ultrasound: oral PDE5 inhibitor or ICI? Y Yang et al 194 and specificity were 66% and 71%, respectively. Therefore, our and phentolamine) than to sildenafil, and the clinical response results suggested that oral sildenafil and tadalafil could bring was significantly better. Moreover, these studies focused on equal presentation of this parameter with a papaverine injection. sildenafil and vardenafil. We hope our research could bring some Although these two parameters were not found to be clues for tadalafil and the comparison between PDE5-Is with statistically different, we found that EDV of the right cavernosal dissimilar structures (as sildenafil and vardenafil have different artery measured during the ICI mode was significantly higher than structures than tadalafil). that of the sildenafil and tadalafil modes 5 min after erection Still, we have to clarify our concerns for the placebo arm. ICI induction, and at 15 min it became lower than those of two PDE5-I plus PCDU has been recommended as the first-line test to mode. Consequently, RI of the right cavernosal artery measured in evaluate penile arterial and veno-occlusive function,15 therefore, the ICI mode changed reversely at 5 and 15 min. These results the necessity of performing a ‘sham injection’ was low. Sildenafil indicated that PDE5-Is brought a quicker but shorter continuance and tadalafil were also used to test their effects compared with ICI, of erectile response than papaverine ICI. Also, it has been which was the main target of our study. Nevertheless, we also suggested that measurement of PSV for up to 30 min after ICI believe it would be more valuable if a placebo were added to could improve the diagnostic value of the test.21 Therefore, if control the effect of PDE5-Is. PDE5-Is were to be used as alternatives for papaverine ICI, their Also, our PCDU results showed only 8% patients with abnormal characteristic of erection induction should be considered to avoid hemodynamics, and nocturnal penile tumescence test showed potential false-positive results. 68% abnormalities. The reason behind this might be because of PDE5-Is and papaverine ICI showed comparable results in the the comorbidities (diabetes mellitus, glycemia, hypogonadism and PCDU parameters, but from the respect of clinical response, only aging) with enrolled patient (for detailed figures see Table 1). 60.0% and 56.0% of patients managed to reach full erection Indeed, we have to admit that a more detailed examination (grade 4) in the sildenafil and tadalafil mode, respectively, which regarding neural and testicular function could give a better was significantly lower than in the ICI mode (80.0%). In early explanation. However, the vascular status has always been our studies, the association between erection hardness and PSV has main concern, and also the main idea of this study. been demonstrated.9 Most patients with erection hardness Potential limits of our study are that comparisons were among over grade 3 showed normal PSV, and an insufficient erection the clinical responses and PCDU results of three different modes would result in falsely lowered PSV. Therefore, oral PDE5-Is failed and no adjustments were made for multiple comparisons. There to bring sufficient clinical response and, thus, may lead to false- could be potential shortcomings for false positives. Also, the positive results. sample number of participants was relatively small, which restricted Besides, oral PDE5-Is administration still showed some pitfalls in further analysis on different age groups and comorbidities. practical use. It was time-consuming and highly dependent on environment, and some patients could not reach sufficient erection with the help of PDE5-Is, but managed to obtain a full CONCLUSIONS erection in the ICI mode. In total, four patients showed this In conclusion, PDE5-Is brought a quicker but shorter-lived erectile phenomenon. We found some possible explanations after in- response than papaverine ICI. Although PDE5-Is and papaverine depth communication with these patients: two patients stated ICI showed similar effects on the PCDU parameters in detecting that they were fond of watching erotic films in their spare time arterial ED, more patients had better clinical responses to ICI, and and, therefore, did not feel enough sexual stimulation from the oral PDE5-Is administration still showed some pitfalls in practical AVSS. Another possible reason was the nervousness and anxiety in use. Therefore, oral administration of sildenafil and tadalafil should an unfamiliar environment. Two patients reached an adequately still not be used to replace vasodilators injection in PCDU, hard erection but became flaccid within 30 s and, therefore, failed although with fewer adverse effects and preferred by more the PCDU tests. But they all reported successful erections later patients. Moreover, if PDE5-Is were to be used as alternatives for after they went back home, suggesting that psychological factors papaverine ICI, their characteristic of erection induction should be may have a greater impact during the PDE5-Is mode. considered to avoid potential false-positive results. Lastly, as to adverse effects, most patients (76.0%) complained about moderate to severe pain and 8.0% had priapism during the ICI mode. Moreover, as mentioned before, significantly more patients had a prolonged erection during the ICI mode that lasted CONFLICT OF INTEREST 2--3 h after injection but detumesce without pharmacological The authors declare no conflict of interest. treatments. Although this kind of ‘prolonged erection’ would not cause acidosis or damage to endothelium, unnaturalness and embarrassment were reported when patients returned to work or ACKNOWLEDGEMENTS even walking. That was also the reason why more patients This study was sponsored by a grant from the key scientific and technological project preferred the mixed mode to the ICI mode. of Science and Technology Commission of Shanghai Municipality (08411951700), During the past few years, there have been some studies China. We are thankful to Professor Fenghua Li, Head of the Department of concerning the application of PDE-Is in PCDU tests, but the results Ultrasonography, Renji Hospital, for providing guidance and ultrasonic instruments remain controversial. Arslan et al.10 suggested that 50 mg sildenafil for our study. administration achieved increased PSV comparably to those after intracavernous papaverine injections, and the sensitivity and selectivity for demonstrating arterial insufficiency were 90% and REFERENCES 100%, respectively. Ardicoglu et al.12 also supported the idea that 1 Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F et al. 10 mg vardenafil plus genital and AVSS could be used as a safer Guidelines on male sexual dysfunction: erectile dysfunction and premature alternative compared with more invasive ICI. However, there were ejaculation. Eur Urol 2010; 57: 804--814. also studies that showed different opinions. The study by Erdogru 2 Vlachopoulos C, Rokkas K, Ioakeimidis N, Aggeli C, Michaelides A, Roussakis G et al.11 indicated that sildenafil citrate plus visual sexual et al. 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& 2012 Macmillan Publishers Limited International Journal of Impotence Research (2012), 191 -- 195