How to avoid the false diagnosis of venous leakage by pharmaco-penile duplex ultrasonography?

Abd Allah M. Attia; Hossam A Yasien; Mohamed S Abdullah; Mohamed S Abo Hola

doi:10.4103/1110-2098.218292

ORIGINAL ARTICLE

Year : 2017 | Volume : 30 | Issue : 3 | Page : 928-934

How to avoid the false diagnosis of venous leakage by pharmaco-penile duplex ultrasonography?

Abd Allah M. Attia, Hossam A Yasien, Mohamed S Abdullah, Mohamed S Abo Hola MSc
Department of Dermatology and Andrology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission	23-Sep-2016
Date of Acceptance	02-Dec-2016
Date of Web Publication	15-Nov-2017

Correspondence Address:
Mohamed S Abo Hola
Tala, Menoufia Egypt, 32611, Tala
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/1110-2098.218292

Abstract

Objectives
The aim of the present study to carefully reassess the erectile hemodynamic status in men previously diagnosed with venous leak on penile duplex ultrasonography (DUS) under the guidelines of the Australasian Society for Ultrasound in Medicine (ASUM).
Background
Erectile dysfunction (ED) is a widespread problem affecting men across all age groups (about 50% in 40–70-year age group) and disturbing the quality of life of sexually active men. Vascular insufficiency is one of the major causes of ED. DUS is a useful, minimally invasive method for evaluating penile hemodynamics in patients with ED, but has a propensity to inaccurately assign a diagnosis of venous leak.
Patients and methods
Fifty patients from 18 to 50 years olds selected from the Andrology Unit, Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Egypt were included in the study. All cases were subjected to the following: detailed history, thorough clinical examination, routine and hormonal investigations, and imaging studies including re-evaluation through DUS under the guidelines of ASUM.
Results
Overall, 50% of the patients previously diagnosed with venous leak were shown to be normal when re-evaluated under the guidelines of ASUM. The other 50% demonstrated a significant improvement in the value of end diastolic velocity (EDV). The study demonstrated a significant increase in the value of peak systolic velocity in repeated DUS with a mean difference of 10.29, and a significant decrease in the value of EDV with a mean difference of 4.19 compared with the original DUS. Our results indicated a significant negative correlation between age and value of peak systolic velocity, and an insignificant positive correlation between age and value of EDV for all participants, in both original and repeated DUS.
Conclusion
Careful assessment should be carried out when performing DUS, especially in younger men without a significant vascular risk factor in history for ED, to avoid misdiagnosis of venous leak.

Keywords: Australasian Society for Ultrasound in Medicine, duplex ultrasonography, erectile dysfunction

How to cite this article:
M. Attia AA, Yasien HA, Abdullah MS, Abo Hola MS. How to avoid the false diagnosis of venous leakage by pharmaco-penile duplex ultrasonography?. Menoufia Med J 2017;30:928-34

How to cite this URL:
M. Attia AA, Yasien HA, Abdullah MS, Abo Hola MS. How to avoid the false diagnosis of venous leakage by pharmaco-penile duplex ultrasonography?. Menoufia Med J [serial online] 2017 [cited 2023 Oct 3];30:928-34. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/928/218292

Introduction

Erectile dysfunction (ED) is defined as the inability to achieve or maintain a sufficient erection to engage in sexual intercourse ^[1].

Earlier, ED was included in the general-term impotence, with nonspecific meaning, which also referred to other disorders of male sexual function, such as orgasmic and ejaculatory dysfunction. ED is the more precise term, especially given the fact that sexual desire and the ability to have an orgasm and ejaculate may be intact despite the inability to achieve or maintain an erection ^[2].

Although ED is a benign disorder, it affects physical and psychosocial health and has a significant impact on the quality of life of sufferers and their partners and families. Approximately, 5–20% of men have moderate to severe ED ^[3].

Risk factors for ED include age, diabetes, hypertension, obesity, lack of exercise, dyslipidemia, smoking, depression, lower urinary tract symptoms, and pelvic surgery, some of which can be modified ^[4].

In accordance with the International Society of Impotence Research, ED may be classified into three subtypes: organic (that includes iatrogenic, neurogenic, vasculogenic, and hormonal), psychogenic, and mixed ED. Therefore, a thorough investigation ought to be performed by a multidisciplinary team to avoide misdiagnosis ^[5].

In the past, psychogenic cause was considered the most important etiological factor of ED; however, currently, organic factors account for 60–90% of this condition ^[6].

The neurologic system is intimately involved in proper erectile function. Peripheral, spinal, supraspinal, and somatic and autonomic pathways are integrated with erectile physiology. In men under 40, common neurologic etiologies of ED include multiple sclerosis, epilepsy, intramedullary nailing of femoral fractures, and lumbar spine procedures ^[7].

Endocrinopathies can potentially affect erectile function, most notably hypogonadism, hyperthyroidism, hypothyroidism, and diabetes. The patient's history can raise suspicion for such diagnoses; however, there is significant variability in presentation. To aid in the diagnosis, several screening surveys have been suggested and tested, particularly in the case of hypogonadism. Yet, lack of sensitivity and specificity has led to limited utility. Ultimately, endocrinopathies are evaluated and diagnosed with the use of serum hormonal levels ^[8].

Many medications used to treat systemic illnesses can lead to ED, including antipsychotic, antidepressant, and antihypertensive drugs. Risperidone, olanzapine, and serotonin re-uptake inhibitors have the highest likelihood of causing sexual dysfunction. Thiazides, spironolactone, and β-blockers can also cause ED, the latter through potentiation of α1-adrenergic activity in the penis. Statins have also been implicated. Clinicians should take a thorough sexual history before prescribing these drugs and be aware of their potential sexual side effects when treating ED ^[9].

Vascular insufficiency is one of the major causes of ED, and historically, vascular evaluation has had a significant role in the assessment of ED ^[10].

Vascular insufficiency can be divided into arterial insufficiency and venous leak (corporal veno-occlusive dysfunction). Before the evolution of penile duplex doppler ultrasound (DUS), cavernosometry existed and permitted the evaluation of the integrity of the cavernosal artery (CA) inflow as well as the veno-occlusive mechanism. The modern sexual medicine clinician is likely not to have been trained in cavernosometry, and given the less invasive nature of DUS, the latter has supplanted cavernosometry in the vast majority of centers including tertiary referral sexual medicine practices. Furthermore, it is suggested that DUS is less time consuming and requires less specialized equipment and facilities than does cavernosometry ^[11],[12].

Despite providing direct assessment of the arterial supply, through peak systolic velocity (PSV) quantification, DUS provides only an indirect measurement of the veno-occlusive mechanism, through end diastolic velocity (EDV). The accuracy of any vascular tests, but especially DUS, is dependent upon complete smooth muscle relaxation (SMR) ^[13].

Excessive sympathetic discharge has the potential to prevent complete SMR in response to the injected vasoactive agent, and a false diagnosis of arterial insufficiency and/or venous leak is possible ^[14].

Assignment of the diagnosis of venous leak is a serious consideration, as typically, these patients fare poorly with oral erectogenic pharmacotherapy and often require long-term intracavernosal injection therapy or penile implant surgery. This concern is amplified when the clinician is dealing with a young man with venous leak, as the interventions often required for such patients are often unpalatable to these young men ^[12].

Patients and Methods

The study was conducted on 50 male patients complaining of ED selected from the Andrology Unit, Dermatology and Andrology Department, Faculty of Medicine, Menoufia University, Egypt. Their ages ranged from 18 to 50 years.

The study was approved by the ethical committee of the hospital and the patients signed an informed consent. All patients were subjected to the following:

Full history:
1. Detailed sexual history regarding onset, course, duration, presence of erection at any time during the period of complaint; degree of firmness of erection; libido; ejaculation; orgasm; sexual habits; extramarital relations; and coital frequency.
2. Psychological history including depression, anxiety, and marital conflict.
3. Medical history including diabetes, drugs, prostatitis, and systemic diseases.
4. History of trauma and operations.
A thorough physical examination:
1. General examination including signs of systemic diseases and secondary sex characteristics.
2. Local genital examination on external genetalia for any abnormality.
Laboratory investigations:
1. Glycated hemoglobin (HbA1c) and prolactin were done for each patient and any patient with any abnormality was excluded from the study.
Imaging studies, which were carried out under the guidelines of Australasian Society for Ultrasound in Medicine (ASUM) ^[15].

Patients who matched these inclusion and exclusion criteria were subjected to re-evaluation through pharmaco-penile DUS as given below.

Examination

Pre-injection

A quiet, relaxed environment free of interruption was maintained before injection; a detailed explanation was provided to the participants, and also a verbal or written consent was obtained.

A high-frequency linear transducer was used to perform a B-mode/color Doppler examination of the penis. The corpus cavernosa, corpus spongiosum, and glans were evaluated.

The injection

DUS was conducted using a single injection of papaverine 30 mg/ml.

A single injection into the base of one of the cavernosa was generally sufficient.

Post-injection

Spectral Doppler waveforms were performed at 0, 2, 5, 10, 15, 20, and 25 min in the proximal one-third of each CA.

The PSV and EDV were recorded using a spectral angle ideally 60°.

Late erectile responses at 30–40 min were reported.

A local protocol was established to determine whether visual or manual stimulation should be used to augment the response.

The examination was curtailed when normal arterial and venous responses were obtained before 30 min.

The engorged penis provided another opportunity for the B-mode and color evaluation for plaques, fibrosis, and anatomical/structural change.

Diagnostic criteria

Awareness of the typical waveforms were seen in a normal and abnormal setting.

B-mode: anatomical asymmetry, fibrous septation, plaques/calcification, masses, and vascular malformation were described in detail.

Arterial: immediately after injection there was an increase in the size of the cavernosal arteries and the blood flow. Cavernosal arterial flow of more than 35 cm/s was widely recognized as being normal, whereas less than 25 cm/s was generally accepted as inadequate arterial supply.

Venous: with increasing intracavernosal pressure, there should be diminishing flow in diastolic. This indicated an appropriate venous response. Persistent significant end diastolic flow was typical in cases of venous leakage. Sustained EDV greater than 5–7 cm/s was an evidence of venous incompetence.

Inadequate arterial supply limited the amount of venogenic response and this decreased the sensitivity and specificity of using EDV to assess venogenic incompetence.

Diagnostic criteria were provided as guidelines.

After the examination

Adequate representative images of the examination were recorded.

The patients were given clear warning about the need to follow-up a persisting erection in the event of priapism.

Results

The results of this study are shown in [Table 1], [Table 2], [Table 3], [Table 4], [Table 5] and [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6].

Table 1: Distribution of the studied cases according to age (n=50)

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Table 2: Comparison between original and repeat duplex ultrasonography with guidelines according to peak systolic velocity (n=50)

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Table 3: Comparison between original and repeat duplex ultrasonography with guidelines according to end diastolic velocity (n=50)

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Table 4: Correlation between age and peak systolic velocity (cm/s) for the total sample

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Table 5: Correlation between age and end diastolic velocity (cm/s) for the total sample

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Figure 1: Distribution of the studied cases according to age (n = 50).

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Figure 2: Comparison between original and repeat duplex ultrasonography with guidelines according to peak systolic velocity (n = 50). DUS, duplex ultrasonography.

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Figure 3: Comparison between original and repeat duplex ultrasonography with guidelines according to end diastolic velocity (n = 50). DUS, duplex ultrasonography.

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Figure 4: Correlation between age and original duplex ultrasonography without guidelines for the total sample. DUS, duplex ultrasonography.

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Figure 5: Correlation between age and repeat duplex ultrasonography with guidelines for the total sample. DUS, duplex ultrasonography.

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Figure 6: (a) Original penile duplex ultrasonography showing peak systolic velocity (PSV) (28 cm/s) and end diastolic velocity (EDV) (10 cm/s). (b) Repeat penile duplex ultrasonography showing PSV (58.1 cm/s) and EDV (-8 cm/s).

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We studied 50 male patients complaining of ED, their ages ranging from 18 to 50 years (mean age: 29 years).

Demographic data of studied patients showed 29 cases between 20 and younger than 30 years (58.0%), 10 cases between 30 and younger than 40 years (20.0%), and 11 cases between more than or equal to 40 and 50 years (22.0%) of age [Table 1] and [Figure 1].

In this study we demonstrated a significant increase in the value of PSV in repeat DUS with guidelines with a mean difference of 10.29 (↑) compared with the original DUS [Table 2] and [Figure 2].

Furthermore, there was a significant decrease in the value of EDV in repeat DUS with guidelines with a mean difference of 4.19 (↓) compared with the original DUS [Table 3] and [Figure 3].

Our results indicated a significant negative correlation between age and PSV (cm/s) for the total sample in both original DUS (r=-0.335, P = 0.017) and repeat DUS (r =-0.357, P = 0.011) [Table 4] and [Figure 4].

Moreover, our results showed an insignificant positive correlation between age and EDV (cm/s) for the total sample in both original DUS (r = 0.253, P = 0.076) and repeat DUS (r = 0.247, P = 0.084) [Table 5] and [Figure 5]).

[Figure 6] shows comparison between both original and repeat DUS showing the difference in results of both PSV and EDV.

Discussion

The aim of this study was to carefully reassess and define the erectile hemodynamic status in men who had been assigned a previous diagnosis of venous leak on DUS by re-evaluation of DUS under the guidelines of ASUM ^[15].

The study included 50 male patients complaining of ED. Their ages ranged from 18 to 50 years old with a mean age of presentation of 32.70 ± 7.18 years. The commonest age of presentation was between 20 and younger than 30 years [29 (58.0%) cases], followed by 11 (22.0%) cases between at least 40 and 50 years of age, and 10 (20.0%) cases between 30 and younger than 40 years of age.

Overall, 50% of the patients previously diagnosed with venous leak were showed to be normal when re-evaluated under the guidelines of ASUM.

The other 50% demonstrated a significant improvement in the value of EDV. The study demonstrated a significant increase in the value of PSV in repeated DUS with a mean difference of 10.29, and a significant decrease in the value of EDV with a mean difference of 4.19 compared with the original DUS. Our results showed a significant negative correlation between age and value of PSV, and an insignificant positive correlation between age and value of EDV for all participants in both original and repeated DUS.

Our results were in agreement with Teloken et al. ^[12] who studied erectile hemodynamics in men previously diagnosed with venous leak on DUS. In total, 292 patients were included in their study. Mean ± SD age was 44 ± 26 years. On repeat DUS, 19% (56/292) had completely normal hemodynamics and 7% (20/292) had arterial insufficiency only without venous leak. DIC revealed normal hemodynamics in 13% (38/292), whereas in 58% (152/292) of patients, the venous leak diagnosis was confirmed. Overall, 47% (137/292) of patients who had been given a diagnosis of venous leak had completely normal hemodynamics, and in only 43% (126/292) the venous leak diagnosis was confirmed upon repeat vascular testing. In addition, on multivariable analysis, younger age (<45 years), failure to obtain an adequate erection during the original DUS and having more than two vascular risk factors were predictive of a false diagnosis of venous leak.

During our study, we observed that changing the site of measurement away from the curve of the CA affected the values of both PSV and EDV. This observation was in line with Pagano and Stahl ^[16] who conducted a study in the Department of Urology, Columbia University Medical Center, to determine the effects of the CA imaging location on measured penile hemodynamics assessed by PDDU. CA PSV and EDV were measured at three points: the origin of the CA within the penile crus, the proximal CA, and mid-CA. Totally, 104 CAs were imaged in 52 men. Mean PSVs at the crus, proximal, and mid-CA were 52.9 ± 20.2, 29.5 ± 15.1, and 21.6 ± 10.6 cm/s, respectively (P < 0.0001); mean EDVs were 2.1 ± 8.9, 3.2 ± 5.4 and 3.3 ± 3.5 cm/s, respectively (P = 0.1225). The distribution of arteriogenic (P < 0.0001) and venogenic (P < 0.0001) diagnoses both differed significantly by location. Significant differences in vasculogenic diagnoses were also observed in the subgroup of CAs with definite maximal SMR (n = 38, arteriogenic P < 0.0001, venogenic P = 0.007) and in those with valid-for-intromission erections (n = 68, arteriogenic P < 0.0001, venogenic P = 0.0002).

We used standard criteria for the diagnosis of arterial insufficiency and venous leak. Indeed, to date, no age-specific criteria for DUS exist. Which parameter cutoffs are used depends on where on the receiver operator characteristics curve we want to position the patient. This is to say, for example, that if we want to be extremely sensitive in diagnosing arterial insufficiency, we would choose 25 cm/s as cutoff, but if we wanted to be highly specific in our diagnosis, we would choose a cutoff of 35 cm/s.

In addition, Gontero et al. ^[17] showed that out of 13 men with an initial EDV more than 5 cm/s on DUS after the use of PGE1 injection, seven were found to have normal hemodynamics after the administration of phentolamine.

Timing of measurements during DUS is also important. Specifically, EDV should be measured after full rigidity has been achieved, because assessment during the tumescent phase will depict a high EDV, falsely suggesting venous leak ^[18]. Even though this aspect could explain some of the discrepancies found between the outside and the repeat DUS exams, we have no data on timing for the formers.

McMahon ^[19] compared penile DUS, DIC, and internal pudendal arteriography for the diagnosis of arterial insufficiency and venous leak in 168 patients. Overall, 145 patients were found to have arterial insufficiency on internal pudendal arteriography. A PSV of more than 30 cm/s was found to have 89% sensitivity and 78% specificity, whereas systemic cavernosal occlusion pressure gradients more than 30 mmHg had 94% sensitivity and 74% specificity for the diagnosis of arterial insufficiency when compared with internal pudendal arteriography. On DIC, 96 cases of venous leak were identified. Upon DUS, resistance indices less than 0.85 were used to define venous leak. Whereas resistance indices measured 5 min after PGE1 injection exhibited 100% sensitivity but only 7% specificity; the indices measured 15 min after injection showed 97% sensitivity and 94% specificity. This clearly shows that unless patients have DUS measurements taken during their maximal response, a significant number of false positives exist.

The repeat DUS, which was performed under guidelines of ASUM ^[15], reduced the false positive rate of venous leak. However, some patients were found to have the diagnosis of venous leak on the repeat DUS. This finding suggests that the positive predictive value of penile DUS for the diagnosis of venous leak is suboptimal.

There are two main possible explanations for the suboptimal diagnostic accuracy of DUS for the venous leak diagnosis. First, as EDV represents an indirect method to assess corporovenocclusive function, it may lack specificity in itself. Second, achieving a 'bedroom-quality' erections may not be sufficient to guarantee that complete SMR has occurred ^[20].

Regardless, an abnormal EDV on DUS may warrant prompting further investigation for diagnostic investigation. Assignment of the diagnosis of venous leak is a serious consideration, as typically, these patients fare poorly with oral erectogenic pharmacotherapy and often require long-term intracavernosal injection therapy or penile implant surgery. This concern is amplified when the clinician is dealing with the young man with venous leak as the interventions often required for such patients are often unpalatable to these young men.

An accurate assessment of erectile hemodynamics requires complete SMR, and the false diagnosis of vasculogenic ED is generally thought to be the result of excess sympathetic discharge. Defining when complete SMR exists is a challenge for the clinician.

As most patients with ED can be managed within the primary care setting, the utility of specific diagnostic tests such as DUS is recommended for few selective cases (e.g. patients with post-traumatic ED or Peyronie's disease) ^[21].

Many urologists continue to perform DUS with nonstandardized techniques in patients for whom it is not critical, despite aforementioned guidelines. Considering the invariable anxiety while undergoing DUS, these patients, most of whom were healthy 'young males' with probable psychogenic ED, should have been evaluated in a supportive environment to reduce negative psychological factors, and also audiovisual stimulation should have been provided.

Conclusion

The findings of the present study illustrate that great care must be taken in conducting penile duplex doppler ultrasonography and that assignment of a false diagnosis of venous leak is not uncommon. Repeat hemodynamic assessment in select men, especially young men, given a diagnosis of venous leak, may be warranted.

The repeat DUS, which was performed under the guidelines of ASUM, reduced the false positive rate of venous leak.

Changing the site of measurement away from the curve of the CA affected the values of both PSV and EDV. Therefore, we recommend that measurement should be done the proximal one-third of each CA as illustrated by the guidelines of ASUM.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Papagiannopoulos D, Khare N, Nehra A. Evaluation of young men with organic erectile dysfunction. Asian J Androl 2015; 17:11–16.
2.	Papadopoulou E, Varouktsi A, Lazaridis A, Boutari C, Doumas M. Erectile dysfunction in chronic kidney disease: from pathophysiology to management. World J Nephrol 2015; 4:379–387.
3.	Gupta BP, Murad MH, Clifton MM, Prokop L, Nehra A, Kopecky SL. The effect of lifestyle modification and cardiovascular risk factor reduction on erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2011; 171:1797–803.
4.	Lee JC, Bénard F, Carrier S, Talwar V, Defoy I. Do men with mild erectile dysfunction have the same risk factors as the general erectile dysfunction clinical trial population? BJU Int 2011; 107:956–960.
5.	Kavoussi L, Novick A, Partin A, Peters C, Wein A, editors. Campbell-walsh urology. ISBN 13-978-8089-2353-4. Philadelphia: Saunders Elsevier; 2007.
6.	Persu C, Cauni V, Gutue S, Albu ES, Jinga V, Geavlete P. Diagnosis and treatment of erectile dysfunction – a pratical update. J Med Life 2009; 2:394–400.
7.	Ludwig W, Phillips M. Organic causes of erectile dysfunction in men under 40. Urol Int 2014; 92:1–6.
8.	El wahed MA, EL Shafi MK, Aminelareef SI. Testosterone in type II diabetic men. Menouf Med J 2014; 27:758–761.
9.	Meller SM, Stilp E, Walker CN, Mena-Hurtado C. The link between vasculogenic erectile dysfunction, coronary artery disease, and peripheral artery disease. Role of metabolic factors and endovascular therapy. J Invasive Cardiol 2013; 25:313–319.
10.	Altinkilic B, Hauck EW, Weidner W. Evaluation of penile perfusion by color-coded duplex sonography in the management of erectile dysfunction. World J Urol 2004; 22:361–364.
11.	Ghanem H, Shamloul R. An evidence-based perspective to commonly performed erectile dysfunction investigations. J Sex Med 2008; 5:1582–1589.
12.	Teloken PE, Park K, Parker M, Guhring P, Narus J. Mulhall JP. The false diagnosis of venous leak: prevalence and predictors. J Sex Med 2011; 8:2344–2349.
13.	Aversa A, Sarteschi LM. The role of penile color-duplex ultrasound for the evaluation of erectile dysfunction. J Sex Med 2007; 4:1437–1447.
14.	Aversa A, Rocchietti-March M, Caprio M, Giannini D, Isidori A, Fabbri A. Anxiety-induced failure in erectile response to intracorporeal prostaglandin-E1 in non-organic male impotence: a new diagnostic approach. Int J Androl 1996; 19:307–313.
15.	Halls J, Bydawell G, Patel U. Erectile dysfunction: the role of penile Doppler ultrasound in diagnosis. Abdom Imaging 2009; 34:712–725.
16.	Pagano MJ, Stahl PJ. Variation in penile hemodynamics by anatomic location of cavernosal artery imaging in penile duplex doppler ultrasound. J Sex Med 2015; 12:1911–1919.
17.	Gontero P, Sriprasad S, Wilkins CJ, Donaldson N, Muir GH, Sidhu PS. Phentolamine re-dosing during penile dynamic colour Doppler ultrasound: a practical method to abolish a false diagnosis of venous leakage in patients with erectile dysfunction. Br J Radiol 2004; 77:922–926.
18.	Mueller SC, Lue TF. Evaluation of vasculogenic impotence. Urol Clin North Am 1988; 15:65–76.
19.	McMahon CG. Comparison of the response to the intracavernosal injection of a combination of papaverine and phentolamine, prostaglandin El alone and a combination of all three in the management of impotence. Int J Impotence Res 1991; 3:133–142.
20.	Vardi Y, Glina S, Mulhall JP, Menchini F, Munarriz R. Cavernosometry: is it a dinosaur? J Sex Med 2008; 5:760–764.
21.	Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010; 57:804–814.