Tulburarile de Dinamica Sexuala - EAU Guidelines

EAU Guidelines on
Erectile Dysfunction,
Premature Ejaculation,
Penile Curvature and
Priapism
K. Hatzimouratidis (Chair), F. Giuliano, I. Moncada,
A. Muneer, A. Salonia (Vice-chair), P. Verze
Guideline Associates: A. Parnham, E.C. Serefoglu
© European Association of Urology 2018
16 Male Sexual Dysfunction_2018_print.indd 1 22-02-18 15:57

TABLE OF CONTENTS PAGE
1. INTRODUCTION 6
1.1 Aim 6
1.2 Publication history 6
1.3 Available Publications 6
1.4 Panel composition 6
2. METHODS 7
2.1 Introduction 7
2.2 Review 7
2.3 Future goals 7
3. MALE SEXUAL DYSFUNCTION 7

3.1 Erectile dysfunction 7
3.1.1 Epidemiology/aetiology/pathophysiology 7
3.1.1.1 Epidemiology 8
3.1.1.2 Risk factors 8
3.1.1.3 Pathophysiology 8
3.1.1.3.1 Post-radical prostatectomy ED, post-radiotherapy
ED & post-brachytherapy ED 9
3.1.1.3.2 Summary of evidence on the epidemiology/aetiology/
pathophysiology of ED 10
3.1.2 Classification 10
3.1.3 Diagnostic evaluation 10
3.1.3.1 Basic work-up 10
3.1.3.1.1 Sexual history 10
3.1.3.1.2 Physical examination 11
3.1.3.1.3 Laboratory testing 11
3.1.3.1.4 Cardiovascular system and sexual activity: the patient
at risk 12
3.1.3.1.4.1 Low-risk category 14
3.1.3.1.4.2 Intermediate- or indeterminate-risk
category 14
3.1.3.1.4.3 High-risk category 14
3.1.3.2 Specialised diagnostic tests 14
3.1.3.2.1 Nocturnal penile tumescence and rigidity test 14
3.1.3.2.2 Intracavernous injection test 14
3.1.3.2.3 Duplex ultrasound of the penis 14
3.1.3.2.4 Arteriography and dynamic infusion cavernosometry
or cavernosography 14
3.1.3.2.5 Psychiatric assessment 14
3.1.3.2.6 Penile abnormalities 14
3.1.3.3 Patient education - consultation and referrals 14
3.1.3.4 Recommendations for the diagnostic evaluation of ED 15
3.1.4 Disease management 15
3.1.4.1 Treatment options 15
3.1.4.1.1 Lifestyle management of ED with concomitant risk
factors 16
3.1.4.1.2 Erectile dysfunction after radical prostatectomy 16
3.1.4.1.3 Causes of ED that can be treated with a curative intent 18
3.1.4.1.3.1 Hormonal causes 18
3.1.4.1.3.2 Post-traumatic arteriogenic ED in young
patients 18
3.1.4.1.3.3 Psychosexual counselling and therapy 18
3.1.4.2 Therapeutic Strategy 18
3.1.4.2.1 First-line therapy 18
3.1.4.2.1.1 Oral pharmacotherapy 18
3.1.4.2.1.2 Vacuum erection devices 22
3.1.4.2.1.3 Topical/Intraurethral Alprostadil 23
2 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

3.1.4.2.1.4 Shockwave therapy 23
3.1.4.2.2 Second-line therapy 23
3.1.4.2.2.1 Intracavernous injections 23
3.1.4.2.2.1.1 Alprostadil 23
3.1.4.2.2.1.2 Combination therapy 24
3.1.4.2.3 Third-line therapy (penile prostheses) 24
3.1.4.2.3.1 Complications 25
3.1.4.2.3.2 Conclusions third-line therapy 25
3.1.4.3 Recommendations for the treatment of ED 25
3.1.4.4 Follow-up 26
3.2 Premature ejaculation 26
3.2.1 Epidemiology/aetiology/pathophysiology 26
3.2.1.1 Epidemiology 26
3.2.1.2 Pathophysiology and risk factors 26
3.2.1.3 Impact of PE on QoL 26
3.2.2 Classification 27
3.2.3 Diagnostic evaluation 27
3.2.3.1 Intravaginal ejaculatory latency time 28
3.2.3.2 PE assessment questionnaires 28
3.2.3.3 Physical examination and investigations 28
3.2.3.4 Recommendations for the diagnostic evaluation of PE 28
3.2.4 Disease management 29
3.2.4.1 Psychological/behavioural strategies 29
3.2.4.2 Pharmacotherapy 29
3.2.4.2.1 Dapoxetine 29
3.2.4.2.2 Off-label use of antidepressants: SSRIs and
clomipramine 30
3.2.4.2.3 Topical anaesthetic agents 31
3.2.4.2.3.1 Lidocaine-prilocaine cream 31
3.2.4.2.4 Tramadol 31
3.2.4.2.5 Phosphodiesterase type 5 inhibitors 32
3.2.4.2.6 Other drugs 32
3.2.5 Summary of evidence on the epidemiology/aetiology/pathophysiology of PE 32
3.2.6 Recommendations for the treatment of PE 32
3.3 Penile curvature 33
3.3.1 Congenital penile curvature 33
3.3.1.1 Epidemiology/aetiology/pathophysiology 33
3.3.1.2 Diagnostic evaluation 33
3.3.1.3 Disease management 34
3.3.1.4 Summary of evidence for congenital penile curvature 34
3.3.1.5 Recommendation for the treatment congenital penile curvature 34
3.3.2 Peyronie’s Disease 34
3.3.2.1.1 Epidemiology 34
3.3.2.1.2 Aetiology 34
3.3.2.1.3 Risk factors 34
3.3.2.1.4 Pathophysiology 34
3.3.2.1.5 Summary of evidence on epidemiology/aetiology/
pathophysiology of Peyronie’s disease 35
3.3.2.2.1 Summary of evidence for the diagnosis of Peyronie’s
disease 35
3.3.2.2.2 Recommendations for the diagnosis of Peyronie’s
disease 36
3.3.2.3.1 Non-operative treatment 36
3.3.2.3.1.1 Oral treatment 36
3.3.2.3.1.2 Intralesional treatment 38
3.3.2.3.1.3 Topical treatments 39
MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 3

3.3.2.3.1.4 Summary of evidence for non-operative
treatment of Peyronie’s disease 40
3.3.2.3.1.5 Recommendations for non-operative
treatment of Peyronie’s disease 40
3.3.2.3.2 Surgical treatment 40
3.3.2.3.2.1 Penile shortening procedures 41
3.3.2.3.2.2 Penile lengthening procedures 41
3.3.2.3.2.3 Penile prosthesis 42
3.3.2.3.2.4 Recommendations for the surgical
treatment of penile curvature 45
3.4 Priapism 45
3.4.1 Ischaemic (Low-Flow or Veno-Occlusive) Priapism 45
3.4.1.1.1 Summary of evidence on the epidemiology, aetiology
and pathophysiology of ischaemic priapism 46
3.4.1.2 Classification 46
3.4.1.3.1 History 47
3.4.1.3.4 Penile imaging 48
3.4.1.3.5 Recommendations for the diagnosis of ischaemic
priapism 48
3.4.1.4.1 First-line treatments 49
3.4.1.4.1.1 Penile anaesthesia/systemic analgesia 50
3.4.1.4.1.2 Aspiration ± irrigation with 0.9% w/v
saline solution 50
3.4.1.4.1.3 Aspiration ± irrigation with 0.9% w/v
saline solution in combination with
intracavernous injection of
pharmacological agents. 50
3.4.1.4.2 Second-line treatments 51
3.4.1.4.2.1 Penile shunt surgery 52
3.4.1.5 Summary of evidence for the treatment of ischaemic priapism 53
3.4.1.6 Recommendations for the treatment of ischaemic priapism 54
3.4.2 Non-ischaemic (high-flow or arterial) priapism 54
and pathophysiology of arterial priapism 54
3.4.2.3.1 History 55
3.4.2.3.5 Recommendations for the diagnosis of non-ischaemic
priapism 55
3.4.2.4.1 Conservative management 55
3.4.2.4.2 Selective arterial embolisation 55
3.4.2.4.3 Surgical management 56
3.4.2.5 Summary of evidence for the treatment of arterial priapism 56
3.4.2.6 Recommendations for the treatment of arterial priapism 56
3.4.3 Stuttering (recurrent or intermittent) priapism 56
and pathophysiology of stuttering priapism 57

3.4.3.3.1 History 57
3.4.3.3.5 Recommendations for the diagnosis of stuttering
priapism 57
3.4.3.4.1 α-adrenergic agonists 58
3.4.3.4.2 Hormonal manipulations of circulating testosterone 58
3.4.3.4.3 Digoxin 58
3.4.3.4.4 Terbutaline 58
3.4.3.4.5 Gabapentin 58
3.4.3.4.6 Baclofen 58
3.4.3.4.7 Hydroxyurea 59
3.4.3.4.8 Phosphodiesterase type 5 inhibitors 59
3.4.3.4.9 Intracavernosal injections 59
3.4.3.5 Summary of evidence for the treatment of stuttering priapism 59
3.4.3.6 Recommendations for the treatment of stuttering priapism 59
4. REFERENCES 60
5. CONFLICT OF INTEREST 81
6. CITATION INFORMATION 81

1. INTRODUCTION
1.1 Aim
These guidelines include four sections. The aim of the first two sections is to present the current evidence
for the diagnosis and treatment of patients suffering from erectile dysfunction (ED) and premature ejaculation
(PE). Erectile Dysfunction and PE are the two main complaints in male sexual medicine [1, 2]. Pharmacological
therapies have completely changed the diagnostic and therapeutic approach to ED.
The aim of the third section is to provide the practicing urologist with the most recent evidence on the
diagnosis and management of penile curvature in order to assist in their decision-making. Penile curvature is
a common urological disorder which can be congenital or acquired. Congenital curvature is briefly discussed
in these guidelines as a distinct pathology in the adult population without any other concomitant abnormality
present (such as urethral abnormalities). For paediatric congenital penile curvature, please refer to the EAU
Guidelines on Paediatric Urology, Chapter on Congenital Penile Curvature [3]. Acquired curvature is mainly due
to Peyronie’s disease but can also be due to the development of fibrosis following penile fracture.
The aim of the fourth section is to present the current evidence for the diagnosis and treatment of patients
suffering from priapism. Priapism is a pathological condition representing a true disorder of penile erection
that persists for more than four hours and beyond, or is unrelated to sexual interest or stimulation [4]. Overall,
erections lasting up to four hours are by consensus defined as ‘prolonged’. Priapism may occur at all ages. The
incidence rate of priapism in the general population is low (0.5-0.9 cases per 100,000 persons per year) [5, 6].
In men with sickle cell disease, the prevalence of priapism is up to 3.6% in men less than eighteen years of age
[7] increasing up to 42% in men more than eighteen years of age [8-11].
It must be emphasised that clinical guidelines present the best evidence available to the experts. However,
following guidelines recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
1.2 Publication history

The first EAU Guidelines on Erectile Dysfunction were published in 2000 with subsequent updates in 2001,
2002, 2004, 2005, 2009, 2013 and 2014. In particular, the 2009 document presented a significant update of the
previous publication with the inclusion of the topic “Premature Ejaculation” and the text was renamed “EAU
Guidelines on Male Sexual Dysfunction” [12]. In 2011 the Panel decided to develop new guidelines addressing
Penile Curvature, which resulted in a new publication in 2012 [13]. In 2014 a guideline on Priapism was
completed [14].
The 2016 edition merged the previous EAU guidelines for ED, PE, penile curvature and priapism into one
guideline [15]. In 2017 a scoping search was performed covering all areas of the guideline and it was updated
accordingly.
1.3 Available Publications

Alongside several scientific summaries published in the EAU scientific journal, European Urology [16-20], a
quick reference document (Pocket Guidelines) is available, both in print and in a number of versions for mobile
devices, presenting the main findings of the Male Sexual Dysfunction guidelines. These are abridged versions
which may require consultation together with the full text version. All available material can be viewed at the
EAU website, which also includes a selection of translations produced by national urological associations:
http://www.uroweb.org/guidelines/online-guidelines/.
1.4 Panel composition

The EAU Guidelines Panel on Male Sexual Dysfunction consists of urologists, selected based on their expertise
to represent the professionals treating patients suffering from ED, PE, penile curvature and priapism.

2. METHODS
2.1 Introduction
For the 2018 edition of the EAU Guidelines, the Guidelines Office have transitioned to a modified GRADE
methodology across all 20 guidelines [21, 22]. For each recommendation within the guidelines there is an
accompanying online strength rating form which addresses a number of key elements namely:
1. the overall quality of the evidence which exists for the recommendation, references used in
this text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [23];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.
These key elements are the basis which panels use to define the strength rating of each recommendation. The
strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [24]. The strength of each
recommendation is determined by the balance between desirable and undesirable consequences of alternative
management strategies, the quality of the evidence (including certainty of estimates), and nature and
variability of patient values and preferences. The strength rating forms will be made available online. Additional
information can be found in the general Methodology section of this print, and online at the EAU website;
http://www.uroweb.org/guideline/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
For the 2018 print, a scoping search was performed covering all areas of the guideline covering the period May
2016 to May 2017. Embase, Medline and the Cochrane Central Register of Controlled Trials (RCTs) databases
were searched, with a limitation to systematic reviews, meta-analyses or randomised controlled trials. A total
of 2,220 unique records were identified, retrieved and screened for relevance, of which 58 were selected
for inclusion. A detailed search strategy is available online: http://www.uroweb.org/guideline/male-sexual
dysfunction/.
2.2 Review
This document was subject to peer review prior to publication in 2015.
2.3 Future goals

The results of ongoing and new systematic reviews will be included in the 2019 update of the Male Sexual
Dysfunction Guidelines. Ongoing systematic reviews include:
• What is the effectiveness (efficacy and safety) of non-operative treatment for Peyronie’s
disease?
• What is the effectiveness (efficacy and safety) of surgical treatment for Peyronie’s disease?
• What are the benefits and harms of testosterone treatment for male sexual dysfunction? [25].
3. MALE SEXUAL DYSFUNCTION

3.1 Erectile dysfunction
3.1.1 Epidemiology/aetiology/pathophysiology
Penile erection is a complex phenomenon which implies a delicate and co-ordinated equilibrium among the
neurological, vascular and the smooth muscle compartment. It includes arterial dilation, trabecular smooth
muscle relaxation and activation of the corporeal veno-occlusive mechanism [26]. Erectile Dysfunction is
defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual
performance [27]. Erectile Dysfunction may affect physical and psychosocial health and may have a significant
impact on the quality of life (QoL) of sufferers and their partner’s [28-30]. There is increasing evidence that ED
can be an early manifestation of coronary artery and peripheral vascular disease. Erectile Dysfunction should
not be regarded only as a QoL issue, but also as a potential warning sign of cardiovascular disease (CVD) [31-33].

3.1.1.1 Epidemiology
Epidemiological data have shown a high prevalence and incidence of ED worldwide. Among others, the
Massachusetts Male Aging Study (MMAS) [28] reported an overall prevalence of 52% ED in non-institutionalised
men aged 40-70 years in the Boston area; specific prevalence for minimal, moderate, and complete ED was
17.2%, 25.2%, and 9.6%, respectively. In the Cologne study of men aged 30-80 years, the prevalence of ED
was 19.2%, with a steep age-related increase from 2.3% to 53.4% [34]. The incidence rate of ED (new cases
per 1,000 men annually) was 26 in the long-term data from the MMAS study [35] and 19.2 (mean follow-up of
4.2 years) in a Dutch study [36]. In a cross-sectional real-life study among men seeking first medical help for
new-onset ED, one in four patients was younger than 40 years, with almost 50% of the young men complaining
of severe ED [37]. Differences between these studies can be explained by differences in methodology, in the ages,
and socio-economic and cultural status of the populations studied.
3.1.1.2 Risk factors

Erectile Dysfunction shares both unmodifiable and modifiable common risk factors with CVD (e.g., obesity,
diabetes mellitus, dyslipidemia, metabolic syndrome, lack of exercise, and smoking) [30, 38-40]. The
association between ED status and age, diabetes mellitus duration, poor glycaemic control, body mass index
(BMI) [41, 42], obstructive sleep apnoea, hyperhomocysteinemia and chronic liver failure associated with
hepatitis B has also been confirmed [43-45]. An association between ED status and vitamin D deficiency has
also been reported [46, 47].
A number of studies have shown some evidence that lifestyle modification [32, 48] and pharmacotherapy
[48, 49] for CVD risk factors may be of help in improving sexual function in men with ED. However, it should
be emphasised that more controlled prospective studies are necessary to determine the effects of exercise or
other lifestyle changes in the prevention or treatment of ED [33].
Epidemiological studies have also demonstrated consistent evidence for an association between lower urinary
tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) and sexual dysfunction, regardless of age, other
comorbidities and various lifestyle factors [50]. The Multinational Survey on the Aging Male (MSAM-7) study -
performed in the USA, France, Germany, Italy, Netherlands, Spain, and the UK - systematically investigated the
relationship between LUTS and sexual dysfunction in > 12,000 men aged 50-80 years. From the 83% of men
who self-reported to be sexually active, the overall prevalence of LUTS was 90%, with the overall prevalence
of ED being 49%, and a reported complete absence of erection in 10% of patients. Moreover, the overall
prevalence of ejaculatory disorders was 46% [51]. An association between chronic prostatitis/chronic pelvic
pain syndrome and ED has also been confirmed [52]. Effects on erectile function vary according to the type of
surgery performed in men with LUTS/BPH [53].
Recent epidemiological data have also highlighted other unexpected risk factors potentially associated with
ED including psoriasis [54-56], gouty arthritis [57, 58] and ankylosing spondylitis [59], non-alcoholic fatty liver
[60], other chronic liver disorders [61], chronic periodontitis [62], open-angle glaucoma [63], inflammatory bowel
disease [64] and following transrectal ultrasound (TRUS)-guided prostate biopsy [65].
3.1.1.3 Pathophysiology
The pathophysiology of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/
or psychogenic (Table 1) [26]. In most cases, numerous pathophysiology pathways can be comorbid and
concomitant negatively impacting on erectile function.
The proposed ED etiological and pathophysiological subdivision is to be considered mainly didactic. In most
cases, erectile dysfunction recognises more than one organic pathophysiological element and very often,
if not always, a psychological component. Likewise, organic components can negatively impact on erectile
function with different and concomitant pathophysiological pathways. Therefore Table 1 must be considered
fordiagnosis orientation.
Table 1: Pathophysiology of ED
Vasculogenic
Recreational habits (e.g. cigarette smoking)
Lack of regular physical exercise
Obesity
Cardiovascular diseases (e.g. hypertension, coronary artery disease, peripheral vasculopathy, etc.)

Type 1 and 2 diabetes mellitus; hyperlipidaemia; metabolic syndrome; hyperhomocysteinemia, etc.
Major pelvic surgery (radical prostatectomy [RP]) or radiotherapy (pelvis or retroperitoneum)
Neurogenic
Central causes
Degenerative disorders (e.g., multiple sclerosis, Parkinson’s disease, multiple atrophy, etc.)
Spinal cord trauma or diseases
Stroke
Central nervous system tumours
Peripheral causes
Type 1 and 2 diabetes mellitus
Chronic renal failure; chronic liver failure
Polyneuropathy
Surgery (major surgery of pelvis/retroperitoneum) or radiotherapy (pelvis or retroperitoneum)
Surgery of the urethra (urethral stricture, urethroplasty, etc.)
Anatomical or structural
Hypospadias; epispadias; micropenis
Phimosis
Peyronie’s disease
Penile cancer (other tumors of the external genitalia)
Hormonal
Diabetes Mellitus; Metabolic Syndrome;
Hypogonadism (any type)
Hyperprolactinaemia
Hyper- and hypothyroidism
Hyper- and hypocortisolism (Cushing’s disease, etc.)
Panhypopituitarism and multiple endocrine disorders
Mixed pathophysiology pathways
Chronic systemic diseases (e.g., diabetes mellitus, hypertension, metabolic syndrome, chronic renal failure,
chronic liver disorders, hyperhomocysteinemia, obstructive sleep apnoea, etc.)
Psoriasis; gouty arthritis; ankylosing spondylitis; non-alcoholic fatty liver; chronic periodontitis; open-angle
glaucoma; inflammatory bowel disease
Iatrogenic causes (e.g. TRUS-guided prostate biopsy, etc.)
Drug-induced
Antihypertensives (e.g., thiazide diuretics, beta-blockers, etc.)
Antidepressants (selective serotonin reuptake inhibitors, tricyclics)
Antipsychotics (e.g., neuroleptics, etc.)
Antiandrogens (GnRH analogues and antagonists; 5-ARIs)
Recreational drugs (e.g., alcohol, heroin, cocaine, marijuana, methadone, synthetic drugs, anabolic steroids,
etc.)
Psychogenic
Generalised type (e.g., lack of arousability and disorders of sexual intimacy)
Situational type (e.g., partner-related, performance-related issues or due to distress)
Trauma
Penile fracture
Pelvic fractures
GnRH = gonadotropin-releasing hormone; 5-ARIs = 5α-Reductase inhibitors.
3.1.1.3.1 Post-radical prostatectomy ED, post-radiotherapy ED & post-brachytherapy ED

Radical prostatectomy in any form (open, laparoscopic, or robotic) is a widely performed procedure for
patients with clinically localised prostate cancer (PCa) and a life expectancy of at least ten years [66]. This
procedure may lead to treatment-specific sequelae affecting health-related QoL. This outcome has become
increasingly important with the more frequent diagnosis of PCa in younger men [67, 68]. Research has shown
that 25-75% of men experience post-RP ED [69]. Of clinical relevance, the rate of unassisted post-operative
erectile function recovery is in the range between 20 and 25% in most studies; (these rates appear not to
have been substantially improved or changed over the past seventeen years [70]. Given the growing clinical
importance of robot-assisted RP (RARP), this type of surgery is becoming the paradigm for post-operative
functional results. A systematic review (SR) has shown a significant advantage in favour of RARP in comparison
with open retropubic RP in terms of twelve month potency rates [71], without significant differences

between laparoscopic RP and RARP. Some recent reports confirm that the possibility of achieving erectile
function recovery is about twice as high for RARP compared with the open RP [72]. Recently a prospective,
controlled, non-randomised trial of patients undergoing RP in fourteen Swedish centres comparing RARP
versus retropubic RP, showed a small improvement regarding erectile function after RARP [73]. Conversely, a
randomised controlled phase 3 study of men assigned to open RP or RARP showed that the two techniques
yielded similar functional outcomes at twelve weeks [74]. As a whole, more controlled prospective studies, with
longer term follow-up, are necessary to determine if RARP is superior to open RP in terms of post-operative ED
rates [75]. Overall, patient age and surgical volume, with the consequent ability to preserve the neurovascular
bundles, seem to be the main factors in promoting the highest rates of post-operative potency [69, 76, 77].
Pre-operative potency is a major factor associated with the recovery of erectile function after surgery [68].
Patients being considered for nerve-sparing RP (NSRP) should ideally be potent pre-operatively [67, 68].
Overall, the chronological aspects are of major clinical importance in terms of post-operative recovery of
erectile function. Available data confirm that post-operative erectile function recovery can also occur years
following RP (up to 48 months) [78]. Likewise, it is shared opinion that the timing of post-operative therapy (any
type) should be commenced as close as possible to the surgical procedure [67, 69].
Erectile dysfunction is also a common sequela after external beam radiotherapy and brachytherapy for PCa
[79-81]. The mechanisms contributing to ED after prostate irradiation involve injury to the neurovascular
bundles, penile vasculature, and cavernosal structural tissue [79]. Alternative treatments for PCa including
cryotherapy and high-intensity focused ultrasound (HIFU) are also associated with equivalent or higher rates of
ED compared to surgery or radiation therapy [82, 83].
3.1.1.3.2 Summary of evidence on the epidemiology/aetiology/pathophysiology of ED
Summary of evidence LE
ED is common worldwide. 2b
ED shares common risk factors with cardiovascular disease. 2b
Lifestyle modification (regular exercise and decrease in BMI) can improve erectile function. 1b
ED is a symptom, not a disease. Some patients may not be properly evaluated or receive treatment 4
for an underlying disease or condition that may be causing ED.
ED is common after RP, irrespective of the surgical technique used. 2b
ED is common after external radiotherapy and brachytherapy. 2b
ED is common after cryotherapy and high-intensity focused US. 2b
3.1.2 Classification
Erectile dysfunction is commonly classified into three categories based on its aetiology. These include organic,
psychogenic and mixed ED. However, this classification should be used with caution since most cases are
actually of mixed aetiology. It is therefore suggested to use the terms primary organic or primary psychogenic.
3.1.3 Diagnostic evaluation

3.1.3.1 Basic work-up
The first step in evaluating ED is always a detailed medical and sexual history of patients and, when available,
their partner’s [84]. In this context, taking a comprehensive medical history may reveal one of the many
common disorders associated with ED [84]. It is important to establish a relaxed atmosphere during history-
taking.
This will make it easier to i) ask questions about erectile function and other aspects of the patient’s sexual
history; and, ii) to explain the diagnosis and therapeutic approach to the patient and his partner. Figure 1 lists
the minimal diagnostic evaluation (basic work-up) in patients with ED.
3.1.3.1.1 Sexual history

The sexual history must include information about sexual orientation, previous and current sexual relationships,
current emotional status, onset and duration of the erectile problem, and previous consultations and
treatments. The sexual health status of the partner(s) (when available) can also be useful. A detailed description
should be made of the rigidity and duration of both sexually-stimulated and morning erections and of problems
with sexual desire, arousal, ejaculation, and orgasm [85, 86]. Validated psychometric questionnaires, such as
the International Index for Erectile Function (IIEF) [87] or its short version the Sexual Health Inventory for Men

(SHIM) [88], help to assess the different sexual function domains (i.e. sexual desire, erectile function, orgasmic
function, intercourse, and overall satisfaction), as well as the potential impact of a specific treatment modality.
Psychometric analyses also support the use of the erectile hardness score for the assessment of penile rigidity
in practice and in clinical trials research [89]. In cases of clinical depression, the use of a two question scale for
depression is recommended in everyday clinical practice, for example: “During the past month have you often
been bothered by feeling down, depressed or hopeless? During the past month have you often been bothered
by little interest or pleasure, doing things?” [90]. Patients should always be screened for symptoms of possible
hypogonadism (testosterone deficiency), including decreased energy, libido, fatigue and cognitive impairment,
as well as for LUTS. In this regard, although LUTS/BPH in itself does not represent a contraindication to treat a
patient for late onset hypogonadism, screening for LUTS severity is clinically relevant [91].
3.1.3.1.2 Physical examination

Every patient must be given a physical examination focused on the genitourinary, endocrine, vascular and
neurological systems [92, 93]. A physical examination may reveal unsuspected diagnoses, such as Peyronie’s
disease, pre-malignant or malignant genital lesions, prostatic enlargement or irregularity/nodularity, or signs
and symptoms suggesting hypogonadism (small testes, alterations in secondary sexual characteristics etc.).
Blood pressure and heart rate should be measured if they have not been assessed in the previous three
to six months. Likewise either BMI calculation or waist circumference measurement should be taken into
consideration in every patient with comorbid conditions.
3.1.3.1.3 Laboratory testing

Laboratory testing must be tailored to the patient’s complaints and risk factors. Patients may need a fasting
blood glucose or HbA1c and lipid profile if they have not recently been assessed. Hormonal tests include an
early morning total testosterone. If indicated, the bio-available or calculated-free testosterone may be needed
to corroborate total testosterone measurements. However, the threshold of testosterone required to maintain
an erection is low and ED is usually a symptom of more severe cases of hypogonadism [39, 94-96]. For levels
> 8 nmol/L the relationship between circulating testosterone and sexual functioning is very low [39, 94-96].
Additional laboratory tests may be considered in selected patients (e.g., prostate-specific antigen [PSA]) [97];
prolactin, and luteinising hormone [98]. Although physical examination and laboratory evaluation of most men
with ED may not reveal the exact diagnosis, these present opportunities to identify critical comorbid conditions
that should not be missed [93].

Figure 1: Minimal diagnostic evaluation (basic work-up) in patients with ED
Paent with ED (self-reported)
Medical and psychosexual history (use of validated instruments, e.g. IIEF)
Idenfy other than Idenfy common Idenfy reversible Assess psychosocial

ED sexual problems causes of ED risk factors for ED status
Focused physical examinaon
Signs of Cardiovascular and

Penile deformies Prostac disease
hypogonadism neurological status
Laboratory tests
Total testosterone (morning sample)

Glucose-lipid profile
if indicated, bio-available or free
(if not assessed in the last 12 months)
testosterone
ED = erectile dysfunction; IIEF = International Index of Erectile Function.
3.1.3.1.4 Cardiovascular system and sexual activity: the patient at risk

Patients who seek treatment for sexual dysfunction have a high prevalence of CVDs. Epidemiological surveys
have emphasised the association between cardiovascular and metabolic risk factors and sexual dysfunction
in both men [99] and women [100]. Overall, ED can improve the sensitivity of screening for asymptomatic
CVD in men with diabetes [101, 102]. Erectile dysfunction significantly increases the risk of CVD, coronary
heart disease, stroke, and all these cause mortality, and the increase is probably independent of conventional
cardiovascular risk factors [31, 32, 103, 104]. Longitudinal data from an observational population-based
study of 965 men without CVD, showed that younger men (< 50 years) with persistent ED have an increased
Framingham risk that is independent of traditional CVD risk factors [105].
The EAU Guidelines for diagnosing and treating men with ED have been adapted from previously published
recommendations from the Princeton Consensus conferences on sexual dysfunction and cardiac risk [106].
The Princeton Consensus (Expert Panel) Conference is dedicated to optimising sexual function and preserving
cardiovascular health [106-108]. Accordingly, patients with ED can be stratified into three cardiovascular risk
categories (Table 2), which can be used as the basis for a treatment algorithm for initiating or resuming sexual
activity (Figure 2). It is also possible for the clinician to estimate the risk of sexual activity in most patients from
their level of exercise tolerance, which can be determined when taking the patient’s history [49].

Table 2: Cardiac risk stratification (based on 2nd and 3rd Princeton Consensus [106, 108])
Low-risk category Intermediate-risk category High-risk category

Asymptomatic, < 3 risk factors for > 3 risk factors for CAD High-risk arrhythmias
CAD (excluding sex) (excluding sex)
Mild, stable angina Moderate, stable angina Unstable or refractory angina
(evaluated and/or being treated)
Uncomplicated previous MI Recent MI (> 2, < 6 weeks) Recent MI (< 2 weeks)
LVD/CHF (NYHA class I or II) LVD/CHF (NYHA class III) LVD/CHF (NYHA class IV)
Post-successful coronary Non-cardiac sequelae of Hypertrophic obstructive and other
revascularisation atherosclerotic disease (e.g., cardiomyopathies
stroke, peripheral vascular disease)
Controlled hypertension Uncontrolled hypertension
Mild valvular disease Moderate-to-severe valvular
disease
CAD = coronary artery disease; CHF = congestive heart failure; LVD = left ventricular dysfunction;
MI = myocardial infarction; NYHA = New York Heart Association.
Figure 2: Treatment algorithm for determining level of sexual activity according to cardiac risk in ED
(based on 3rd Princeton Consensus) [106]
Sexual inquiry of all men
ED confirmed
Exercise abilitya
Low risk Intermediate risk High risk
Elecve risk
assessment
Stress testb
Pass Fail
Low risk High risk
Advice, treat ED Cardiologist
a Sexual activity is equivalent to walking 1 mile on the flat in 20 minutes or briskly climbing two flights of stairs in
10 seconds.
b Sexual activity is equivalent to four minutes of the Bruce treadmill protocol.

3.1.3.1.4.1 Low-risk category
The low-risk category includes patients who do not have any significant cardiac risk associated with sexual
activity. Low-risk is typically implied by the ability to perform exercise of modest intensity, which is defined as,
≥ 6 metabolic equivalents of energy expenditure in the resting state without symptoms. According to current
knowledge of the exercise demand or emotional stress associated with sexual activity, low-risk patients do
not need cardiac testing or evaluation before the initiation or resumption of sexual activity or therapy for sexual
dysfunction.
3.1.3.1.4.2 Intermediate- or indeterminate-risk category

The intermediate- or indeterminate-risk category consists of patients with an uncertain cardiac condition
or patients whose risk profile requires testing or evaluation before the resumption of sexual activity. Based
upon the results of testing, these patients may be moved to either the high- or low-risk group. A cardiology
consultation may be needed in some patients to help the primary physician determine the safety of sexual
activity.
3.1.3.1.4.3 High-risk category

High-risk patients have a cardiac condition that is sufficiently severe and/or unstable for sexual activity to
carry a significant risk. Most high-risk patients have moderate-to-severe symptomatic heart disease. High-risk
individuals should be referred for cardiac assessment and treatment. Sexual activity should be stopped until
the patient’s cardiac condition has been stabilised by treatment, or a decision made by the cardiologist and/or
internist that it is safe to resume sexual activity.
3.1.3.2 Specialised diagnostic tests

Most patients with ED can be managed based on medical and sexual history; conversely, some patients may
need specific diagnostic tests (Tables 3 and 4).
3.1.3.2.1 Nocturnal penile tumescence and rigidity test

The nocturnal penile tumescence and rigidity assessment should be performed on at least two separate nights.
A functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on the tip of
the penis that lasts for ten or more minutes [109].
3.1.3.2.2 Intracavernous injection test

The intracavernous injection test gives limited information about the vascular status. A positive test is a rigid
erectile response (unable to bend the penis) that appears within ten minutes after the intracavernous injection
and lasts for 30 minutes [110]. Overall, the test is inconclusive as a diagnostic procedure and a duplex Doppler
study of the penis should be requested, if clinically warranted.
3.1.3.2.3 Duplex ultrasound of the penis

A peak systolic blood flow > 30 cm/s, an end-diastolic velocity of < 3 cm/s and a resistance index > 0.8 are
generally considered normal [111, 112]. Further vascular investigation is unnecessary if a duplex ultrasound
(US) examination is normal.
3.1.3.2.4 Arteriography and dynamic infusion cavernosometry or cavernosography

Arteriography and dynamic infusion cavernosometry or cavernosography should be performed only in
patients who are being considered for vascular reconstructive surgery [113]. Recent data suggested the use
of computed tomography angiography in cases of penile artery angioplasty for patients with ED and isolated
penile artery stenoses [114].
3.1.3.2.5 Psychiatric assessment

Whenever clinically indicated, patients with psychiatric disorders should be referred to a psychiatrist who
is particularly interested in sexual health. In younger patients (< 40 years) with long-term primary ED [37],
psychiatric assessment may be helpful before any clinical assessment is carried out.
3.1.3.2.6 Penile abnormalities

Surgical correction may be needed in patients with ED and penile abnormalities (e.g. hypospadias, congenital
curvature, or Peyronie’s disease with preserved rigidity).
3.1.3.3 Patient education - consultation and referrals

Consultation with the patient should include a discussion of the expectations and needs of both the patient
and their sexual partner. It should also review both the patient’s and partner’s understanding of ED and the

results of diagnostic tests, and provide a rational selection of treatment options [115]. Patient and partner
education is an essential part of ED management [115, 116].
Table 3: Indications for specific diagnostic tests
Primary ED (not caused by organic disease or psychogenic disorder).

Young patients with a history of pelvic or perineal trauma, who could benefit from potentially curative
revascularisation surgery or angioplasty.
Patients with penile deformities which might require surgical correction (e.g., Peyronie’s disease, congenital
penile curvature).
Patients with complex psychiatric or psychosexual disorders.
Patients with complex endocrine disorders.
Specific tests may be indicated at the request of the patient or his partner.
Medico-legal reasons (e.g., implantation of penile prosthesis to document end stage ED, sexual abuse).
Table 4: Specific diagnostic tests
Nocturnal Penile Tumescence and Rigidity (NTPR) using Rigiscan®

Vascular studies
- Intracavernous vasoactive drug injection
- Penile Dynamic Duplex Ultrasonography
- Penile Dynamic Infusion Cavernosometry and Cavernosography
- Internal pudendal arteriography
Neurological studies (e.g., bulbocavernosus reflex latency, nerve conduction studies)
Endocrinological studies
Specialised psychodiagnostic evaluation
3.1.3.4 Recommendations for the diagnostic evaluation of ED
Recommendations Strength rating

Take a comprehensive medical and sexual history in every patient. Strong
Use a validated questionnaire related to erectile dysfunction to assess all sexual function Strong
domains and the effect of a specific treatment modality.
Include a physical examination in the initial assessment of men with erectile dysfunction Strong
(ED) to identify underlying medical conditions and comorbid genital disorders that may be
associated with ED.
Assess routine laboratory tests, including glucose-lipid profile and total testosterone, to Strong
identify and treat any reversible risk factors and lifestyle factors that can be modified.
Include specific diagnostic tests in the initial evaluation of ED in the presence of the Strong
conditions presented in Table 3.
3.1.4 Disease management

3.1.4.1 Treatment options
Erectile dysfunction may be associated with modifiable or reversible risk factors, including lifestyle or drug-
related factors [33]. These factors may be modified either before, or at the same time as, specific therapies
are used. Likewise, ED may be associated with concomitant and underlying conditions (such as, endocrine
disorders and metabolic disorders - e.g. diabetes - some cardiovascular problems - e.g. hypertension) which
should always be well-controlled as the first step of any ED treatment [117]. As a rule, ED can be treated
successfully with current treatment options, but it cannot be cured. The only exceptions are psychogenic
ED, post-traumatic arteriogenic ED in young patients, and hormonal causes (e.g. hypogonadism and
hyperprolactinaemia) [95, 98], which potentially can be cured with specific treatment. Most men with ED will
be treated with therapeutic options that are not cause specific. This results in a structured treatment strategy
that depends on invasiveness, efficacy, safety, and cost, as well as patient preference [115]. In this context,
physician-patient (partner, if available) dialogue is essential throughout the management of ED. The assessment
of treatment options must be tailored according to patient and partner satisfaction, QoL factors as well as
treatment-related invasiveness safety and efficacy. A treatment algorithm for ED is shown in Figure 3.

3.1.4.1.1 Lifestyle management of ED with concomitant risk factors
The basic work-up of the patient must identify reversible risk factors for ED. Lifestyle changes and risk factor
modification must precede or accompany any physical or/and pharmacological treatment. Major clinical
potential benefits of lifestyle changes may be achieved in men with specific comorbid cardiovascular or
metabolic disorders, such as diabetes or hypertension [33, 118].
3.1.4.1.2 Erectile dysfunction after radical prostatectomy

Use of pro-erectile drugs following RP is important in achieving post-operative erectile function. Several trials
have shown higher rates of erectile function recovery after RP in patients receiving any drug (therapeutic or
prophylactic) for ED. Early compared with delayed erectile function treatment seems to impact on the natural
recovery time for potency [67], although there is a lack of data to support any specific regimen for penile
rehabilitation [119]. Currently available therapeutic armamentarium follows the treatment algorithm for ED which
is shown in Figure 3.
The management of post-RP ED has been revolutionised by the advent of phosphodiesterase 5 inhibitors
(PDE5Is), with their demonstrated efficacy, ease of use, good tolerability, excellent safety, and positive impact
on QoL. It must be emphasised that post-RP, ED patients are poor responders to PDE5Is. However, PDE5Is
are still considered as the first-line therapy in patients who have undergone nerve-sparing (NS) surgery
regardless of the surgical technique used [67, 68]. A number of clinical parameters have been identified
as potential predictors of PDE5Is in men undergoing RP. Patient age and quality of NS technique are key
factors in preserving post-RP erectile function [67, 68, 71, 120]. The response rate to sildenafil treatment for
ED after RP in different trials has ranged from 35% to 75% among those who underwent NSRP and from
0% to 15% among those who underwent non-NSRP [67, 121]. Early use of high-dose sildenafil after RP has
been suggested to be associated with preservation of smooth muscle within the corpora cavernosa [122].
Daily sildenafil also results in a greater return of spontaneous normal erectile function after RP compared to
placebo following bilateral NSRP in patients who were fully potent before surgery [123]. Conversely, a recent
prospective, randomised, placebo-controlled study, which assessed the effects of nightly sildenafil citrate
therapy during penile rehabilitation using nocturnal penile rigidity score in addition to the IIEF-EF, showed
no therapeutic benefit for nightly sildenafil when compared to on-demand dosing in determining recovery of
erectile function post-prostatectomy [124].
The effectiveness of tadalafil and vardenafil as on-demand treatment has been evaluated in post-RP ED.
A large multicentre trial in Europe and the USA has investigated the effects of tadalafil in patients with ED
following bilateral NS surgery. Erectile function was improved in 71% of patients treated with 20 mg tadalafil
vs. 24% of those treated with placebo, while the rate of successful intercourse attempts was 52% with 20
mg tadalafil vs. 26% with placebo [125]. Similarly, vardenafil has been tested in patients with ED following
NSRP in a randomised, multicentre, prospective, placebo-controlled study in North America [126]. Following
bilateral NSRP, erectile function improved by 71% and 60% with 10 and 20 mg vardenafil, respectively. An
extended analysis of the same cohort of patients showed the benefit of vardenafil compared to placebo in
terms of intercourse satisfaction, hardness of erection, orgasmic function, and overall satisfaction with sexual
experience [127]. Moreover, a randomised, double-blind, double-placebo trial in men < 68 years of age and
with normal pre-operative erectile function who underwent NSRP at 50 centres from nine European countries
and Canada, compared tadalafil once daily with placebo [128]. Tadalafil was most effective for drug-assisted
erectile function in men with ED following NSRP, and data suggested a potential role for tadalafil once daily -
provided early after surgery - in contributing to the recovery of post-operative erectile function and maintaining
penile length [128]. Unassisted erectile function was not improved after cessation of active therapy for nine
months [128]. Moreover, taking tadalafil once daily significantly shortened time to erectile function recovery
versus placebo over the nine month double/blind treatment period. Conversely tadalafil on demand did not
[129]. Likewise, tadalafil once daily improved QoL post-operatively, both at double-blind treatment and open
label treatment period [130].
A randomised, double-blind, double-dummy, multicentre, parallel-group study in 87 centres across Europe,

Canada, South Africa and the USA, compared on-demand and nightly dosing of vardenafil in men with ED
following bilateral NSRP [131]. In patients whose pre-operative erectile function domain score was > 26,
vardenafil was efficacious when used on demand, supporting a paradigm shift towards on-demand dosing with
PDE5Is in post-RP ED [131]. A double-blind, placebo-controlled, parallel-group study in 298 patients with ED
after bilateral NSRP randomised to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity)
for twelve weeks showed significantly greater increases in sexual encounter profile (SEP) question 2 and SEP3
as well as in mean change of IIEF erectile function domain score with 100 and 200 mg avanafil vs. placebo
(p < 0.01) [108].

For dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at fifteen minutes or less were successful
vs. 4.5% (2 of 44) for placebo (p < 0.01) [132]. A recently conducted meta-analysis confirmed that avanafil had
comparable efficacy with sildenafil, vardenafil and tadalafil treatments [133]. Although some authors reported
improved erectile function when long-term tadalafil 5 mg once daily is combined with sildenafil as needed
[134], more safety analyses are required to recommend such a therapy.
Historically, the treatment options for post-RP ED have included intracavernous injections [135], urethral
microsuppository [67, 136], vacuum device therapy [67, 119, 137, 138], and penile implants [67, 139, 140]].
Intracavernous injections and penile implants are still suggested as second- and third-line treatments,
respectively, when oral PDE5Is are not adequately effective or contraindicated for post-operative patients
[141] (Sections 3.1.4.3 and 3.1.4.4). There are currently several potential novel treatment modalities for ED,
from innovative vasoactive agents and trophic factors to stem cell therapy and gene therapy. Most of these
therapeutic approaches require further investigation in large-scale, blinded, placebo-controlled randomised
studies in order to achieve an adequate evidence base and clinically-reliable grade of recommendation [142].
Figure 3: Management algorithm for erectile dysfunction
Management of erecle dysfuncon
Idenfy and treat Lifestyle changes and Provide educaon

“curable” causes of risk factor and counselling to
erecle dysfuncon modificaons paent (and partner,
if available)
Idenfy paent needs and expectaons

Shared decision-making
Offer conjoint psycho-sexual and
medical/physical treatment
Phosphodiesterase 5 inhibitors
Topical/intraurethral alprostadil
Vacuum device
Low intensity shockwave treatment
Assess therapeuc outcomes

• Paent self-perceived treatment invasiveness
• Treatment-associated improvement in
Inadequate treatment outcome
erecle funcon
• Treatment-related side effects
• Treatment-associated sasfacon
• Assess adequate use of treatment opons

• Provide new instrucons and counselling
• Retrial
• Consider treatment alternave or
combined therapies

• Paent self-perceived treatment invasiveness
• Treatment-associated improvement in
erecle funcon
• Treatment-associated sasfacon
Intracavernosal injecons

Penile prostheses • Treatment-associated sasfacon

3.1.4.1.3 Causes of ED that can be treated with a curative intent
3.1.4.1.3.1 Hormonal causes
The advice of an endocrinologist may be beneficial for managing patients with hormonal abnormalities [98].
Testosterone deficiency is either a result of primary testicular failure or secondary to pituitary/hypothalamic
causes (e.g. a functional pituitary tumour resulting in hyperprolactinaemia) [98, 143]. When clinically indicated
[144], testosterone supplementation (TS) (intramuscular, oral, or transdermal) is effective, but should only be
used after other endocrinological causes for testicular failure have been excluded [39, 95, 145]. Before initiating
TS, digital rectal examination (DRE), serum PSA , haematocrit, liver function tests and lipid profile should be
performed [39, 95, 146]. Patients who are given TS should be monitored for a clinical response, elevation of
haematocrit and development of hepatic or prostatic disorders [39, 95, 146]. Testosterone supplementation is
controversial in men with a history of PCa (LE: 4) [147]. Since there is limited evidence suggesting that TS may
not pose an undue risk of PCa recurrence or progression, TS is contraindicated in patients with untreated PCa
(LE: 4).
Testosterone supplementation is contraindicated in patients with unstable cardiac disease [91, 148].
Conversely, the role of testosterone in the cardiovascular health of men is controversial. Clinical trials
examining TS have been insufficiently powered to provide definitive and unequivocal evidence of adverse
events in terms of cardiovascular outcomes [149-154]. Current guidelines from the Endocrine Society make
no recommendations on whether patients with heart disease should be screened for hypogonadism and do
not recommend supplementing testosterone in patients with heart disease to improve survival [94]. However,
a comprehensive SR and meta-analysis of all placebo-controlled RCTs on the effect of TS on cardiovascular-
related problems did not support a causal role between TS and adverse cardiovascular events [148].
3.1.4.1.3.2 Post-traumatic arteriogenic ED in young patients

In young patients with pelvic or perineal trauma, surgical penile revascularisation has a 60-70% long-
term success rate [155, 156]. The lesion must be confirmed by penile pharmaco-arteriography. Corporeal
veno-occlusive dysfunction is a contraindication to revascularisation and must be excluded by dynamic
infusion cavernosometry or cavernosography. Vascular surgery for veno-occlusive dysfunction is no longer
recommended because of poor long-term results [155].
3.1.4.1.3.3 Psychosexual counselling and therapy

For patients with a significant psychological problem [157], psychosexual therapy may be given either alone or
with another therapeutic approach in order to improve couple sexual satisfaction and female sexual function
[158]. Psychosexual therapy requires ongoing follow-up and has had variable results [159].
3.1.4.2 Therapeutic Strategy

Based on the currently available peer-reviewed literature and the consensus of the panel, the new therapeutic
and decision-making algorithm (Figure 3) for treating ED considers both the level of invasiveness of each
therapy and the efficacy of the therapy itself.
3.1.4.2.1 First-line therapy

3.1.4.2.1.1 Oral pharmacotherapy
Phosphodiesterase 5 hydrolyses (PDE5Is) cyclic guanosine monophosphate (cGMP) in the cavernosal tissue.
Inhibition of PDE5 results in smooth muscle relaxation with increased arterial blood flow, leading to
compression of the subtunical venous plexus followed by penile erection [160]. Four potent selective PDE5Is
have been approved by the European Medicines Agency (EMA) for the treatment of ED [161]. They are not
initiators of erection and require sexual stimulation to facilitate an erection. Efficacy is defined as an erection
with rigidity sufficient for penetration [117].
Sildenafil
Sildenafil was launched in 1998 and was the first PDE5I available on the market [162]. It is administered in
doses of 25, 50 and 100 mg. The recommended starting dose is 50 mg and should be adapted according to
the patient’s response and side-effects [162]. Sildenafil is effective 30-60 minutes after administration [162].
Its efficacy is reduced after a heavy, fatty meal due to delayed absorption. Efficacy may be maintained for up
to twelve hours [163]. The pharmacokinetic data for sildenafil is presented in Table 5. Adverse events (Table
6) are generally mild in nature and self-limited [164, 165]. After 24 weeks in a dose-response study, improved
erections were reported by 56%, 77% and 84% of a general ED population taking 25, 50 and 100 mg sildenafil,
respectively, compared to 25% of men taking placebo [166]. Sildenafil significantly improved patient scores for
IIEF, SEP2, SEP3, and General Assessment Questionnaire (GAQ) and treatment satisfaction. The efficacy of
sildenafil in almost every subgroup of patients with ED has been successfully established. (LE: 1), irrespective

of age [167]. Recently, an orally disintegrating tablet (ODT) of sildenafil citrate at a dosage of 50 mg has been
developed mainly for the benefit of patients who have difficulty swallowing solid dosage forms.
Tadalafil
Tadalafil was licensed for treatment of ED in February 2003 and is effective from 30 minutes after
administration, with peak efficacy after about two hours [168]. Efficacy is maintained for up to 36 hours [168]
and is not affected by food. It is administered in on-demand doses of 10 and 20 mg or a daily dose of 5 mg.
The recommended on-demand starting dose is 10 mg and should be adapted according to the patient’s
response and side-effects [168, 169]. Pharmacokinetic data for tadalafil is presented in Table 5. Adverse events
(Table 6) are generally mild in nature and self-limited by continuous use. In pre-marketing studies, after twelve
weeks of treatment in a dose-response study, improved erections were reported by 67% and 81% of a general
ED population taking 10 and 20 mg tadalafil, respectively, compared to 35% of men in the control placebo
group [168]. Tadalafil significantly improved patient scores for IIEF, SEP2, SEP3, and GAQ and treatment
satisfaction [168].
Efficacy has been confirmed in post-marketing studies [161, 170]. The efficacy of tadalafil in almost every
subgroup of patients with ED, including difficult-to-treat subgroups (e.g. diabetes mellitus), has been
successfully established [171]. Daily tadalafil has also been licensed for the treatment of LUTS secondary to
BPH. Therefore, it is useful in patients with concomitant ED and LUTS [172]. Recent data also states that 40%
of men aged > 45 years were combined responders for ED and LUTS/BPH to treatment with tadalafil 5 mg
once daily, with symptoms improved after twelve weeks [173].
Vardenafil
Vardenafil became commercially available in March 2003 and is effective from 30 minutes after administration
[171], with up to one out of three patients achieving satisfactory erections within 15 minutes of ingestion [174].
Its effect is reduced by a heavy, fatty meal (> 57% fat). Doses of 5, 10 and 20 mg have been approved for
on-demand treatment of ED. The recommended starting dose is 10 mg and should be adapted according
to the patient’s response and side-effects [175]. Pharmacokinetic data for vardenafil is presented in Table 5.
Adverse events (Table 6) are generally mild in nature and self-limited by continuous use [175]. After twelve
weeks in a dose-response study, improved erections were reported by 66%, 76% and 80% of a general ED
population taking 5, 10 and 20 mg vardenafil, respectively, compared with 30% of men taking placebo [175,
176]. Vardenafil significantly improved patient scores for IIEF, SEP2, SEP3, and GAQ and treatment satisfaction.
Efficacy has been confirmed in post-marketing studies [175, 176]. The efficacy of vardenafil in almost
every subgroup of patients with ED, including difficult-to-treat subgroups (e.g. diabetes mellitus), has been
successfully established. More recently, an ODT form of vardenafil has been released [176]. Orodispersable
tablet formulations offer improved convenience over film-coated formulations and may be preferred by
patients. Absorption is unrelated to food intake and they exhibit better bio-availability compared to film-coated
tablets [177]. The efficacy of vardenafil ODT has been demonstrated in several RCTs and did not seem to differ
from the regular formulation [177-179].
Avanafil
Avanafil is a highly-selective PDE5I that became commercially available in 2013 [180]. Avanafil has a high
ratio of inhibiting PDE5 as compared with other PDE subtypes allowing for the drug to be used for ED while
minimising adverse effects [181]. Doses of 50 mg, 100 mg, and 200 mg have been approved for on-demand
treatment of ED [180]. The recommended starting dose is 100 mg taken as needed approximately 15 to 30
minutes before sexual activity and the dosage may be adapted according to efficacy and tolerability [180, 182,
183]. In the general population with ED, the mean percentage of attempts resulting in successful intercourse
was approximately 47%, 58%, and 59% for the 50 mg, 100 mg, and 200 mg avanafil groups, respectively,
as compared with approximately 28% for placebo [180, 182]. Data from sexual attempts made within fifteen
minutes of dosing showed successful attempts in 64%, 67%, and 71% of cases, with avanafil 50, 100, and 200
mg, respectively. The maximum recommended dosing frequency is once per day. Dosage adjustments are not
warranted based on renal function, hepatic function, age or gender [182]. Pharmacokinetic data for avanafil is
presented in Table 5 [180, 182]. Adverse events are generally mild in nature (Table 6) [180, 182]. Pairwise meta-
analytic data from available studies suggested that avanafil significantly improved patient scores for IIEF, SEP2,
SEP3, and GAQ, with an evident dose-response relationship [180, 184]. Administration with food may delay the
onset of effect compared with administration in the fasting state but avanafil can be taken with or without food.
The efficacy of avanafil in many groups of patients with ED, including difficult-to-treat subgroups (e.g diabetes
mellitus), has been successfully established.

Choice or preference between the different PDE5Is
To date, no data are available from double- or triple-blind multicentre studies comparing the efficacy and/or
patient preference for sildenafil, tadalafil, vardenafil, and avanafil. Choice of drug will depend on the frequency
of intercourse (occasional use or regular therapy, three to four times weekly) and the patient’s personal
experience. Patients need to know whether a drug is short- or long-acting, its possible disadvantages, and how
to use it. A recent meta-analysis demonstrated that ED patients who prioritise high efficacy must use sildenafil
50 mg whereas those who optimise tolerability should initially use tadalafil 10 mg and switch to udenafil 100
mg if the treatment is not sufficient [170]. Of clinical relevance, udenafil is not an EMEA or FDA approved drug.
In addition, results of another clinical trial revealed that tadalafil 5 mg once daily may improve the erectile
function outcomes among men who had a partial response to on-demand PED5I therapy [185].
Continuous use of PDE5Is

Animal studies have shown that chronic use of PDE5Is significantly improves or prevents the intracavernous
structure alterations due to age, diabetes, or surgical damage [186-190]. No data exists for a human
population. In humans, it has been clinically demonstrated that treatment with tadalafil 5 mg once daily in men
complaining of ED of various severities was well tolerated and effective [191]. In 2007, tadalafil 2.5 and 5 mg
were approved by the EMA for daily treatment of ED. According to the EMA, a once daily regimen with tadalafil
2.5 mg or 5 mg might be considered suitable, based on patient choice and the physician’s judgement. In these
patients, the recommended dose is 5 mg, taken once a day at approximately the same time. Overall, tadalafil,
5 mg once daily, provides an alternative to on-demand dosing of tadalafil for couples who prefer spontaneous
rather than scheduled sexual activities or who anticipate frequent sexual activity, with the advantage that
dosing and sexual activity no longer need to be temporally linked. The appropriateness of the continuous
use of a daily regimen should be re-assessed periodically [191, 192]. A recently published integrated analysis
showed that no clinical populations of patients with ED seemed to benefit overwhelmingly from tadalafil
once daily over on-demand dosing regimen and vice versa [193]. Continuous dosing may also be used in the
comorbid patient with LUTS and ED.
Table 5: Summary of the key pharmacokinetic data for the four PDE5Is currently EMA-approved to treat
ED*
Parameter Sildenafil, 100 mg Tadalafil, 20 mg Vardenafil, 20 mg Avanafil, 200mg

Cmax 560 μg/L 378 μg/L 18.7 μg/L 5.2 μg/L
Tmax (median) 0.8-1 hours 2 hours 0.9 hours 0.5-0.75 hours
T1/2 2.6-3.7 hours 17.5 hours 3.9 hours 6-17 hours
AUC 1,685 μg.h/L 8,066 μg.h/L 56.8 μg.h/L 11.6 μg.h/L
Protein binding 96% 94% 94% 99%
Bioavailability 41% NA 15% 8-10%
* Fasted state, higher recommended dose. Data adapted from EMA statements on product characteristics.
Cmax: maximal concentration, Tmax: time-to-maximum plasma concentration; T1/2: plasma elimination halftime;
AUC: area under curve or serum concentration time curve.
Table 6: Common adverse events of the four PDE5Is currently EMA-approved to treat ED*
Adverse event Sildenafil Tadalafil Vardenafil Avanafil, 200mg

Headache 12.8% 14.5% 16% 9.3%
Flushing 10.4% 4.1% 12% 3.7%
Dyspepsia 4.6% 12.3% 4% uncommon
Nasal congestion 1.1% 4.3% 10% 1.9%
Dizziness 1.2% 2.3% 2% 0.6%
Abnormal vision 1.9% < 2% none
Back pain 6.5% < 2%
Myalgia 5.7% < 2%
* Adapted from EMA statements on product characteristics.
Safety issues for PDE5Is

(i) Cardiovascular safety
Clinical trial results for the four PDE5Is and post-marketing data of sildenafil, tadalafil, and vardenafil have
demonstrated no increase in myocardial infarction rates in patients receiving PDE5Is, as part of either RCTs or

open-label studies, or compared to expected rates in age-matched male populations. None of the PDE5Is had
an adverse effect on total exercise time or time-to-ischaemia during exercise testing in men with stable angina.
Chronic or on-demand use is well tolerated with a similar safety profile. All PDE5Is are contraindicated in:
i) patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia within the
last six months; ii) patients with resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood
pressure > 170/100 mmHg); iii) patients with unstable angina, angina with sexual intercourse, or congestive
heart failure categorised as New York Heart Association Class IV [106, 194-196].
(ii) Nitrates are contraindicated with PDE5Is

Absolute contraindication to PDE5Is is represented by patients who are using any form of organic nitrate
(e.g.nitroglycerine, isosorbide mononitrate, and isosorbide dinitrate) or nitric oxide (NO) donors (e.g. other
nitrate preparations used to treat angina, as well as amyl nitrite or amyl nitrate such as “poppers” which
are used for recreation). They result in cGMP accumulation and unpredictable falls in blood pressure and
symptoms of hypotension. The duration of interaction between organic nitrates and PDE5Is depends upon
the PDE5I and nitrate used. If a PDE5I is taken and the patient develops chest pain, nitroglycerine must be
withheld for at least 24 hours if sildenafil (and probably also vardenafil) is used (half-life, four hours), or at least
48 hours if tadalafil is used (half-life, 17.5 hours), and for no less than twelve hours if avanafil is used (half-life,
6-17 hours) [197].
(iii) Antihypertensive drugs

Co-administration of PDE5Is with antihypertensive agents (angiotensin-converting enzyme inhibitors,
angiotensin-receptor blockers, calcium blockers, β-blockers, and diuretics) may result in small additive
decreases in blood pressure, which are usually minor [106]. In general, the adverse event profile of a PDE5I
is not worsened by a background of antihypertensive medication, even when the patient is taking several
antihypertensive agents [198].
α-Blocker interactions
All PDE5Is show some interaction with α-blockers, which under some conditions may result in orthostatic
hypotension.
• Sildenafil labelling advises that 50 or 100 mg sildenafil should be used with caution in patients taking an
α-blocker (especially doxazosin). Hypotension is more likely to occur within four hours following treatment
with an α-blocker. A starting dose of 25 mg is recommended [164].
• Concomitant treatment with vardenafil should only be initiated if the patient has been stabilised on
his α-blocker therapy. Co-administration of vardenafil with tamsulosin is not associated with clinically
significant hypotension [171, 175, 176].
• Tadalafil is not recommended in patients taking doxazosin, but this is not the case for tamsulosin [168,
199].
• Avanafil labelling currently reports that patients should be stable on α-blocker therapy prior to initiating
avanafil. In these patients, avanafil should be initiated at the lowest dose of 50 mg. Conversely, in those
patients already taking an optimised dose of avanafil, α-blocker therapy should be initiated at the lowest
dose.
Dosage adjustment
Drugs that inhibit the CYP34A pathway will inhibit the metabolic breakdown of PDE5Is, thus increasing
PDE5Is blood levels (e.g. ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,
nelfinavir, saquinavir and telithromycin). Therefore, lower doses of PDE5Is are necessary. However, other
agents, such as rifampin, phenobarbital, phenytoin and carbamazepine, may induce CYP3A4 and enhance the
breakdown of PDE5Is, so that higher doses of PDE5Is are required. Severe kidney or hepatic dysfunction may
require dose adjustments or warnings.
Management of non-responders to PDE5Is

The two main reasons why patients fail to respond to a PDE5I are either incorrect drug use or lack of efficacy
of the drug. Data suggest that an adequate trial involves at least six attempts with a particular drug [200]. The
management of non-responders depends upon identifying the underlying cause. Check that the patient has
been using a licensed medication. There is a large counterfeit market in PDE5Is. The amount of active drug in
these medications varies enormously and it is important to check how and from which source the patient has
obtained his medication.
Check that the medication has been properly prescribed and correctly used. The main reason why
patients fail to use their medication correctly is inadequate counselling from their physician. The most common
causes of incorrect drug use are: i) failure to use adequate sexual stimulation; ii) failure to use an adequate

dose; and, iii) failure to wait an adequate amount of time between taking the medication and attempting sexual
intercourse.
PDE5I action is dependent on the release of NO by the parasympathetic nerve endings in the
erectile tissue of the penis. The usual stimulus for NO release is sexual stimulation, and without adequate
sexual stimulation (and NO release), the medication is ineffective. Oral PDE5Is take different times to reach
maximal plasma concentrations [163, 165, 177, 184, 201-203]. Although pharmacological activity is achieved
at plasma levels well below the maximal plasma concentration, there will be a period of time following oral
ingestion of the medication during which the drug is ineffective. Even though all four drugs have an onset of
action in some patients within 15-30 minutes of oral ingestion [165, 177, 184, 201-203], most patients require a
longer delay between taking the medication [175, 184, 204, 205]. Absorption of sildenafil can be delayed by a
meal, and absorption of vardenafil can be delayed by a fatty meal [206]. Absorption of tadalafil is less affected
provided there is enough delay between oral ingestion and an attempt at sexual intercourse [201]. When
avanafil is taken with a high fat meal, the rate of absorption is reduced with a mean delay in Tmax of 1.25 hours
and a mean reduction in Cmax of 39% (200 mg). There is no effect on the extent of exposure (AUC). The small
changes in avanafil Cmax are considered to be of minimal clinical significance [180, 181, 184].
It is possible to wait too long after taking the medication before attempting sexual intercourse.
The half-life of sildenafil and vardenafil is about four hours, suggesting that the normal window of efficacy is
six to eight hours following drug ingestion, although responses following this time period are well recognised.
The half-life of avanafil is six to seventeen hours. Tadalafil has a longer half-life of ~17.5 hours, so the window
of efficacy is much longer at ~36 hours. Data from uncontrolled studies suggest patient education can help
salvage an apparent non-responder to a PDE5I [207-211]. After emphasising the importance of dose, timing,
and sexual stimulation to the patient, erectile function can be effectively restored following re-administration of
the relevant PDE5I [207-209].
Recent data suggested that response to sildenafil treatment was also dependent on polymorphism in the
PDE5A gene, which encodes the principal cGMP-catalysing enzyme in the penis, regulating cGMP clearance,
and it is the primary target of sildenafil [212]. Overall, the findings of a meta-regression aimed at evaluating the
effectiveness and prognostic factors of PDE5I to treat ED showed that PDE5Is are more effective in Caucasians
than Asians, and in patients with more severe ED [213].
Clinical strategies in patients correctly using a PDE5Is

Data suggest that almost half of patients abandon first-generation PDE5Is within one year, with no single
specific factor playing a major role in PDE5Is dropout rates [214].
There is controversial evidence suggesting that, in patients with testosterone deficiency, TS might improve
a patient’s response to a PDE5I [95, 215-218]. Modification of other risk factors may also be beneficial as
discussed in section 3.1.4.1.1. Limited data suggest that some patients might respond better to one PDE5I
than to another [219]. Although these differences might be explained by variations in drug pharmacokinetics,
they do raise the possibility that, despite an identical mode of action, switching to a different PDE5I might be
helpful. Moreover, mainly in patients with severe ED, it has been suggested to combine tadalafil daily dosing
with a short acting PDE5I (such as sildenafil), without any significant increase in terms of side-effects [220]. If
drug treatment fails, then patients should be offered an alternative therapy such as intracavernous injection
therapy or use of a vacuum erection device (VED).
The combination of long-acting injectable testosterone undecanoate and tadalafil 5 mg once daily produced a
significant improvement in terms of erectile function of combined treatment [221]. Moreover, the improvement
in erectile function was well maintained, even after the cessation of treatment.
3.1.4.2.1.2 Vacuum erection devices

Vacuum erection devices (VED) provide passive engorgement of the corpora cavernosa, together with a
constrictor ring placed at the base of the penis to retain blood within the corpora. Published data report that
efficacy, in terms of erections satisfactory for intercourse, is as high as 90%, regardless of the cause of ED
and satisfaction rates range between 27% and 94% [222, 223]. Most men who discontinue use of VEDs do so
within three months. Long-term use of VEDs decreases to 50-64% after two years [224]. The most common
adverse events include pain, inability to ejaculate, petechiae, bruising, and numbness, which occur in < 30%
of patients [223]. Serious adverse events (skin necrosis) can be avoided if patients remove the constriction
ring within 30 minutes after intercourse. Vacuum erection devices are contraindicated in patients with bleeding
disorders or on anticoagulant therapy. Vacuum erection devices may be the treatment of choice in well-
informed older patients with infrequent sexual intercourse and comorbidity requiring non-invasive, drug-free
management of ED [222, 223, 225].

3.1.4.2.1.3 Topical/Intraurethral Alprostadil
The vasoactive agent alprostadil can be administered per urethra in two different ways. A first less invasive
way is the topical route using a cream that includes a permeation enhancer in order to facilitate absorption
of alprostadil (200 and 300μg) via the urethral meatus [226, 227]. Clinical data are still limited. Significant
improvement compared to placebo was recorded for IIEF-EF domain score, SEP2 and SEP3 in a broad
range of patients with mild-to-severe ED [228]. Side-effects include penile erythema, penile burning and pain
that usually resolve within two hours of application. Systemic side effects are very rare. Topical alprostadil
(VITAROSTM) at the dose of 300 μg is currently approved and it is available in some European countries.
The second route of administration is intraurethral insertion of a specific formulation of alprostadil (125-1000
μg) in a medicated pellet (MUSE™) [229]. Erections sufficient for intercourse are achieved in 30-65.9% of
patients. In clinical practice, it is recommended that intra-urethral alprostadil be initiated at a dose of 500 μg,
as it has a higher efficacy than the 250 μg dose, with minimal differences with regard to adverse events. In
case of unsatisfactory clinical response the dose can be increased to 1000 μg [229-231]. The application of a
constriction ring at the root of the penis (ACTIS™) may improve efficacy [230, 231].
The most common adverse events are local pain (29-41%) and dizziness with possible hypotension (1.9-14%).
Penile fibrosis and priapism are very rare (< 1%). Urethral bleeding (5%) and urinary tract infections (0.2%) are
adverse events related to the mode of administration. Efficacy rates are significantly lower than intracavernous
pharmacotherapy [232], with a very low rate (~30%) of adherence to long-term therapy. Intraurethral
pharmacotherapy provides an alternative to intracavernous injections in patients who prefer a less-invasive,
although less-efficacious treatment.
3.1.4.2.1.4 Shockwave therapy

The use of low-intensity extracorporeal shockwave therapy (LI-SWT) has been increasingly proposed as a
treatment for ED over the last decade [233-239]. Overall, most of these studies reported encouraging results,
regardless of variation in LI-SWT set-up parameters or treatment protocols [240]. As a whole these studies
suggest that LI-SWT could significantly improve the IIEF and Erection Hardness Score of mild ED patients
[241]. Likewise, data suggest that LI-SWT could ameliorate erection quality even in patients with severe
ED who are PDE5Is non-responders [238, 242] or inadequate responders [241]. However, the publication
of unequivocal evidence from additional RCTs and longer-term follow-up would provide more confidence
regarding the use of LI-SWT (including detailed number of pulses per patient, treatment protocols) for ED
patients [243]. Therefore clear and definitive recommendations cannot be given [240, 241].
3.1.4.2.2 Second-line therapy

Patients not responding to oral drugs may be offered intracavernous injections. The success rate is high (85%)
[232, 244]. Intracavernous administration of vasoactive drugs was the first medical treatment for ED introduced
more than twenty years ago [211, 245].
3.1.4.2.2.1 Intracavernous injections

3.1.4.2.2.1.1 Alprostadil
Alprostadil (CaverjectTM, Edex/ViridalTM) was the first and only drug approved for intracavernous treatment of
ED [211, 245]. Intracavernous alprostadil is most efficacious as monotherapy at a dose of 5-40 μg (of note,
40 μg dose is not registered in every European country). The erection appears after five to fifteen minutes
and lasts according to the dose injected. An office-training programme is required for the patient to learn the
correct injection process. In cases of limited manual dexterity, the technique may be taught to their partners.
The use of an automatic special pen that avoids a view of the needle can resolve fear of penile puncture
and simplifies the technique. Efficacy rates for intracavernous alprostadil of > 70% have been found in the
general ED population, as well as in patient subgroups (e.g. diabetes or CVD), with reported sexual activity
of 94% after the injections and satisfaction rates of 87-93.5% in patients and 86-90.3% in partners [211,
245]. Complications of intracavernous alprostadil include penile pain (50% of patients reported pain only after
11% of total injections), prolonged erections (5%), priapism (1%), and fibrosis (2%) [211, 245, 246]. Pain is
usually self-limited after prolonged use. It can be alleviated with the addition of sodium bicarbonate or local
anaesthesia [211, 245, 247]. Cavernosal fibrosis (from a small haematoma) usually clears within a few months
after temporary discontinuation of the injection programme. However, tunical fibrosis suggests early onset of
Peyronie’s disease and may indicate stopping intracavernous injections indefinitely. Systemic side-effects are
uncommon. The most common is mild hypotension, especially when using higher doses. Contraindications
include men with a history of hypersensitivity to alprostadil, men at risk of priapism, and men with bleeding
disorders. Despite these favourable data, drop-out rates of 41-68% have been described for intracavernous
pharmacotherapy [211, 245, 248, 249], with most drop-outs occurring within the first two to three months. In a

comparative study, alprostadil monotherapy had the lowest discontinuation rate (27.5%) compared to overall
drug combinations (37.6%), with an attrition rate after the first few months of therapy of 10% per year. Reasons
for discontinuation included desire for a permanent modality of therapy (29%), lack of a suitable partner (26%),
poor response (23%) (especially among early drop-out patients), fear of needles (23%), fear of complications
(22%), and lack of spontaneity (21%). Careful counselling of patients during the office-training phase as well
as close follow-up is important in addressing patient withdrawal from an intracavernous injection programme
[250].
3.1.4.2.2.1.2 Combination therapy

Combination therapy enables a patient to take advantage of the different modes of action of the drugs being
used, as well as alleviating side-effects by using lower doses of each drug.
• Papaverine (20-80 mg) was the first oral drug used for intracavernous injections. It is most commonly
used in combination therapy due to its high incidence of side-effects as monotherapy. Papaverine is
currently not licensed for the treatment of ED.
• Phentolamine has been used in combination therapy to increase efficacy. As monotherapy, it produces a
poor erectile response.
• Sparse data in the literature support the use of other drugs, such as vasoactive intestinal peptide (VIP),
NO donors (linsidomine), forskolin, potassium channel openers, moxisylyte or calcitonin gene-related
peptide, usually combined with the main drugs [251, 252]. Most combinations are not standardised and
some drugs have limited availability worldwide.
• Papaverine (7.5-45 mg) plus phentolamine (0.25-1.5 mg), and papaverine (8-16 mg) plus phentolamine
(0.2-0.4 mg) plus alprostadil (10-20 μg), have been widely used with improved efficacy rates, although
they have never been licensed for ED [253, 254]. The triple combination regimen of papaverine,
phentolamine and alprostadil has the highest efficacy rates, reaching 92%; this combination has similar
side-effects as alprostadil monotherapy, but a lower incidence of penile pain due to lower doses of
alprostadil. However, fibrosis is more common (5-10%) when papaverine is used (depending on total
dose).
• Vasoactive intestinal peptide (25 μg) plus phentolamine mesylate (1-2 mg InvicorpTM), currently licensed
in Scandinavia, is a combination of two active components with complementary modes of action.
Clinical studies showed that the combination is an effective treatment for intracavernous injections in >
80% of men with ED, including those who have failed to respond to other therapies and, unlike existing
intracavernous therapies, is associated with a very low incidence of penile pain and virtually negligible risk
of priapism [255].
Despite high efficacy rates, 5-10% of patients do not respond to combination intracavernous injections. The
combination of sildenafil with intracavernous injection of the triple combination regimen may salvage as many
as 31% of patients who do not respond to the triple combination alone [256]. However, combination therapy
is associated with an increased incidence of adverse effects in 33% of patients, including dizziness in 20% of
patients. This strategy can be considered in carefully selected patients before proceeding to a penile implant
(LE: 4).
3.1.4.2.3 Third-line therapy (penile prostheses)

The surgical implantation of a penile prosthesis may be considered in patients who do not respond to
pharmacotherapy or who prefer a permanent solution to their problem [257]. The two currently available
classes of penile implants include inflatable (2- and 3-piece) and semi-rigid devices (malleable, mechanical,
soft flexible) [67, 139, 258-260]. Most patients prefer the 3-piece inflatable devices due to the more “natural”
erections obtained. Likewise, 3-piece inflatable devices provide the best rigidity and the best flaccidity because
they will fill every part of the corporal bodies. However, the 2-piece inflatable prosthesis can be a viable option
among patients who are deemed at high-risk of complications with reservoir placements. Semi-rigid prostheses
result in a firm penis, which may be manually placed in an erect or flaccid state and offer the advantage of a
feasible implant technique as well as a simpler use for the patient [67, 139, 258, 259]. On the contrary, they
have the disadvantage of unnatural erection, reduce concealability,suboptimal penile length and girth [259,
261].
There are two main surgical approaches for penile prosthesis implantation: penoscrotal and infrapubic [258,
259, 261, 262]. The penoscrotal approach provides an excellent exposure, it affords proximal crural exposure
if necessary, avoids dorsal nerve injury and permits direct visualisation of pump placement. However, with this
approach, the reservoir either placed blindly into the retropubic space, which can be a problem in patients
with a history of major pelvic surgery (mainly radical cystectomy) or a separate incision in the abdomen
is used to insert the reservoir under direct vision. The infrapubic approach has the advantage of reservoir

placement under direct vision, but the implantation of the pump may be more challenging, and patients are at
a slightly increased risk of penile dorsal nerve injury. Revision surgery is associated with decreased outcomes
and may be more challenging. Regardless of the indication, prosthesis implantation has one of the highest
satisfaction rates (92-100% in patients and 91-95% in partners) among the treatment options for ED based
on appropriate consultation [67, 139, 258, 263-270]. In patients with favourable oncologic prognosis after RP
for PCa, combination surgery for treatment of ED, with the implant of a penile prosthesis, and stress urinary
incontinence (male sling or artificial urinary sphincter) is effective and durable and has an established, definitive
role to address this problem [67, 139, 271-273]. Structured psychosexual counselling may improve sexual
activities and erotic functions in both patients and their partners after penile implants [274].
3.1.4.2.3.1 Complications
The two main complications of penile prosthesis implantation are mechanical failure and infection. Several
technical modifications of the most commonly used 3-piece prosthesis (AMS 700CX/CXRTM and Coloplast
Titan Zero degreeTM resulted in mechanical failure rates of < 5% after five years of follow-up [139, 275, 276].
Careful surgical techniques with proper antibiotic prophylaxis against Gram-positive and Gram-negative
bacteria reduces infection rates to 2-3% with primary implantation in low-risk patients and in high volume
centres [277-279]. The infection rate may be further reduced to 1-2% by implanting an antibiotic-impregnated
prosthesis (AMS Inhibizone™) or hydrophilic-coated prosthesis (Coloplast Titan™) [139, 277, 280-283]. As a
whole, growing evidence exists that the risk of penile prosthesis infection has reduced over the decades with
device improvement and surgical expertise [284].
Higher-risk populations include patients undergoing revision surgery, those with impaired host defences
(immunosuppression, diabetes mellitus, spinal cord injury) or those with penile corporal fibrosis [17, 139,
258, 279, 285, 286]. Infection requires removal of the prosthesis and antibiotic administration. Alternatively,
removal of the infected device with immediate replacement with a new prosthesis has been described using
a washout protocol with successful salvages achieved in > 80% of cases [278, 279, 285, 287]. The majority of
revisions are secondary to mechanical failure and combined erosion or infection [282, 288]. 93% of cases are
successfully revised, providing functioning penile prosthesis [277-279, 289, 290].
3.1.4.2.3.2 Conclusions third-line therapy

Penile implants are an effective solution for patients who do not respond to more conservative therapies. There
is sufficient evidence to recommend this approach in patients not responding to less-invasive treatments due
to its high efficacy, safety and satisfaction rates [291].
Table 7: Penile prostheses models available on the market
Semi-rigid prostheses Inflatable prostheses

Two-piece Three-piece
Spectra ™ [AMS] Ambicor™ [AMS] Titan OTR ™ (One Touch Release)
[Coloplast]
Genesis ™ [Mentor] Titan OTR NB ™ (Narrow base)
[Coloplast]
Titan Zero Degree ™
Tube ™ [Promedon] AMS 700 CX ™ [Boston Scientific]
ZSI 100 ™ [Zephyr] AMS 700 LGX ™ [Boston Scientific]
Virilis II ™ [Subrini] AMS 700 CXR ™ [Boston Scientific]
ZSI 475 ™ [Zephyr]
3.1.4.3 Recommendations for the treatment of ED

Enact lifestyle changes and risk factor modification prior to or accompanying erectile Strong
dysfunction (ED) treatment.
Support the resumption of sexual activity through pro-erectile treatments at the earliest Strong
opportunity after radical prostatectomy.
Treat a curable cause of ED first, when found. Weak
Use phosphodiesterase type 5 inhibitors (PDE5Is) as first-line therapy. Strong

Assess all patients for inadequate/incorrect information about the mechanism of action Weak
and the ways in which drugs should be taken, since they are the main causes of a lack of
response to PDE5Is.
Use vacuum erection devices as a first-line therapy in well-informed older patients Weak
with infrequent sexual intercourse and comorbidity requiring non-invasive, drug-free
management of ED.
Use low intensity shockwave treatment in mild organic ED patients or poor responders to Weak
PDE5Is.
Use topical/intraurethral Alprostadil as an alternative to intracavernous injections in patients Weak
who prefer a less-invasive therapy.
Use intracavernous injections as second-line therapy. Strong
Use implantation of a penile prosthesis as third-line therapy. Strong
3.1.4.4 Follow-up
Follow-up is important in order to assess efficacy and safety of the treatment provided. It is also essential to
assess patient satisfaction since successful treatment for ED goes beyond efficacy and safety. Physicians
must be aware that there is no single treatment that fits all patients or all situations as described in detail in the
previous section.
3.2 Premature ejaculation

3.2.1 Epidemiology/aetiology/pathophysiology
Although premature ejaculation is a common male sexual dysfunction, it is poorly understood. Patients are
often unwilling to discuss their symptoms and many physicians do not know about effective treatments. As a
result, patients may be misdiagnosed or mistreated [2].
3.2.1.1 Epidemiology
The major problem in assessing the prevalence of PE is the lack of an accurate (validated) definition at the
time the surveys were conducted [292]. The highest prevalence rate of 31% (men aged 18-59 years) was
found by the USA National Health and Social Life Survey (NHSLS) study [293]. Prevalence rates were 30%
(18-29 years), 32% (30-39 years), 28% (40-49 years) and 55% (50-59 years). It is, however, unlikely that the
PE prevalence is as high as 20-30% based on the relatively low number of men who present for treatment of
PE. These high prevalence rates may be a result of the dichotomous scale (yes/no) in a single question asking
if ejaculation occurred too early, as the prevalence rates in European studies have been significantly lower
[294]. According to the four PE subtypes proposed by Waldinger et al. [295], the prevalence rates were 2.3%
(lifelong PE), 3.9% (acquired PE), 8.5% (natural variable PE) and 5.1% (premature-like ejaculatory dysfunction)
[296]. An approximately 5% prevalence of acquired PE and lifelong PE in general populations is consistent
with epidemiological data indicating that around 5% of the population have an ejaculation latency of less than
2 minutes [297].
3.2.1.2 Pathophysiology and risk factors

The aetiology of PE is unknown, with little data to support suggested biological and psychological hypotheses,
including anxiety, penile hypersensitivity, and 5-HT receptor dysfunction [298]. In addition, the pathophysiology
of PE is largely unknown. All the physiological events leading up to the forceful expulsion of sperm at the
urethral meatus are not impaired in PE patients. A significant proportion of men with ED also experience PE
[299, 300]. High levels of performance anxiety related to ED may worsen PE, with a risk of misdiagnosing PE
instead of the underlying ED. According to the NHSLS, the prevalence of PE is not affected by age [293, 294],
unlike ED, which increases with age. Premature ejaculation is not affected by marital or income status [293].
However, PE is more common in Black men, Hispanic men and men from Islamic backgrounds [301, 302]
and may be higher in men with a lower educational level [293, 300]. Other risk factors may include a genetic
pre-disposition [303], poor overall health status and obesity [293], prostate inflammation [304-306], thyroid
hormone disorders [307], diabetes [308, 309], lack of physical activity [310], emotional problems and stress
[293, 311, 312], and traumatic sexual experiences [293, 300]. In the only published study on risk modification/
prevention strategies [313], successful eradication of causative organisms in patients with chronic prostatitis
and PE produced marked improvements in intravaginal ejaculatory latency time (IELT) and ejaculatory control
compared to untreated patients [314].
3.2.1.3 Impact of PE on QoL

Men with PE are more likely to report low satisfaction with their sexual relationship, low satisfaction with
sexual intercourse, difficulty relaxing during intercourse, and less frequent intercourse [315, 316]. However,
the negative impact of PE extends beyond sexual dysfunction. Premature ejaculation can have a detrimental

effect on self-confidence and the relationship with the partner, and may sometimes cause mental distress,
anxiety, embarrassment and depression [315, 317]. Sex drive and overall interest in sex does not appear to be
affected by PE [318]. However, the partner’s satisfaction with the sexual relationship decreases with increasing
severity of the man’s condition [319]. Despite the possible serious psychological and QoL consequences of PE,
few men seek treatment. In the Global Study of Sexual Attitudes and Behaviors survey, 78% of men who self-
reported a sexual dysfunction sought no professional help or advice for their sexual problems [300], with men
more likely to seek treatment for ED than for PE [300]. In the Premature Ejaculation Prevalence and Attitudes
survey, only 9% of men with self-reported PE consulted a doctor [294]. The main reasons for not discussing
PE with their physician are embarrassment and a belief that there is no treatment. Physicians are often
uncomfortable discussing sexuality with their patients usually because of embarrassment and a lack of training
or expertise in treating PE [320, 321]. Physicians need to encourage their patients to talk about PE.
3.2.2 Classification
There have previously been two official definitions of PE, neither of which have been universally accepted:
In the Diagnostic and Statistical Manual of Mental Disorders IV-Text Revision (DSM-IV-TR), PE is defined as a
‘persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and
before the person wishes it. The clinician must take into account factors that affect duration of the excitement
phase, such as age, novelty of the sexual partner or situation, and recent frequency of sexual activity’ [322]. This
DSM definition has been recently updated in the DSM V edition [323].
The International Society for Sexual Medicine (ISSM) has adopted a completely new definition of PE which
is the first evidence-based definition [324]. Premature ejaculation (lifelong and acquired) is a male sexual
dysfunction characterised by the following:
• Ejaculation that always or nearly always occurs prior to or within about one minute of vaginal penetration
(lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about three
minutes or less (acquired PE).
• The inability to delay ejaculation on all or nearly all vaginal penetrations.
• Negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual
intimacy.
Two more PE syndromes have been proposed [325]:

• ‘Variable PE’ is characterised by inconsistent and irregular early ejaculations, representing a normal
variation in sexual performance.
• ‘Subjective PE’ is characterised by subjective perception of consistent or inconsistent rapid ejaculation
during intercourse, while ejaculation latency time is in the normal range or can even last longer. It should
not be regarded as a symptom or manifestation of true medical pathology.
The addition of these new types may aid patient stratification, diagnosis and treatment, but their exact role
remains to be defined [326].
3.2.3 Diagnostic evaluation

Diagnosis of PE is based on the patient’s medical and sexual history [327, 328]. History should classify PE as
lifelong or acquired and determine whether PE is situational (under specific circumstances or with a specific
partner) or consistent. Special attention should be given to the duration time of ejaculation, degree of sexual
stimulus, impact on sexual activity and QoL, and drug use or abuse. It is also important to distinguish PE
from ED. Many patients with ED develop secondary PE caused by the anxiety associated with difficulty in
attaining and maintaining an erection [299, 329]. Furthermore, some patients are not aware that loss of erection
after ejaculation is normal and may erroneously complain of ED, while the actual problem is PE [330]. There
are several overlapping definitions of PE, with four shared factors (Table 7), resulting in a multidimensional
diagnosis [331].
Table 7: Common factors in different definitions of PE
Time to ejaculation assessed by IELT

Perceived control
Distress
Interpersonal difficulty related to the ejaculatory dysfunction

3.2.3.1 Intravaginal ejaculatory latency time
The use of IELT alone is not sufficient to define PE, as there is significant overlap between men with and
without PE [332, 333]. Intravaginal ejaculatory latency time has a significant direct effect on perceived control
over ejaculation, but not a significant direct effect on ejaculation-related personal distress or satisfaction with
sexual intercourse [334]. In addition, perceived control over ejaculation has a significant direct effect on both
ejaculation-related personal distress and satisfaction with sexual intercourse (each showing direct effects on
interpersonal difficulty related to ejaculation). In everyday clinical practice, self-estimated IELT is sufficient
[335]. Self-estimated and stopwatch-measured IELT are interchangeable and correctly assign PE status with
80% sensitivity and 80% specificity [336]. Specificity can be improved further to 96% by combining IELT with a
single-item patient-reported outcome (PRO) on control over ejaculation and satisfaction with sexual intercourse
(scale ranging from 0 = very poor to 4 = very good) and on personal distress and interpersonal difficulty
(0 = not at all, to 4 = extremely). However, self-estimated IELT may be over-estimated by approximately one
minute and therefore it must be carefully substituted with stopwatch-measured IELT while identifying men with
the complaint of lifelong PE in a clinical setting [337]. Stopwatch-measured IELT is necessary in clinical trials.
While IELT is an objective tool for PE assessment, a recent study reported that sexual satisfaction and distress
correlated more strongly with the feeling of control than with the self-reported latency time [338].
3.2.3.2 PE assessment questionnaires

The need to assess PE objectively has led to the development of several questionnaires based on the use of
PROs [331]. Only two questionnaires can discriminate between patients who have PE and those who do not:
• Premature Ejaculation Diagnostic Tool (PEDT): five-item questionnaire based on focus groups and
interviews from the USA, Germany and Spain. Assesses control, frequency, minimal stimulation, distress
and interpersonal difficulty [339, 340]. A total score > 11 suggests a diagnosis of PE, a score of 9 or 10
suggests a probable diagnosis of PE while a score of < 8 indicates a low likelihood of PE.
• Arabic Index of Premature Ejaculation (AIPE): seven-item questionnaire developed in Saudi Arabia
assesses sexual desire, hard erections for sufficient intercourse, time to ejaculation, control, satisfaction
for the patient and partner, anxiety or depression [341]. A cut-off score of 30 (range of scores 7-35)
discriminated best PE diagnosis. Severity of PE was classified as severe (score: 7-13), moderate
(score: 14-19), mild-to-moderate (score: 20-25) and mild (score: 26-30).
The most widely used tool is the PEDT. However, there is a low correlation between a diagnosis provided by
PEDT and a self-reported diagnosis. A recent study reported that only 40% of men with PEDT-diagnosed PE
and 19% of men with probable PE self-reported the condition [342]. Questionnaires are a significant step in
simplifying the methodology of PE drug studies, although further cross-cultural validation is needed [343].
Other questionnaires used to characterise PE and determine treatment effects include the PEP [333], Index of
Premature Ejaculation (IPE) [344] and Male Sexual Health Questionnaire Ejaculatory Dysfunction (MSHQ-EjD)
[345]. Currently, their role is optional in everyday clinical practice.
3.2.3.3 Physical examination and investigations

Physical examination may be part of the initial assessment of men with PE. It may include a brief examination
of the endocrine and neurological systems to identify underlying medical conditions associated with PE or
other sexual dysfunctions, such as endocrinopathy, Peyronie’s disease, urethritis or prostatitis. Laboratory or
physiological testing should be directed by specific findings from history or physical examination and is not
routinely recommended [327].
3.2.3.4 Recommendations for the diagnostic evaluation of PE

Perform the diagnosis and classification of premature ejaculation (PE) based on medical Strong
and sexual history, which should include assessment of intravaginal ejaculatory latency time
(IELT) (self-estimated), perceived control, distress and interpersonal difficulty due to the
ejaculatory dysfunction.
Do not use stopwatch-measured IELT in clinical practice. Weak
Use patient-reported outcomes in daily clinical practice. Weak
Include physical examination in the initial assessment of PE to identify anatomical Strong
abnormalities that may be associated with PE or other sexual dysfunctions, particularly
erectile dysfunction.
Do not perform routine laboratory or neuro-physiological tests. They should only be directed Strong
by specific findings from history or physical examination.

3.2.4 Disease management
In men for whom PE causes few, if any, problems, treatment is limited to psychosexual counselling and
education. Before beginning treatment, it is essential to discuss the patient’s expectations thoroughly.
Furthermore, it is important firstly to treat, if present, ED and possibly prostatitis. Various behavioural
techniques have been beneficial in treating PE and are indicated for patients uncomfortable with
pharmacological therapy. In lifelong PE, behavioural techniques are not recommended for first-line treatment.
They are time-intensive, require the support of a partner and can be difficult to perform. In addition, long-term
outcomes of behavioural techniques for PE are unknown. Pharmacotherapy is the basis of treatment in lifelong
PE. Dapoxetine is the only on-demand pharmacological treatment approved for PE in many countries except
for the USA. All other medications used in PE are off-label indications. Chronic antidepressants including
selective serotonin re-uptake inhibitors (SSRIs) and clomipramine, a tricyclic antidepressant and on-demand
topical anaesthetic agents have consistently shown efficacy in PE. Long-term outcomes for pharmacological
treatments are unknown. An evidence-based analysis of all current treatment modalities was performed. Levels
of evidence and grades of recommendation are provided and a treatment algorithm is presented (Figure 4).
3.2.4.1 Psychological/behavioural strategies

Behavioural strategies mainly include the ‘stop-start’ programme developed by Semans [346] and its
modification, the ‘squeeze’ technique, proposed by Masters and Johnson [347]:
• In the ‘stop-start’ programme, the partner stimulates the penis until the patient feels the urge to ejaculate.
At this point, he instructs his partner to stop, waits for the sensation to pass and then stimulation is
resumed.
• The ‘squeeze’ technique is similar but the partner applies manual pressure to the glans just before
ejaculation until the patient loses his urge.
Both these procedures are typically applied in a cycle of three pauses before proceeding to orgasm.
Behavioural strategies are based on the hypothesis that PE occurs because the man fails to appreciate the
sensations of heightened arousal and to recognise the feelings of ejaculatory inevitability. Re-training may
attenuate stimulus-response connections by gradually exposing the patient to progressively more intense
and more prolonged stimulation, while maintaining the intensity and duration of the stimulus just below the
threshold for triggering the response. There are several modifications of these techniques making comparison
difficult.
Masturbation before anticipation of sexual intercourse is a technique used by younger men. Following
masturbation, the penis is desensitised resulting in greater ejaculatory delay after the refractory period is over.
In a different approach, the man learns to recognise the signs of increased sexual arousal and how to keep
his level of sexual excitement below the intensity that elicits the ejaculatory reflex. Efficacy is similar to the
‘stop-start’ programme [348].
Psychological factors may be associated with PE and should be addressed in treatment. These factors
mainly relate to anxiety, but could also include relationship factors [316]. The limited studies available suggest
that behavioural therapy, as well as functional sexological treatment, lead to improvement in the duration of
intercourse and sexual satisfaction [349, 350].
Overall, short-term success rates of 50-60% have been reported [349, 350] with limited evidence on the
efficacy of these behavioural therapies on IELT improvement [351]. A double-blind, randomised, crossover
study showed that pharmacological treatment (chlomipramine, sertraline, paroxetine and sildenafil) resulted
in greater IELT prolongation than behavioural therapy [352]. Furthermore, clinical experience suggests that
improvements achieved with these techniques are generally not maintained long-term [353, 354]. Behavioural
therapy may be most effective when used to ‘add value’ to medical interventions. A combination of dapoxetine
and behavioural treatment was more effective than dapoxetine alone in patients with lifelong PE in a
prospective, randomised trial [355]. Validated assessment instruments need to be used as end-points. Longer
follow-up periods are necessary to confirm these findings.
3.2.4.2 Pharmacotherapy
3.2.4.2.1 Dapoxetine
Dapoxetine hydrochloride is a short-acting SSRI, with a pharmacokinetic profile suitable for on-demand
treatment for PE. It has a rapid Tmax (1.3 hours) and a short half-life (95% clearance rate after
24 hours) [356]. Dapoxetine has been investigated in 6,081 subjects to date [357]. It is approved for
on-demand treatment of PE in European countries and elsewhere, but not in the USA. Both available
doses of dapoxetine (30 mg and 60 mg) have shown 2.5- and 3.0-fold increases, respectively, in IELT
overall, rising to 3.4- and 4.3-fold in patients with a baseline average ELT of < 0.5 minutes [358, 359].

In RCTs, dapoxetine, 30 mg or 60 mg one to two hours before intercourse, was effective from the
first dose on IELT and increased ejaculatory control, decreased distress, and increased satisfaction.
Dapoxetine has shown a similar efficacy profile in men with lifelong and acquired PE [359-361].
Treatment-related side-effects were dose-dependent and included nausea, diarrhoea, headache
and dizziness. Side-effects were responsible for study discontinuation in 4% (30 mg) and 10% (60 mg)
of subjects [335]. There was no indication of an increased risk of suicidal ideation or suicide attempts and little
indication of withdrawal symptoms with abrupt dapoxetine cessation [362]. Moreover, dapoxetine is found to
be safer compared with other anti-depressants which are used for the treatment of PE [363].
Regarding a combination of PDE5Is with dapoxetine, the addition of dapoxetine to a given regimen of PDE5Is
may increase the risk of possible prodromal symptoms that may progress to syncope compared to both
PDE5Is inhibitors and SSRIs administered alone. Generally, when dapoxetine is co-administered with PDE5Is,
it is well tolerated, with a safety profile consistent with previous phase 3 studies of dapoxetine alone [364].
A low rate of vasovagal syncope was reported in phase 3 studies. According to the summary of product
characteristics, orthostatic vital signs (blood pressure and heart rate) must be measured prior to starting
dapoxetine. No cases of syncope were observed in a post-marketing observational study, which had identified
patients at risk for orthostatic reaction using the patient’s medical history and orthostatic testing [365].
The mechanism of action of short-acting SSRIs in PE is still speculative. Dapoxetine resembles the
antidepressant SSRIs in the following ways: the drug binds specifically to the 5-HT re-uptake transporter
at subnanomolar levels, has only a limited affinity for 5-HT receptors and is a weak antagonist of the
1A-adrenoceptors, dopamine D1 and 5-HT2B receptors. The rapid absorption of dapoxetine might lead to
an abrupt increase in extracellular 5-HT following administration that might be sufficient to overwhelm the
compensating autoregulation processes. Does the mechanism of action of short-acting SSRIs differ from that
of the conventional chronic SSRI mechanism of action? Either such agents do not cause the auto-receptor
activation and compensation reported using chronic SSRIs, or these effects occur, but they simply cannot
prevent the action of short-acting SSRIs [366].
3.2.4.2.2 Off-label use of antidepressants: SSRIs and clomipramine

Ejaculation is commanded by a spinal ejaculation generator [367, 368] under excitatory or inhibitory influences
from the brain and the periphery [308]. 5-hydroxytryptamine (5-HT or serotonin) is involved in ejaculatory
control, with its ejaculation-retarding effects likely to be attributable to activation of 5-HT1B and 5-HT2C
receptors, both spinally and supraspinally. By contrast, stimulation of 5-HT1A receptors precipitates ejaculation
[366].
Selective serotonin re-uptake inhibitors are used to treat mood disorders, but can delay ejaculation and are
therefore widely used ‘off-label’ for PE. As for depression, SSRIs must be given for one to two weeks to be
effective in PE [366]. Administration of chronic SSRIs causes prolonged increases in synaptic cleft serotonin,
which desensitises the 5-HT1A and 5-HT1B receptors [369]. Clomipramine, the most serotoninergic tricyclic
antidepressant, was first reported in 1973 as an effective PE treatment [370]. Selective serotonin re-uptake
inhibitors have revolutionised treatment of PE, but they have also changed our understanding of PE since
the first publication on paroxetine in 1970 [371]. Before dapoxetine, daily treatment with SSRIs was the first
choice of treatment in PE. Commonly used SSRIs include citalopram, fluoxetine, fluvoxamine, paroxetine and
sertraline, all of which have a similar pharmacological mechanism of action.
Several SRs and meta-analyses of all drug treatment studies reported that, despite methodological problems in
most studies, there still remained several, well-designed, double-blind, placebo-controlled trials supporting the
therapeutic effect of daily SSRIs on PE [372, 373]. Nevertheless, despite significant increase in IELT, there are
no data available concerning the PROs in PE patients treated with daily SSRIs. Based on this meta-analysis,
SSRIs were expected to increase the geometric mean IELT by 2.6-fold to 13.2-fold. Paroxetine was found
to be superior to fluoxetine, clomipramine and sertraline. Sertraline was superior to fluoxetine, whereas the
efficacy of clomipramine was not significantly different from fluoxetine and sertraline. Paroxetine was evaluated
in doses of 20-40 mg, sertraline 25-200 mg, fluoxetine 10-60 mg and clomipramine 25-50 mg; there was no
significant relationship between dose and response among the various drugs. There is limited evidence that
citalopram may be less efficacious compared to other SSRIs, while fluvoxamine may not be effective [374,
375].
Ejaculation delay may start a few days after drug intake, but it is more evident after one to two weeks since
receptor de-sensitisation requires time to occur. Although efficacy may be maintained for several years,
tachyphylaxis (decreasing response to a drug following chronic administration) may occur after six to twelve
months [370]. Common side-effects of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry

mouth, diarrhoea and perspiration; which are usually mild and gradually improve after two to three weeks [326,
358]. Decreased libido, anorgasmia, anejaculation and ED have also been reported.
Because of a theoretical risk of suicidal ideation or suicide attempts, caution is suggested in prescribing SSRIs
to young adolescents with PE aged eighteen years or less, and to men with PE and a comorbid depressive
disorder, particularly when associated with suicidal ideation. Patients should be advised to avoid sudden
cessation or rapid dose reduction of daily dosed SSRIs which may be associated with a SSRI withdrawal
syndrome [335].
In one controlled trial, on-demand use of clomipramine (but not paroxetine), three to five hours before
intercourse, was reported to be efficacious, though IELT improvement was inferior compared to daily
treatment with the same drug [376]. However, on-demand treatment may be combined with an initial trial
of daily treatment or concomitant low-dose daily treatment reducing adverse effects [377, 378]. Individual
countries’ regulatory authorities strongly advise against prescribing medication for indications if the medication
in question is not licensed/approved and prescription of off-label medication may present difficulties for
physicians.
3.2.4.2.3 Topical anaesthetic agents

The use of local anaesthetics to delay ejaculation is the oldest form of pharmacological therapy for PE [379].
Several trials [380, 381] support the hypothesis that topical desensitising agents reduce the sensitivity of the
glans penis thereby delaying ejaculatory latency, but without adversely affecting the sensation of ejaculation. A
recent meta-analysis confirmed the efficacy and safety of these agents for the treatment of PE [382].
3.2.4.2.3.1 Lidocaine-prilocaine cream

In a randomised, double-blind, placebo-controlled trial, lidocaine-prilocaine cream increased the IELT from one
minute in the placebo group to 6.7 minutes in the treatment group [383]. In another randomised, doubleblind,
placebo-controlled trial, lidocaine-prilocaine cream significantly increased the stop-watch-measured IELT
from 1.49 to 8.45 minutes while no difference was recorded in the placebo group (1.67 to 1.95 minutes) A
recent internet-based prospective study revealed that lidocaine-based spray may be beneficial for men with
subjective PE as well [384].
Alternatively, the condom may be removed prior to sexual intercourse and the penis washed clean of any
residual active compound. Although no significant side-effects have been reported, topical anaesthetics are
contraindicated in patients or partners with an allergy to any ingredient in the product.
An experimental aerosol formulation of lidocaine, 7.5 mg, plus prilocaine, 2.5 mg (Topical Eutectic Mixture for
Premature Ejaculation [TEMPE]), was applied five minutes before sexual intercourse in 539 males. There was
an increase in the geometric mean IELT from a baseline of 0.58 minutes to 3.17 minutes during three months of
double-blind treatment; a 3.3-fold delay in ejaculation compared with placebo (p < 0.001) [385].
3.2.4.2.4 Tramadol
Tramadol is a centrally acting analgesic agent that combines opioid receptor activation and re-uptake inhibition
of serotonin and noradrenaline. Tramadol is readily absorbed after oral administration and has an elimination
half-life of five to seven hours. For analgesic purposes, tramadol can be administered between three and four
times daily in tablets of 50-100 mg. Side-effects were reported at doses used for analgesic purposes (up to
400 mg daily) and include constipation, sedation and dry mouth. Tramadol is a mild-opioid receptor agonist,
but it also displays antagonistic properties on transporters of noradrenaline and 5-HT [386]. This mechanism
of action distinguishes tramadol from other opioids, including morphine. However, in May 2009, the US Food
and Drug Administration released a warning letter about tramadol’s potential to cause addiction and difficulty in
breathing [387].
A large, randomised, double-blind, placebo-controlled, multicentre twelve week study was carried out to
evaluate the efficacy and safety of two doses of tramadol (62 and 89 mg) by ODT in the treatment of PE [388].
A bioequivalence study had previously been performed that demonstrated equivalence between tramadol ODT
and tramadol HCI. In patients with a history of lifelong PE and an IELT < 2 minutes, increases in the median
IELT of 0.6 minutes (1.6-fold), 1.2 minutes (2.4-fold) and 1.5 minutes (2.5-fold) were reported for placebo,
62 mg of tramadol ODT, and 89 mg of tramadol ODT, respectively. It should be noted that there was no dose
response effect with tramadol. The tolerability during the twelve-week study period was acceptable. Several
other studies also reported that tramadol exhibits a significant dose-related efficacy and side-effects over
placebo for treatment of PE [389]. Moreover, the efficacy and safety of tramadol have been confirmed in SRs
and meta-analyses [390, 391].

Tramadol has shown a moderate beneficial effect with a similar efficacy as dapoxetine. From what is known
about the neuropharmacology of ejaculation and the mechanism of action of tramadol, the delaying effect
on ejaculation could be explained by combined central nervous system μ-opioid receptor stimulation and
increased brain 5-HT availability. However, efficacy and tolerability of tramadol would have to be confirmed in
more patients and longer-term.
3.2.4.2.5 Phosphodiesterase type 5 inhibitors

There is only one well-designed, randomised, double-blind, placebo-controlled study comparing sildenafil to
placebo [392]. Although IELT was not significantly improved, sildenafil increased confidence, the perception
of ejaculatory control and overall sexual satisfaction, reduced anxiety and decreased the refractory time to
achieve a second erection after ejaculation.
Several open-label studies showed that PDE5Is combined with an SSRI is superior to SSRI monotherapy:
• Sildenafil combined with paroxetine improved IELT significantly and satisfaction vs. paroxetine alone
[393];
• Sildenafil combined with sertraline improved IELT and satisfaction significantly vs. sertraline alone [394];
• Sildenafil combined with paroxetine and psychological and behavioural counselling significantly improved
IELT and satisfaction in patients in whom other treatments failed [395];
• Sildenafil combined with dapoxetine (30 mg.) improved IELT, satisfaction scores and PEDT vs. in
comparison with dapoxetine, paroxetine or sildenafil monotherapy [396];
• Tadalafil combined with paroxetine significantly improved IELT and satisfaction vs. paroxetine and
tadalafil alone [397];
• Finally, sildenafil combined with behavioural therapy significantly improved IELT and satisfaction vs.
behavioural therapy alone [398].
There are very limited data on the efficacy of other PDE5Is (tadalafil and vardenafil) [399, 400]. However, recent
meta-analyses demonstrated that the combined use of SSRIs and PDE5Is may be more effective compared
with SSRIs or PDE5Is monotherapy [401-404].
3.2.4.2.6 Other drugs

In addition to the aforementioned drugs, there is continuous research for other treatment options. Considering
the abundant alpha 1a adrenergic receptors in seminal vesicles and prostate, and the role of sympathetic
system in the ejaculation physiology, the efficacy of selective alpha-blockers in the treatment of PE has
been assessed [405]. A recent study demonstrated that wake-promoting agent modafinil may be effective in
delaying ejaculation and improving the patient reported outcome measures [406]. Some authors compared
the efficacy of acupuncture and dapoxetine for the treatment of PE [407]. Although the authors demonstrated
that acupuncture had a significant ejaculation-delaying effect, this was less effective compared with that of
dapoxetine.
3.2.5 Summary of evidence on the epidemiology/aetiology/pathophysiology of PE
Pharmacotherapy includes either dapoxetine on demand (a short-acting SSRI that is the only 1a
approved pharmacological treatment for PE) or other off-label antidepressants, i.e. daily SSRIs and
clomipramine, that are not amenable to on-demand dosing. With all antidepressant treatment for PE,
recurrence is likely after treatment cessation.
3.2.6 Recommendations for the treatment of PE

Treat erectile dysfunction (ED), other sexual dysfunction or genitourinary infection Strong
(e.g. prostatitis) first.
Use pharmacotherapy as first-line treatment for lifelong premature ejaculation (PE). Strong
Use off-label topical anaesthetic agents as a viable alternative to oral treatment with Strong
selective serotonin re-uptake inhibitor (SSRIs).
Use tramadol on demand as a weak alternative to SSRIs. Strong
Use PDE5Is alone or in combination with other therapies in patients with PE (without ED). Strong
Use psychological/behavioural therapies in combination with pharmacological treatment in Weak
the management of acquired PE.

Figure 4: Management of Premature Ejaculation*
Clinical diagnosis of premature ejaculaon

based on paent +/- partner history
• Time to ejaculaon (IELT)
• Perceived degree of ejaculatory control
• Degree of bother/stress
• Onset and duraon of PE
• Psychosocial/relaonship issues
• Medical history
• Physical examinaon
Treatment of premature ejaculaon

Paent counselling/educaon
Discussion of treatment opons
If PE is secondary to ED, treat ED first or
concomitantly
• Pharmacotherapy (recommended as first-line

treatment opon in lifelong PE)
o Dapoxene for on-demand use (the only
approved drug for PE)
o Off-label treatments include chronic daily use
of andepressants (SSRIs or clomipramine)
and topical anaesthecs or oral tramadol on
demand
• Behavioural therapy, includes stop/start
technique, squeeze and sensate focus
• Combinaon treatment
* Adapted from Lue et al. 2004 [408].

ED = erectile dysfunction; PE = premature ejaculation; IELT = intravaginal ejaculatory latency time;
SSRI = selective serotonin receptor inhibitor.
3.3 Penile curvature

3.3.1 Congenital penile curvature
3.3.1.1 Epidemiology/aetiology/pathophysiology
Congenital curvature is rare. One well-performed study reports an incidence of less than 1% [409] while there
are reports from studies which claim that it is more common with prevalence rates of 4-10% in the absence of
hypospadias [410].
Congenital penile curvature results from disproportionate development of the tunica albuginea of the corporal
bodies and is not associated with urethral malformation. In the majority of cases the curvature is ventral but it
can also be lateral though rarely dorsal.
3.3.1.2 Diagnostic evaluation

Taking a medical and sexual history is usually sufficient to establish a diagnosis of congenital penile curvature.
Patients usually present after reaching puberty as the curvature becomes more apparent with erections,
and severe curvature can make intercourse difficult or impossible. Physical examination during erection
(autophotograph or after intracavernous injection of vasoactive drugs) is useful to document curvature and
exclude other pathologies [411].

3.3.1.3 Disease management
The treatment of this disorder is surgical correction deferred until after puberty. Results from a recent survey
suggest that men with possible untreated ventral penile curvature reported more dissatisfaction with penile
appearance, increased difficulty with intercourse, and more unhealthy mental days therefore supporting
correction of congenital penile curvature in childhood [412]. Surgical treatments for congenital penile curvature
generally share the same principles as in Peyronie’s disease (presented in detail in the next section). Nesbit
procedure with excision of an ellipse of the tunica albuginea is the gold standard treatment but many other
techniques have been described and employed. Plication techniques are widely used including techniques
producing a de-rotation of the corporal bodies [413]. A new modification of the latter technique has been
suggested; Shaeer’s corporal rotation enables correction of ventral congenital penile curvature, with minimal
narrowing and shortening [414]. Most of the time, dissection of the dorsal neurovascular bundle is required in
order to avoid loss of sensation and ischaemic lesions in the glans penis [415-417].
3.3.1.4 Summary of evidence for congenital penile curvature
Medical and sexual history are usually sufficient to establish a diagnosis of congenital penile 3
curvature. Physical examination during erection is useful for documentation of the curvature and
exclusion of other pathologies.
Surgery is the only treatment option which is deferred until after puberty and can be performed at any 3
time in adult life.
3.3.1.5 Recommendation for the treatment congenital penile curvature
Recommendation Strength rating

Use Nesbit and other plication techniques for the treatment of congenital penile curvature in Strong
patients who undergo surgery.
3.3.2 Peyronie’s Disease

3.3.2.1.1 Epidemiology
Epidemiological data on Peyronie’s disease (PD) are limited. Prevalence rates of 0.4-9% have been published,
with a higher prevalence in patients with ED and diabetes [418-425]. A recent, well conducted survey indicates
that the prevalence of definitive and probable cases of PD in the US is 0.7% and 11%, respectively, suggesting
that PD is an under-diagnosed problem [426]. The typical age of a patient with PD is 55-60 years.
3.3.2.1.2 Aetiology
The aetiology of PD is unknown. However, an insult (repetitive microvascular injury or trauma) to the tunica
albuginea is the most widely accepted hypothesis on the aetiology of the disease [427]. A prolonged
inflammatory response will result in the remodelling of connective tissue into a fibrotic plaque [427-429]. Penile
plaque formation can result in curvature which, if severe, may prevent penetrative sexual intercourse.
3.3.2.1.3 Risk factors

The most commonly associated comorbidities and risk factors are diabetes, hypertension, lipid abnormalities,
ischaemic cardiopathy, ED, smoking, and excessive consumption of alcohol [421, 425, 430, 431]. Dupuytren’s
contracture is more common in patients with PD affecting 9-39% of patients [422, 432-434] while 4% of
patients with Dupuytren’s contracture reported Peyronie’s disease [433].
3.3.2.1.4 Pathophysiology
Two phases of the disease can be distinguished [435]. The first is the acute inflammatory phase, which may be
associated with pain in the flaccid state or painful erections and a palpable nodule or plaque in the tunica of
the penis; typically a penile curvature begins to develop. The second is the fibrotic phase (chronic phase) with
the formation of hard palpable plaques that can be calcified, which also results in disease stabilisation and
no further progressive curvature. With time, penile curvature is expected to worsen in 30-50% of patients or
stabilise in 47-67% of patients, while spontaneous improvement has been reported by only 3-13% of patients
[430, 436, 437]. Pain is present in 35-45% of patients during the early stages of the disease [438]. Pain tends to
resolve with time in 90% of men, usually during the first twelve months after the onset of the disease [436, 437].

In addition to the physiological and functional alteration of the penis, affected men also suffer significant
distress. Validated mental health questionnaires have shown that 48% of men with PD have mild or moderate
depression, sufficient to warrant medical evaluation [439].
3.3.2.1.5 Summary of evidence on epidemiology/aetiology/pathophysiology of Peyronie’s disease
Peyronie’s disease is a connective tissue disorder, characterised by the formation of a fibrotic lesion 2b
or plaque in the tunica albuginea, which leads to penile deformity.
The contribution of associated comorbidities or risk factors (e.g. diabetes, hypertension, lipid 3
abnormalities and Dupuytren’s contracture) to the pathophysiology of PD is still unclear.
Two phases of the disease can be distinguished. The first phase is the acute inflammatory phase 2b
(painful erections, ‘soft’ nodule/plaque), and the second phase is the fibrotic/calcifying phase with
formation of hard palpable plaques (disease stabilisation).
Spontaneous resolution is uncommon (3-13%) and most patients experience disease progression 2a
(30-50%) or stabilisation (47-67%). Pain is usually present during the early stages of the disease but
tends to resolve with time in 90% of men.

The aim of the initial evaluation is to provide information on the presenting symptoms and their duration
(erectile pain, palpable nodules, curvature, length, rigidity, and girth) and erectile function status. It is
mandatory to obtain information on the distress provoked by the symptoms and the potential risk factors for
ED and PD. A disease-specific questionnaire (Peyronie’s disease questionnaire (PDQ)) has been designed
to collect data, and it has been validated for use in clinical practice [440]. Also, the utility of the PDQ for
monitoring PD-specific psychosexual symptom severity, progression, and treatment response, both clinically
and in trials of men with PD has been reported [441].
Major attention should be given to whether the disease is still active, as this will influence medical treatment
or the timing of surgery. Patients who are still likely to have an active disease are those with a short symptom
duration, pain during erection, or a recent change in penile curvature. Resolution of pain and stability of the
curvature for at least three months are well-accepted criteria of disease stabilisation and patients’ referral for
surgical intervention when indicated [436].
The examination should start with a routine genitourinary assessment, which is then extended to the hands and
feet for detecting possible Dupuytren’s contracture or Ledderhose scarring of the plantar fascia [437]. Penile
examination is performed to assess the presence of a palpable node or plaque. There is no correlation between
plaque size and the degree of curvature [442]. Measurement of penile length during erection is important
because it may have an impact on the subsequent treatment decisions [443].
An objective assessment of penile curvature with an erection is mandatory. This can be obtained by a
home (self) photograph of a natural erection (preferably) or using a vacuum-assisted erection test or an
intracavernous injection using vasoactive agents [444]. Erectile function can be assessed using validated
instruments such as the IIEF although this has not been validated in PD patients [87]. Erectile dysfunction is
common in patients with PD (> 50%) but it is important to define whether it pre- or post-dates the onset of
PD. It is mainly due to penile vascular disease [430, 442]. The presence of ED and psychological factors may
impact on the treatment strategy [445].
Ultrasound measurement of the plaque’s size is inaccurate and it is not recommended in everyday clinical
practice [446]. Doppler US may be required for the assessment of vascular parameters [445].
3.3.2.2.1 Summary of evidence for the diagnosis of Peyronie’s disease
Ultrasound measurement of the plaque’s size is inaccurate and operator dependent. 3
Doppler US is required to ascertain vascular parameters associated with ED. 2a

3.3.2.2.2 Recommendations for the diagnosis of Peyronie’s disease

In the medical and sexual history of patients with Peyronie’s disease, include duration of Strong
the disease, penile pain, change of penile deformity, difficulty in vaginal intromission due to
deformity, and erectile dysfunction (ED).
In the physical examination, include assessment of palpable plaques, penile length, extent Strong
of curvature (self-photograph, vacuum-assisted erection test or pharmacological-induced
erection) and any other possibly related diseases (Dupuytren’s contracture, Ledderhose
disease).
Do not use Peyronie’s disease specific questionnaire in everyday clinical practice. Weak
Do not use ultrasound (US) measurement of plaque size in everyday clinical practice. Weak
Use Doppler US only in the case of diagnostic evaluation of ED, to ascertain vascular Weak
parameters associated with ED.

3.3.2.3.1 Non-operative treatment
Conservative treatment of PD is primarily focused on patients in the early stage of the disease [437, 447].
Several options have been suggested, including oral pharmacotherapy, intralesional injection therapy and other
topical treatments (Table 8). Shockwave treatment of calcified plaques and clostridium collagenase (CCH)
injection in patients with densely fibrotic or calcified plaques have also been suggested [435, 448]. Clostridium
collagenase is the only drug approved for the treatment of PD by the FDA and the EMA. The results of the
studies on conservative treatment for PD are often contradictory making it difficult to provide recommendations
in the everyday, real-life setting. This is due to several methodological problems including uncontrolled studies,
limited number of patients treated, short-term follow-up and different outcome measures [448]. Moreover, the
efficacy of conservative treatment in distinct patient populations in terms of early (inflammatory) or late (fibrotic)
phases of the disease is not yet available.
Table 8: Non-operative treatments for Peyronie’s disease
Oral treatments
Vitamin E
Potassium para-aminobenzoate (Potaba)
Tamoxifen
Colchicine
Acetyl esters of carnitine
Pentoxifylline
Phosphodiesterase type 5 inhibitors
Intralesional treatments
Steroids
Verapamil
Clostridium collagenase
Interferon
Topical treatments
Verapamil
Iontophoresis
H-100 gel
Extracorporeal shockwave treatment
Traction devices
3.3.2.3.1.1 Oral treatment

Vitamin E
Vitamin E (tocopherol, a fat-soluble compound that acts as a natural antioxidant to reduce the number of
oxygen-free radicals produced in energy metabolism) is commonly prescribed at once or twice daily doses of
400 IU because of its wide availability, low cost and safety [449]. A double-blind, placebo-controlled crossover
study failed to show a significant effect on penile deformity or plaque size [450]. Moreover, there is conflicting
evidence as to the long-term cardiovascular effects of vitamin E usage at the large doses, which urologists use
for penile deformity treatment [451].

Potassium para-aminobenzoate (PotabaTM)
Potassium para-aminobenzoate is thought to exert an antifibrotic effect through an increase in oxygen uptake
by the tissues, a rise in the secretion of glycosaminoglycans, and an enhancement of the activity of monoamine
oxidases [452]. Preliminary studies reported an improvement in penile curvature, penile plaque size, and penile
pain during erection [453]. In a prospective double-blinded controlled study in 41 patients with PD, Potaba
(12 g/day for twelve months) improved penile pain significantly, but not penile curvature or penile plaque size
[454]. In another similar study in 103 patients with PD, Potaba decreased penile plaque size significantly,
but had no effect on penile curvature or penile pain [455]. However, the pre-existing curvature under
Potaba remained stable, suggesting a protective effect on the deterioration of penile curvature. Treatment-
related adverse events are nausea, anorexia, pruritus, anxiety, chills, cold sweats, confusion and difficulty
concentrating, but no serious adverse events were reported [456].
Tamoxifen
Tamoxifen is a non-steroidal oestrogen receptor antagonist modulating transforming growth factor β1 (TGF β1)
secretion by fibroblasts. Preliminary studies reported that tamoxifen (20 mg twice daily for three months)
improved penile pain, penile curvature, and reduced the size of penile plaque [457]. However, a placebo-
controlled, randomised study (in only 25 patients, at a late stage of the disease with a mean duration of twenty
months) using the same treatment protocol, failed to show any significant improvement in pain, curvature, or
plaque size in patients with PD [458].
Colchicine
Colchicine has been introduced into the treatment of PD on the basis of its anti-inflammatory effect [459].
Clinical data should be interpreted with caution since they come from only uncontrolled studies. Preliminary
results showed that half of the men given colchicine (0.6-1.2 mg daily for three to five months) found that
painful erections and penile curvature improved, while penile plaque decreased or disappeared in 50% of
24 men [460]. In another study in 60 men (colchicine 0.5-1 mg daily for three to five months with escalation to
2 mg twice daily), penile pain resolved in 95% and penile curvature improved in 30% [459]. Similar results have
been reported in another uncontrolled retrospective study in 118 patients [461]. Reported treatment-related
adverse events with colchicine are gastrointestinal effects (nausea, vomiting, diarrhoea) that can be improved
with dose escalation [459].
The combination of vitamin E and colchicine (600 mg/day and 1 mg every twelve hours, respectively for six
months) in patients with early-stage PD resulted in significant improvement in plaque size and curvature, but
not in pain compared to ibuprofen 400 mg/day for six months [462].
Acetyl esters of carnitine

Acetyl-L-carnitine and propionyl-L-carnitine are proposed to inhibit acetyl coenzyme-A and produce an
anti-proliferative effect on human endothelial cells. This may eventually suppress fibroblast proliferation and
collagen production, thus reducing penile fibrosis. In a randomised, double-blind study in 48 patients with
early-stage PD, patients were randomised to acetyl-L-carnitine (1 g twice daily) compared to tamoxifen (20 mg
twice daily). After three months, acetyl-L-carnitine was significantly more effective than tamoxifen in pain and
curvature reduction and inhibition of disease progression, but not in penile plaque size reduction (both drugs
significantly reduced plaque size) [463]. Tamoxifen induced significantly more side-effects.
Finally, the combination of intralesional verapamil (10 mg weekly for ten weeks) with propionyl-l-carnitine
(2 g/day for three months) significantly reduced penile curvature, plaque size, and disease progression
compared to intralesional verapamil combined with tamoxifen (40 mg/day) for three months [464].
Pentoxifylline
Pentoxifylline is a non-specific phosphodiesterase inhibitor which down-regulates TGF β1 and increases
fibrinolytic activity [465]. Moreover, an increase of NO levels may be effective in preventing progression of PD
or reversing fibrosis [466]. Preliminary data from a case report showed that pentoxifylline (400 mg three times
daily for six months) improved penile curvature and the findings on US of the plaque [466]. In another study in
62 patients with PD, pentoxifylline treatment for six months appeared to stabilise or reduce calcium content in
penile plaques [467].
Phosphodiesterase type 5 inhibitors

The rationale for the use of PDE5Is in PD comes from animal studies showing that they can reduce the
collagen/smooth muscle and collagen III/I ratios and increase the apoptotic index in a PD-like plaque [468]. In a
retrospective controlled study, daily tadalafil (2.5 mg for six months) resulted in statistically significant (p < 0.05)

resolution of septal scar in 69% of patients compared to 10% in the control group (no treatment). However,
this study included patients with isolated septal scars without evidence of penile deformity [469]. Therefore, no
recommendation can be given for PDE5Is in patients with PD.
3.3.2.3.1.2 Intralesional treatment

Injection of pharmacologically active agents directly into penile plaques represents another treatment option.
It allows a localised delivery of a particular agent that provides higher concentrations of the drug inside the
plaque. However, delivery of the compound to the target area is difficult to ensure particularly when a dense or
calcified plaque is present.
Steroids
Intralesional steroids are thought to act by opposing the inflammatory milieu responsible for Peyronie’s plaque
progression via inhibition of phospholipase A2, suppression of the immune response and by decreasing
collagen synthesis [470]. In small, non-randomised studies, a decrease in penile plaque size and pain resolution
was reported [471, 472]. In the only single-blind, placebo-controlled study with intralesional administration
of betamethasone, no statistically significant changes in penile deformity, penile plaque size, and penile
pain during erection were reported [473]. Adverse effects include tissue atrophy, thinning of the skin and
immunosuppression [471].
Verapamil
The rationale for intralesional use of verapamil (a calcium channel antagonist) in patients with PD is based
on in-vitro research [474, 475]. A number of studies have reported that intralesional verapamil injection may
induce a significant reduction in penile curvature and plaque volume [476-480]. These findings suggested
that intralesional verapamil injections could be advocated for the treatment of non-calcified acute phase or
chronic plaques to stabilise disease progression or possibly reduce penile deformity, although large scale,
placebo-controlled trials have not yet been conducted [479]. Side-effects are uncommon (4%). Minor side-
effects include nausea, light-headedness, penile pain, and ecchymosis [479]. However, in the only randomised,
placebo-controlled study, no statistically significant differences on plaque size, penile curvature, penile pain
during erection or plaque ‘softening’ were reported [481]. Younger age and larger baseline penile curvature
were found to be predictive of favourable curvature outcomes in a case-series study [482].
Clostridium collagenase
Clostridium collagenase (CCH) is a chromatographically purified bacterial enzyme that selectively attacks
collagen, which is known to be the primary component of the PD plaque [483-485]. Clostridium collagenase
is now approved by the FDA for PD in adult men with a palpable plaque and a curvature deformity of at least
30° at the start of therapy. Findings from two independent, double-blind, placebo controlled studies, reveal the
efficacy and tolerability of CCH for improving the co-primary outcomes of physical penile curvature and the
psychological patient reported PD symptom bother domain of the PDQ in adults with PD. Participants were
given up to four treatment cycles of CCH or placebo and were then followed for 52 weeks. Overall, of the 551
treated men with CCH 60.8% were global responders compared with 29.5% of the 281 patients who received
the placebo. The most commonly reported side-effects were penile pain, penile swelling, and ecchymosis at
the site of injection [484]. The data from these two large RCTs were analysed by subgroups including: baseline
penile curvature deformity, PD duration, degree of penile calcification, and baseline erectile function severity
with better results in patients with less than 60º of curvature, more than two years of evolution, no calcification
in the plaque and good erectile function [486].
Clostridium collagenase was approved by the EMA in 2014 who specified that CCH should be
administered by a healthcare professional who is experienced in the treatment of male urological diseases.
The Risk Management Plan (RMP) requires participating healthcare professionals to be certified within the
programme by enrolling and completing training in the administration of CCH treatment for PD [487].
A recent paper which studied a pooled safety analysis of 1,044 CCH-treated patients from six clinical studies
showed that the majority of Peyronie’s patients experienced at least one adverse reaction (Global Safety
database, 92.5%). Most adverse reactions were localised to the penis or groin and the majority of these events
were of a mild or moderate severity. Most of these resolved within fourteen days of the injection. The adverse
reaction profile was similar after each injection, regardless of the number of injections administered. The most
frequently reported treatment-related adverse events in the clinical trials in subjects with PD (Global Safety
database) were penile haematoma (50.2%), penile pain (33.5%), penile swelling (28.9%) and injection site pain
(24.1%) [488].

Interferon
Interferon α-2b has been shown to decrease fibroblast proliferation, extracellular matrix production and
collagen production from fibroblasts and improve the wound healing process from PD plaques in-vitro [489].
Intralesional injections (5 x 106 units of interferon α-2b in 10 mL saline, two times per week for twelve weeks)
significantly improved penile curvature, plaque size and density, and pain compared to placebo [490, 491].
Side-effects include myalgias, arthralgia, sinusitis, fever and flu-like symptoms. They can be effectively treated
with non-steroidal anti-inflammatory drugs before interferon injection.
Hyaluronic Acid
In a prospective, single-arm, multicentre pilot study, 65 patients underwent a ten week cycle of weekly
intraplaque injections with hyaluronic acid. Plaque size significantly decreased, penile curvature decreased in
37%, as well as overall sexual satisfaction and seems preferably indicated in the early (active) phase of the
disease [492].
In a case controlled, single site study, 81 patients underwent a ten week cycle of weekly plaque injections.
Patients included had curvatures < 45o and were in the active phase of the disease. Hyaluronic acid
demonstrated statistically significant improvement over controls (non-treatment, n=81) in plaque size, penile
curvature (-9.01o, p<0.0001), and improvement in penile rigidity (mean IIEF score +3.8) at twelve months [493].
3.3.2.3.1.3 Topical treatments

Topical verapamil
There is no evidence that topical treatments applied to the penile shaft result in adequate levels of the active
compound within the tunica albuginea. Verapamil gel has been used in this context [494]. Iontophoresis – now
known as transdermal electromotive drug administration (EMDA) - has been introduced to try and overcome
limitations on the local uptake of the drugs themselves. Small studies using iontophoresis with verapamil 5 mg
and dexamethasone 8 mg resulted in inconsistent results [495, 496].
H-100 Gel
H-100 Gel is composed of nicardipine, superoxide dismutase and emu oil. Twenty-two patients (PD twelve
months duration) were studied in a prospective randomised, double-blind, placebo-controlled study. H-100
showed significant improvement in all PD parameters at six months: mean stretched penile length increase
(22.6%, p=0.0002), mean curvature reduction (40.8%, p=0.0014), and mean pain level reduction (85.7%,
p=0.004). Placebo group showed no significant improvement except for mean stretched penile length
increase (6.8%, p=0.009). Crossover patients from placebo to H-100 showed significant improvement in all
parameters: mean stretched penile length increase (17.5%, p=0.000007), mean curvature reduction (37.1%,
p=0.006), and mean pain level reduction (40%, p=0.17). Treatment was well tolerated. A self-limited rash was
the only side-effect in three patients. Statistically significant improvements in flaccid-stretched penile length,
curvature and pain suggest that H-100 is a safe and possibly effective non-invasive, topically applied treatment
for acute phase PD [497].
Extracorporeal shockwave treatment

The mechanism of action involved in shockwave treatment (ESWT) for PD is still unclear, but there are two
hypotheses. In the first hypothesis, shockwave therapy works by directly damaging and remodelling the
penile plaque. In the second hypothesis, shockwave lithotripsy increases the vascularity of the area by
generating heat resulting in an inflammatory reaction, with increased macrophage activity causing plaque
lysis and eventually leading to plaque resorption [498]. Most uncontrolled studies failed to show significant
improvements in patients with PD [499-501]. In a prospective, randomised, double-blind, placebo-controlled
study, four weekly treatment sessions of ESWT, with each session consisting of 2,000 focused shockwaves,
resulted in significant improvement only for penile pain [502].
Traction devices
The application of continuous traction in Dupuytren’s contracture increases the activity of degradative enzymes
[503]. This initially leads to a loss of tensile strength and ultimately to solubilisation. It is followed by an increase
in newly synthesised collagen [503]. This concept has been applied in an uncontrolled study, including ten
patients with PD. The FastSize Penile Extender was applied as the only treatment for two to eight hours per
day for six months [139]. Reduced penile curvature of 10-40° was found in all men with an average reduction
of 33% (range: 51-34o). The stretched penile length increased 0.5-2.0 cm and the erect girth [139] increased
0.5-1.0 cm, with a correction of hinge effect in four out of four men. Treatment can be uncomfortable and
inconvenient due to use of the device for two to eight hours daily for an extended period, but has been shown
to be tolerated by highly motivated patients [433]. There were no serious adverse events, including skin
changes, ulcerations, hypoesthesia or diminished rigidity.

In another prospective study, there was a significant reduction in penile curvature (mean 20° reduction). Erectile
function and erection hardness also improved significantly. The percentage of patients who were not able to
achieve penetration decreased from 62% to 20% (p < 0.03). Importantly, the need for surgery was reduced in
40% of patients who would otherwise have been candidates for surgery and simplified the complexity of the
surgical procedure (from grafting to plication) in one in three patients [504].
3.3.2.3.1.4 Summary of evidence for non-operative treatment of Peyronie’s disease
Conservative treatment for PD is primarily aimed at treating patients in the early stage of the disease. 3
Oral treatment with potassium para-aminobenzoate may result in a significant reduction in penile 1b
plaque size and penile pain as well as penile curvature stabilisation.
Intralesional treatment with verapamil may induce a significant reduction in penile curvature and 1b
plaque volume.
Intralesional treatment with CCH showed significant decreases in the deviation angle, plaque width 1b
and plaque length.
Intralesional treatment with interferon may improve penile curvature, plaque size and density, and pain. 1b
Topical verapamil gel 15% may improve penile curvature and plaque size. 1b
Iontophoresis with verapamil 5 mg and dexamethasone 8 mg may improve penile curvature and 1b
plaque size.
Extracorporeal shockwave treatment does not improve penile curvature and plaque size, but it may be 1b
offered for penile pain.
Intralesional treatment with steroids is not associated with significant reduction in penile curvature, 2b
plaque size or penile pain.
3.3.2.3.1.5 Recommendations for non-operative treatment of Peyronie’s disease

Use conservative treatment in patients not fit for surgery or when surgery is not acceptable Weak
to the patient.
Do not use extracorporeal shockwave treatment to improve penile curvature and reduce Weak
plaque size.
Use penile traction devices and vacuum devices to reduce penile deformity and increase Weak
penile length.
Do not use intralesional treatment with steroids to reduce penile curvature, plaque size or Weak
pain.
Do not use oral treatment with vitamin E and tamoxifen for significant reduction in penile Strong
curvature or plaque size.
Do not offer other oral treatments (acetyl esters of carnitine, pentoxifylline, colchicine) for Weak
the treatment of PD.
3.3.2.3.2 Surgical treatment

Although conservative treatment for PD should resolve painful erections in most men, only a small percentage
will experience any significant straightening of the penis. The aim of surgery is to correct curvature and allow
satisfactory intercourse. Surgery is indicated in patients with penile curvature that does not allow satisfactory
intercourse and which is associated with sexual bother [115]. Patients must have a stable disease for at least
three months, although a six to twelve month period has also been suggested [505].
The potential aims and risks of surgery should be discussed with the patient so that he can make an informed
decision. Specific issues that should be mentioned during this discussion are the risks of penile shortening, ED,
penile numbness, the risk of recurrent curvature, the potential for palpation of knots and stitches underneath
the skin, and the potential need for circumcision at the time of surgery [435]. Two major types of repair may be
considered for both congenital penile curvature and PD: penile shortening and penile lengthening procedures
[506].
Penile shortening procedures include the Nesbit wedge resection and the plication techniques performed on
the convex side of the penis. Penile lengthening procedures are performed on the concave side of the penis
and require the use of a graft. They aim to minimise penile shortening caused by Nesbit or plication of the

tunica albuginea or correct complex deformities. Penile de-gloving with associated circumcision (as a means
of preventing post-operative phimosis) is considered the standard approach for all types of procedures [506].
However, recent data suggest that circumcision is not always necessary e.g. in cases where the foreskin is
normal pre-operatively [507]. Finally, in patients with PD and ED not responding to medical treatments, surgical
correction of the curvature with concomitant penile prosthesis implantation should be considered [508].
Selection of the most appropriate surgical intervention is based on penile length assessment, curvature severity
and erectile function status, including response to pharmacotherapy in cases of ED [435]. Patient expectations
from surgery must also be included in the pre-operative assessment. There are no standardised questionnaires
for the evaluation of surgical outcomes [115]. Data from well-designed prospective studies are scarce, with a
low level of evidence. Most data are mainly based on retrospective studies, typically non-comparative and non-
randomised, or on expert opinion [435, 509].
3.3.2.3.2.1 Penile shortening procedures

In 1965, Nesbit was the first to describe the removal of the tunical ellipses opposite a non-elastic corporal
segment to treat congenital penile curvature [510]. Fourteen years later, this technique became a successful
treatment option, also for PD [511]. This operation is based on a 5-10 mm transverse elliptical excision of
the tunica albuginea or approximately 1 mm for each 10° of curvature [506]. The overall short- and long-term
results of the Nesbit operation are excellent. Complete penile straightening is achieved in more than 80%
of patients [512]. Recurrence of the curvature and penile hypoesthesia are uncommon (about 10%) and the
risk of post-operative ED is minimal [506, 513]. Penile shortening is the most commonly reported outcome
of the Nesbit procedure [513]. Shortening of 1-1.5 cm has been reported for about 85% of patients, which
is rarely the cause of post-operative sexual dysfunction [511, 514]. Patients often perceive the loss of length
as greater than it actually is [512, 513]. It is therefore advisable to measure and document the penile length
peri-operatively, both before and after the straightening procedure, whatever the technique used. Only one
modification of the Nesbit procedure has been described (partial thickness shaving instead of conventional
excision of a wedge of tunica albuginea) [515].
Plication procedures are based on the same principle as the Nesbit operation but are simpler to perform.
Many of them have been described as Nesbit modifications in the older literature. They are based on single or
multiple longitudinal incisions on the convex side of the penis closed in a horizontal way, applying the Heineke-
Miculicz principle or plication is performed without making an incision [516-521]. Another modification has
been described as the ‘16 dot’ technique with minimal tension under local anaesthesia [522]. The use of non-
absorbable sutures reduced recurrence of the curvature. Results and satisfaction rates are similar to the Nesbit
procedure [506]. However, numerous different modifications have been described and the level of evidence is
not sufficient to recommend one method over the other.
3.3.2.3.2.2 Penile lengthening procedures

Tunical lengthening procedures entail an incision in the short (concave) side of the tunica to increase the length
of this side, creating a tunical defect, which is covered by a graft. However, plaque removal may be associated
with high rates of post-operative ED due to venous leak [523].
Devine and Horton introduced dermal grafting in 1974 [524]. Since then, a variety of grafting materials and
techniques have been reported (Table 10) [525-539]. Unfortunately, the ideal material for grafting has yet to be
identified [540]. In addition, grafting procedures are associated with ED rates as high as 25%. Despite excellent
initial surgical results, graft contracture and long-term failures resulted in a 17% re-operation rate [541].
Vein grafts have the theoretical advantage of endothelial-to-endothelial contact when grafted to underlying
cavernosal tissue. The Saphenous vein is the most common vein draft used, followed by the dorsal penile vein
[506]. Post-operative curvature (20%), penile shortening (17%) and graft herniation (5%) have been reported
after vein graft surgery [530, 535, 538]. Tunica vaginalis is relatively avascular, easy to harvest and has little
tendency to contract due to its low metabolic requirements [528].
Dermal grafts are commonly associated with contracture resulting in recurrent penile curvature (35%),
progressive shortening (40%), and a 17% re-operation rate at ten years [542]. Cadaveric pericardium
(Tutoplast©) offers good results by coupling excellent tensile strength and multidirectional elasticity/expansion
by 30% [539]. In a retrospective telephone interview, 44% of patients with pericardium grafting reported
recurrent curvature, although most of them continued to have successful intercourse and were pleased with
their outcomes [539, 542].

Small intestinal submucosa (SIS), a collagen-based xenogenic graft derived from the submucosal layer of the
porcine small intestine, has been shown to promote tissue-specific regeneration, and supports the growth of
endothelial cells. Small intestinal submucosa acts as a scaffold to promote angiogenesis, host cell migration
and differentiation, resulting in tissue structurally and functionally similar to the original. It has been used
successfully to repair severe chordee and PD, without significant contraction or histological alterations, but
data are limited [536].
More recently the use of buccal mucosa grafts (BMG) has been advocated. Buccal mucosa grafts provided
excellent short-term results, suggested by the fast return of spontaneous erections and prevented shrinkage,
which is the main cause of graft failure. It also proved to be safe and reproducible, thus representing a valuable
treatment option for PD [527].
Grafting by collagen fleece (TachoSil©) in PD is feasible and promising. Major advantages are decreased
operative times and easy application. Moreover, an additional haemostatic effect is provided [543].
Tunical incision, preferably with grafting, offers an excellent surgical option for men with curvatures over 60o
as well as patients with an hour-glass deformity and good erectile function that are willing to risk a higher
rate of post-operative ED [469]. The presence of pre-operative ED, the use of larger grafts, age more than
60 years, and ventral curvature are considered poor prognostic factors for functional outcome after grafting
surgery [508]. Although the risk for penile shortening is significantly less compared to the Nesbit or plication
procedures, it is still an issue and patients must be informed accordingly [506]. The use of geometric principles
introduced by Egydio helps to determine the exact site of the incision, and the shape and size of the defect to
be grafted [529].
The use of a penile extender device on an eight to twelve hour daily regimen has been advocated as an
effective and safe treatment for loss of penile length in patients operated on for PD [544].
Table 9: Types of grafts used in Peyronie’s disease surgery
Autologous grafts
Dermis
Vein grafts
Tunica albuginea
Tunica vaginalis
Temporalis fascia
Buccal mucosa
Allografts
Cadaveric pericardium
Cadaveric fascia lata
Cadaveric dura matter
Cadaveric dermis
Xenografts
Porcine small intestinal submucosa
Bovine pericardium
Porcine dermis
Synthetic grafts
Gore-Tex®
Dacron®
Collagen fleece (TachoSil®)
3.3.2.3.2.3 Penile prosthesis

Penile prosthesis (PP) implantation is typically reserved for the treatment of PD in patients with ED, especially
when they are non-responders to PED5Is [433]. Although all types of penile prosthesis can be used, the
implantation of inflatable penile prosthesis seems to be most effective in these patients [538].
Most patients with mild-to-moderate curvature can expect an excellent outcome simply by cylinder insertion.
In cases of severe deformity, intra-operative ‘modelling’ of the penis over the inflated cylinders (manually
bent on the opposite side of the curvature for 90 seconds, often accompanied by an audible crack) has

been introduced as an effective treatment [545, 546]. If there is a residual curvature of less than 30o, no
further treatment is recommended, as the prosthesis will act as a tissue expander and will result in complete
correction of curvature after a few months of cycling the prosthesis [545]. While this technique is effective in
most patients, a Nesbit/plication procedure or plaque excision/incision and grafting may be required in order to
achieve adequate straightening [547-549].
The risk of complications (infection, malformation, etc.) is not increased compared to the general population.
However, a small risk of urethral perforation (3%) has been reported in patients with ‘modelling’ over the
inflated prosthesis [546].
In selected cases of end-stage PD with ED and significant penile shortening, a lengthening procedure, which
involves simultaneous PP implantation and penile length restoration, such as the ‘sliding’ technique, can be
considered but only in the hands of experienced high-volume surgeons [550].
Table 10: Results of surgical treatments for Peyronie’s disease (data from different, non-comparable
studies) [469, 523-539, 542]
Tunical shortening procedures Tunical lengthening procedures

Nesbit Plication Grafts
Penile shortening 4.7-30.8% 41-90% 0-40%
Penile straightening 79-100% 58-100% 74-100%
Persistent or recurrent curvature 4-26.9% 7.7-10.6% 0-16.7%
Post-operative erectile dysfunction 0-13% 0-22.9% 0-15%
Penile hypoesthesia 2-21% 0-21.4% 0-16.7%
Technical modifications 1 At least 3 Many types of grafts and
techniques used
Treatment algorithm
The decision on the most appropriate surgical procedure to correct penile curvature is based on pre-operative
assessment of penile length, the degree of the curvature and erectile function status. If the degree of curvature
is less than 60o, penile shortening is acceptable and the Nesbit or plication procedures are usually the method
of choice. This is typically the case for congenital penile curvature. If the degree of curvature is over 60o
or is a complex curvature, or if the penis is significantly shortened in patients with a good erectile function
(with or without pharmacological treatment), then a grafting procedure is feasible. If there is ED, which is
not responding to pharmacological treatment, the best option is the implantation of an inflatable PP, with or
without an associated procedure over the penis (modelling, plication or even grafting plus the prosthesis). The
treatment algorithm is presented in Figure 5.

Figure 5: Treatment algorithm for Peyronie’s disease
Treatment of Peyronie’s disease
Discuss natural history of the disease

Reassure pa ent that Peyronie’s is a benign disease
Discuss current treatment modali es
Shared decision-making
Ac ve disease Stable disease

(pain, deformity deteriora on, (no pain, no deformity
no calcifica on on US) deteriora on, calcifica on
plaques on US)
Curvature < 30° Curvature > 30°

Conserva ve treatment No severe deformity Severe deformity
(hour-glass, hinge)
No ED ED
No further treatment Surgical treatment
ED = erectile dysfunction; US = ultrasound.
The results of the different surgical approaches are presented in Table 10. It must be emphasised that there
are no RCTs available addressing surgery in PD. The risk of ED seems to be greater for penile lengthening
procedures [435, 506]. Recurrent curvature implies either failure to wait until the disease has stabilised, a
re-activation of the condition following the development of stable disease, or the use of re-absorbable sutures
that lose their strength before fibrosis has resulted in acceptable strength of the repair [149]. Accordingly, it is
recommended that only non-absorbable sutures or slowly re-absorbed absorbable sutures be used. Although
with non-absorbable sutures, the knot should be buried to avoid troublesome irritation of the penile skin but
this issue may be alleviated by the use of slowly re-absorbed absorbable sutures [513]. Penile numbness is
a potential risk of any surgical procedure involving mobilisation of the dorsal neurovascular bundle. This will
usually be a neuropraxia, due to bruising of the dorsal sensory nerves. Given that the usual deformity is a
dorsal deformity, the procedure most likely to induce this complication is a lengthening (grafting) procedure
[506].

3.3.2.3.2.4 Recommendations for the surgical treatment of penile curvature

Perform surgery only when Peyronie’s disease (PD) has been stable for at least three Strong
months (without pain or deformity deterioration), which is usually the case after twelve
months from the onset of symptoms, and intercourse is compromised due to deformity.
Prior to surgery, assess penile length, curvature severity, erectile function (including Strong
response to pharmacotherapy in case of erectile dysfunction (ED)) and patient expectations.
Use tunical shortening procedures, especially plication techniques as the first treatment Strong
option for congenital penile curvature and for PD with adequate penile length, curvature
< 60° and absence of special deformities (hour-glass, hinge).
Use grafting techniques for patients with PD and normal erectile function, with no adequate Weak
penile length, curvature > 60º and presence of special deformities (hour-glass, hinge).
Use penile prosthesis implantation, with or without any additional procedure (modelling, Strong
plication or grafting), in PD patients with ED not responding to pharmacotherapy.
3.4 Priapism
3.4.1 Ischaemic (Low-Flow or Veno-Occlusive) Priapism
Ischaemic priapism is the most common of the priapism subtypes, accounting for more than 95% of all
priapism episodes [551, 552]. It presents as a painful rigid erection characterised clinically by an absent or
reduced intracavernous arterial inflow (although proximally there is a compensated high velocity picture with
little flow distally [553]. In ischaemic priapism, there are time-dependent metabolic alterations within the corpus
cavernosum progressively leading to hypoxia, hypercapnia, glucopenia and acidosis [554].
Ischaemic priapism which lasts beyond four hours is similar to a compartment syndrome, characterised by
the development of ischaemia within the closed space of the corpora cavernosa, which severely compromises
cavernous circulation. Emergency medical intervention is required to minimise irreversible consequences, such
as smooth muscle necrosis, corporal fibrosis and the development of permanent ED [555, 556]. The duration
of ischaemic priapism represents the most significant predictor for the development of ED. In this context,
interventions beyond 48-72 hours of onset may help to relieve the erection and pain, but have little benefit in
preventing long-term ED [557].
Histological analysis of corporal smooth muscle biopsies show that at twelve hours, there are features of
interstitial oedema, progressing to destruction of the sinusoidal endothelium, exposure of the basement
membrane and thrombocyte adherence by 24 hours. At 48 hours, thrombi can be found in the sinusoidal
spaces and smooth muscle necrosis with fibroblast-like cell transformation is evident [479].
In terms of the pathophysiology (Table 11), no specific cause can be identified in the majority of cases
[552, 558] although the common aetiological factors for ischaemic priapism include sickle cell disease,
haematological dyscrasias, neoplastic syndromes, and with the use of a number of pharmacological agents.
Ischaemic priapism may occur (0.4-35%) after intracavernous injections of erectogenic agents [244, 552, 555,
559, 560]. The risk is higher with papaverine-based combinations, while the risk of priapism is < 1% following
prostaglandin E1 injection [561].
Since their introduction onto the market, a few cases of priapism have been described in men who have taken
PDE5Is [552]. However, most of these men also had other risk factors for priapism, and it is unclear whether
PDE5Is per se can cause ischaemic priapism [552]. Since most men who experienced priapism following
PDE5I use had additional risk factors for ischaemic priapism, PDE5I use is usually not regarded as a risk factor
in itself. Sickle cell disease is the most common cause in childhood, accounting for 63% of the cases. It is
the primary aetiology in 23% of adult cases [561], with a lifetime probability of developing ischaemic priapism
of 29-42% in men with sickle cell disease [561-563] (LE: 4). Mechanisms of sickle cell disease associated
priapism may involve dysfunctional NO synthase and Rho-associated protein kinase (ROCK) signalling, and
increased oxidative stress associated with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
mediated signalling [564].
Priapism resulting from metastatic or regional infiltration by tumour is rare and usually reflects an infiltrative
process [565]. As such, the recommendations for pharmacological treatment are unlikely to work and certainly
all of these men should have a magnetic resonance imaging (MRI) scan of the penis and be offered supportive

care and medical intervention for their primary cancer. In selected cases where palliative treatment options fail
to control penile pain, a palliative penectomy can be considered.
Priapism in children is extremely rare and is most commonly related to malignancy, haematological or
otherwise. The investigative focus should be on identifying any underlying causes.
Partial priapism, or idiopathic partial segmental thrombosis of the corpus cavemosum, is a very rare condition.
It is an often classified as a subtype of priapism limited to a single crura but ischaemia does not develop, rather
it is a thrombus within the corpus. Its aetiology is unknown, but bicycle riding, trauma, drug usage, sexual
intercourse, haematological diseases and α-blockers have been associated with partial segmental thrombosis
[566]. The presence of a congenital web within the corpora is also a risk factor [567].
Table 11: Aetiological factors for the development of priapism
Idiopathic
Haematological dyscrasias (sickle cell disease, thalassemia, leukaemia; multiple myeloma, Hb Olmsted
variant, fat emboli during hyperalimentation, haemodialysis, glucose-6-phosphate dehydrogenase deficiency,
Factor V Leiden mutation)
Infections (toxin-mediated) (i.e. scorpion sting, spider bite, rabies, malaria)
Metabolic disorders (i.e. amyloidosis, Fabry’s disease, gout)
Neurogenic disorders (i.e. syphilis, spinal cord injury, cauda equina syndrome, autonomic neuropathy, lumbar
disc herniation, spinal stenosis, cerebrovascular accident, brain tumour, spinal anaesthesia)
Neoplasms (metastatic or regional infiltration) (i.e. prostate, urethra, testis, bladder, rectal, lung, kidney)
Medications
Vasoactive erectile agents (i.e. papaverine, phentolamine, prostaglandin E1/alprostadil, combination of
intracavernous therapies)
α-adrenergic receptor antagonists (i.e. prazosin, terazosin, doxazosin, tamsulosin)
Anti-anxiety agents (hydroxyzine)
Anticoagulants (heparin, warfarin)
Antidepressants and antipsychotics (i.e. trazodone, bupropion, fluoxetine, sertraline, lithium, clozapine,
risperidone, olanzapine, chlorpromazine, thiorizadine, phenothiazines)
Antihypertensives (i.e. hydralazine, guanethidine, propranolol)
Hormones (i.e. gonadotropin-releasing hormone, testosterone)
Recreational drugs (i.e. alcohol, marijuana, cocaine [intranasal and topical], crack, cocaine)
3.4.1.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of ischaemic priapism
Ischaemic priapism is most common, accounting for more than 95% of all cases. 1b
Ischaemic priapism is identified as idiopathic in the vast majority of patients, while sickle cell anaemia 1b
is the most common cause in childhood.
Ischaemic priapism occurs relatively often (about 5%) after intracavernous injections of papaverine 2a
based combinations, while it is rare (< 1%) after prostaglandin E1 monotherapy.
Priapism is rare in men who have taken PDE5Is with only sporadic cases reported. 1a
3.4.1.2 Classification
Ischaemic priapism is a persistent erection marked by rigidity of the corpora cavernosa and by little or no
cavernous arterial inflow [552]. The patient typically complains of penile pain and examination reveals a rigid
erection. Resolution of ischaemic priapism is characterised by a return to a flaccid non-painful state. In many
cases, persistent penile oedema, ecchymosis and partial erections can occur and may mimic unresolved
priapism. The partial erections may reflect reactive hyperaemia and are sometimes misdiagnosed as persistent
priapism. When ischaemic priapism is left untreated, resolution may take days and ED invariably results.

Figure 6: Differential diagnosis of priapism
Prolonged erecon
for > 4 hours
Ischaemic Non-ischaemic
priapism priapism
Penile Penile
Penile Penile
History blood gas History blood gas
Doppler US Doppler US
analysis analysis
Normal arterial
Perineal or
Dark blood; Bright red flow and
Sluggish or penile trauma;
Painful, rigid hypoxia, blood; may show
non-existent painless,
erecon hypercapnia arterial blood turbulent flow
blood flow fluctuang
and acidosis gas values at the site of
erecon
a fistula
3.4.1.3.1 History
Taking a comprehensive history is critical in priapism diagnosis [552, 568]. The medical history must specifically
ask about sickle cell disease or any other haematological abnormality [9, 569] and a history of pelvic, genital or
perineal trauma. The sexual history must include details relating to the duration of the erection, the presence
and degree of pain, prior medical drug use, any previous history of priapism and erectile function prior to the
last priapism episode (Table 12). The history can help to determine the underlying priapism subtype (Table 13).
Ischaemic priapism is classically associated with progressive penile pain and the erection is rigid. Non-
ischaemic priapism however is often painless and the erections fluctuating.
Table 12: Key points in the history for a priapism patient (adapted from Broderick et al. [552])
Duration of erection
Presence and severity of pain
Previous episodes of priapism and method of treatment
Current erectile function, especially the use of any erectogenic therapies prescription or nutritional supplements
Medications and recreational drug use
Sickle cell disease, haemoglobinopathies, hypercoagulable states
Trauma to the pelvis, perineum, or penis

In ischaemic priapism, the corpora are fully rigid and tender, but the glans penis is soft. The patient complains
of severe pain. Pelvic examination may reveal an underlying pelvic or genitourinary malignancy.

Laboratory testing should include a complete blood count, white blood count with blood cell differential,
platelet count and coagulation profile to assess anaemia and detect haematological abnormalities [552, 568].
Aspiration of blood from the corpora cavernosa shows dark ischaemic blood (Table 13) (LE: 2b). Blood gas
analysis is essential to differentiate between ischaemic and non-ischaemic priapism (Table 14). Further
laboratory testing should be directed by the history, clinical examination and laboratory findings. These may

include specific tests for the diagnosis of sickle cell anaemia or other haemoglobinopathies (e.g. haemoglobin
electrophoresis) or urine and plasma toxicological studies when there is suspected use of recreational
psychoactive drugs.
3.4.1.3.4 Penile imaging

Colour Doppler US of the penis and perineum is recommended and can differentiate ischaemic from non-
ischaemic priapism as an alternative or adjunct to blood gas analysis [553, 570-572] (LE: 2b). If possible,
scanning of the penis should be performed before corporal blood aspiration in ischaemic priapism to prevent
aberrant blood flow which can mimic a non-ischaemic picture.
Examination of the penile shaft and perineum is recommended. In ischaemic priapism there will be an absence
of blood flow in the cavernous arteries. The return of the cavernous artery waveform will result in successful
detumescence [552, 572, 573]. After aspiration, a reactive hyperaemia may develop with a high arterial flow
proximally that may mislead the diagnosis as non-ischaemic priapism.
Penile MRI can be used in the diagnostic evaluation of priapism and is helpful in selected cases of ischaemic
priapism to assess the viability of the corpora cavernosa and the presence of penile fibrosis. In a prospective
study of 38 patients with ischaemic priapism, the sensitivity of MRI in predicting non-viable smooth muscle
was 100%, when correlated with corpus cavernosum biopsies [574]. In this study, all patients with viable
smooth muscle on MRI maintained erectile function on clinical follow-up with the non-viable group being
offered an early prosthesis (LE: 3).
Table 13: Key findings in priapism (adapted from Broderick et al. [552])
Ischaemic priapism Non-ischaemic priapism

Corpora cavernosa fully rigid Usually Seldom
Penile pain Usually Seldom
Abnormal penile blood gas Usually Seldom
Haematological abnormalities Sometimes Seldom
Recent intracavernosal injection Sometimes Sometimes
Perineal trauma Seldom Usually
Table 14: Typical blood gas values (adapted from Broderick et al. [552])
Source pO2 (mmHg) pCO2 (mmHg) pH

Normal arterial blood (room air) > 90 < 40 7.40
[similar values are found in non-ischaemic priapism]
Normal mixed venous blood (room air) 40 50 7.35
Ischaemic priapism (first corporal aspirate) < 30 > 60 < 7.25
3.4.1.3.5 Recommendations for the diagnosis of ischaemic priapism

Take a comprehensive history to establish the diagnosis which can help to determine the Strong
priapism subtype.
Include a physical examination of the genitalia, the perineum and the abdomen in the Strong
diagnostic evaluation.
For laboratory testing, include complete blood count, white blood count with blood cell Strong
differential, platelet count and coagulation profile. Direct further laboratory testing based on
history, and clinical and laboratory findings. In children with priapism, perform a complete
evaluation of all possible causes.
Analyse the blood gas parameters from blood aspirated from the penis to differentiate Strong
between ischaemic and non-ischaemic priapism.
Perform colour duplex ultrasound of the penis and perineum for the differentiation between Strong
ischaemic and non-ischaemic priapism as an alternative or adjunct to blood gas analysis.
In cases of prolonged ischaemic priapism, use magnetic resonance imaging of the penis to Strong
predict smooth muscle viability and confirm erectile function restoration.
Perform selected pudendal arteriogram when embolisation is planned for the management Strong
of non-ischaemic priapism.

Acute ischaemic priapism is a medical emergency. Urgent intervention is compulsory (LE: 4), and should follow
a stepwise approach. The aim of any treatment is to restore penile detumescence, without pain, in order to
prevent long-term damage to the corpora cavernosa.
Figure 7: Treatment of ischaemic priapism
The treatment is sequential and the physician should move on to the next stage if the treatment fails.
Inial conservave measures

• Local anaesthesia of the penis
• Insert wide bore bu erfly (16-18 G) through the glans into the corpora cavernosa
• Aspirate cavernosal blood unl bright red arterial blood is obtained
Cavernosal irrigaon
• Irrigate with 0.90% w/v saline soluon
Intracavernosal therapy
• Inject intracavernosal adrenoceptor agonist
• Current first-line therapy is phenylephrine* with aliquots of 200 µg being injected every 3-5
minutes unl detumescence is achieved (maximum dose of phenylephrine is 1mg within 1 hour)*
Surgical therapy
• Surgical shunng
• Consider primary penile implantaon if priapism has been present for more than 36 hours
(*) The dose of phenylephrine should be reduced in children. It can result in significant hypertension and
should be used with caution in men with cardiovascular disease. Monitoring of pulse, blood pressure and
electrocardiogram (ECG) is advisable in all patients during administration and for 60 minutes afterwards. Its
use is contraindicated in men with a history of cerebro-vascular disease and significant hypertension.
3.4.1.4.1 First-line treatments

First-line treatments in ischaemic priapism of more than four hours duration are strongly recommended before
any surgical treatment (LE: 4). Conversely, first-line treatments initiated beyond 72 hours while relieving the
priapism have little documented benefit in terms of long-term potency preservation (LE: 4).
Historically, several first-line treatments have been described including exercise, ejaculation,
ice packs, cold baths, and cold water enemas [552]. However, there is lack of evidence of benefit for such
measures.
Partial priapism usually resolves spontaneously with analgesic treatment while surgical intervention
is rarely needed [575].

3.4.1.4.1.1 Penile anaesthesia/systemic analgesia
It is possible to perform blood aspiration and intracavernous injection of a sympathomimetic agent without any
anaesthesia. However, anaesthesia may be necessary when there is severe penile pain. While it is recognised
that the anaesthesia may not alleviate the ischaemic pain, cutaneous anaesthesia will facilitate subsequent
therapies. The treatment options for penile anaesthesia/systemic analgesia include:
• dorsal nerve block;

• circumferential penile block;
• subcutaneous local penile shaft block;
• oral conscious sedation (for paediatric patients).
3.4.1.4.1.2 Aspiration ± irrigation with 0.9% w/v saline solution

The first intervention for an episode of priapism lasting more than four hours consists of corporal blood
aspiration (LE: 4) to drain stagnant blood from the corporal bodies, making it possible to relieve the
compartment syndrome-like condition within the corpus cavernosum. Blood aspiration may be performed with
intracorporeal access either through the glans or via percutaneous needle access on the lateral aspect of the
proximal penile shaft, using a 16 G or 18 G angiocatheter or butterfly needle. The needle must penetrate the
skin, the subcutaneous tissue and the tunica albuginea to drain blood from the corpus cavernosum (LE: 4).
Some clinicians use two angiocatheters or butterfly needles at the same time to accelerate drainage, as well as
aspirating and irrigating simultaneously with a saline solution [562] (LE: 4). Aspiration should be continued until
bright red, oxygenated, blood is aspirated (LE: 4).
This approach has up to a 30% chance of resolving the priapism. There are insufficient data to determine
whether aspiration followed by saline intracorporeal irrigation is more effective than aspiration alone (LE: 4).
3.4.1.4.1.3 Aspiration ± irrigation with 0.9% w/v saline solution in combination with intracavernous injection of
pharmacological agents.
This combination is currently considered the standard of care in the treatment of ischaemic priapism
[4, 552, 576] (LE: 4). Pharmacological agents include sympathomimetic drugs or α-adrenergic agonists.
Options for intracavernous sympathomimetic agents include phenylephrine, etilephrine, ephedrine,
epinephrine, norepinephrine and metaraminol with a resolution rate of up to 80%. [552, 576-584] (LE: 2b). The
use of intracavernous adrenaline injection alone has also been sporadically reported [585].
Phenylephrine
Phenylephrine is currently the drug of choice due to its high selectivity for the α-1-adrenergic receptor, without
concomitant β-mediated inotropic and chronotropic cardiac effects [577, 581, 582] (LE: 4).
Phenylephrine is diluted in normal saline to a concentration of 100-500 μg/mL. Usually 200 μg are given every
three to five minutes directly into the corpus cavernosum. The maximum dosage is 1 mg within one hour
(LE: 4). A lower concentration or volume is applicable for children and patients with severe cardiovascular
disease (LE: 4).
Phenylephrine use has potential cardiovascular side-effects [552, 576-578, 581, 582] and it is recommended
that blood pressure and pulse are monitored every fifteen minutes for an hour after the injection. This is
particularly important in older men with pre-existing cardiovascular diseases. After injection, the puncture site
should be compressed and the corpora cavernosa massaged to facilitate drug distribution.
The potential treatment-related side-effects of intracavernous phenylephrine (and other sympathomimetic

agents) include headache, dizziness, hypertension, reflex bradycardia, tachycardia and palpitations, cardiac
arrythmias and sporadic subarachnoid haemorrhage [48]. Monitoring of blood pressure, pulse and cardiac
rhythm should be performed during intracavernous administration of sympathomimetic agents.
Overall, the administration of intracavernous sympathomimetic agents is contraindicated in patients suffering

from malignant or poorly controlled hypertension and in those who are concurrently taking monoamine oxidase
inhibitors (LE: 4).
Etilephrine
Etilephrine is the second most widely used sympathomimetic agent, administered by intracavernous injection
at a concentration of 2.5 mg in 1-2 mL normal saline [578] (LE: 3).

Methylene blue
Methylene blue is a guanylate cyclase inhibitor, which may be a potential inhibitor of endothelial-mediated
cavernous relaxation. It has been used for treating short-term pharmacologically induced priapism [586, 587]
(LE: 3). Methylene blue, 50-100 mg [586], should be injected intracavernously and left for five minutes. It is then
aspirated and the penis compressed for an additional five minutes [587]. Treatment-related side-effects include
a transient burning sensation and blue discolouration of the penis.
Adrenaline
Intracavernosal adrenaline (dosage of 2 mL of 1/100,000 adrenaline solution up to five times over a 20-minute
period [585]), has been used in patients with ischaemic priapism due to an intracavernous injection of
vasoactive agents. A success rate of over 50% after a single injection, with an overall success rate of 95% with
repeated injections is achieved (LE: 3).
Oral terbutaline
Oral terbutaline is a β-2-agonist with minor β-1 effects and some α-agonist activity. A dose of 5 mg has been
suggested to treat prolonged erections lasting more than two and a half hours, after intracavernous injection
of vasoactive agents, although the mechanism of action is not yet fully understood [588-590] (LE: 1b). Its main
use is in the prevention of recurrent episodes of prolonged erection. Terbutaline should be given cautiously in
patients with coronary artery disease, increased intravascular fluid volume, oedema and hypokalaemia [590].
Table 15: Medical treatment of ischaemic priapism
Drug Dosage/Instructions for use

Phenylephrine • Intracavernous injection of 200 μg every three to five minutes.
• Maximum dosage is 1 mg within one hour.
• Lower doses are recommended in children and patients with severe
cardiovascular disease.
Etilephrine • Intracavernosal injection at a concentration of 2.5 mg in 1-2 mL normal
saline.
Methylene blue • Intracavernous injection of 50-100 mg, left for five minutes. It is then
aspirated and the penis compressed for an additional five minutes.
Adrenaline • Intracavernous injection of 2 mL of 1/100,000 adrenaline solution up to five
times over a twenty-minute period.
Terbutaline • Oral administration of 5 mg for prolonged erections lasting more than
2.5 hours, after intracavernous injection of vasoactive agents.
Management of sickle cell disease related priapism

Urgent intervention is essential (LE: 4) and the general approach is similar to that described for other cases of
ischaemic priapism and should be co-ordinated with a haematologist [591-593] (LE: 4).
However, as with other haematological disorders, other therapeutic practices may also need to be implemented
[591, 593, 594]. Specific measures for sickle cell disease related priapism include intravenous hydration and
parental narcotic analgesia while preparing the patient for aspiration and irrigation. In addition, supplemental
oxygen administration and alkalinisation with bicarbonate can be helpful [563, 592].
Exchange blood transfusion has also been proposed, with the aim of increasing the tissue delivery of oxygen
[595]. The transfused blood should be HbS negative, Rh and Kell antigen matched [596]. However, the
evidence is inconclusive as to whether exchange transfusion itself helps to resolve the priapism in these men.
It should also be noted that several reports suggest that this treatment may result in serious neurological
sequelae [597]. although a series of ten patients with sickle cell related priapism, reported that it was safe
to perform exchange transfusion [595]. Due to these considerations, the routine use of this therapy is not
recommended (LE: 4).
3.4.1.4.2 Second-line treatments

Second-line intervention typically refers to surgical intervention in the form of penile shunt surgery and should
only be considered when other conservative management options fail (LE: 4). There is no evidence detailing
the amount of time allowed for first-line treatment before moving on to surgery. Consensus recommendations
suggest a period of at least one hour of first-line therapy prior to moving to surgery (LE: 4). A number of clinical
indicators suggest failure of first-line treatment including continuing corporal rigidity, cavernosal acidosis

anoxia, severe glucopenia, absence of cavernosal artery inflow by penile colour duplex US, and elevated
intracorporal pressures by pressure monitoring (LE: 4).
3.4.1.4.2.1 Penile shunt surgery

Penile shunt surgery aims to produce an outflow for ischaemic blood from the corpora cavernosa thereby
allowing the restoration of normal circulation within these structures. Accordingly, any shunt creates an opening
in the tunica albuginea, which may communicate with either the glans, the corpus spongiosum or a vein for
blood drainage [552, 576, 598].
In general, the type of shunt procedure chosen is according to the surgeon’s preference and familiarity with
the procedure. It is conventional for distal shunt procedures to be tried before considering proximal shunting
(LE: 4). Cavernosal smooth muscle biopsy has been used to diagnose smooth muscle necrosis (which, if
present, would suggest that shunting is likely to fail) which helps decision making and patient counselling,
particularly if they are being considered for an acute prosthesis.
It is important to assess the success of surgery by either direct observation or by investigation (e.g. cavernous
blood gas testing, penile colour duplex US) (LE: 4) [552, 576, 599, 600].
The recovery rates of erectile function in men undergoing shunt surgery following prolonged episodes of
priapism are low and directly relate to the duration of the priapism [599, 600]. Priapism for more than 36
hours appears to irreversibly impair erectile tissue both structurally and functionally [599]. In general, shunt
procedures undertaken after this time period may only serve to limit pain without any benefit for erectile
function (LE: 4) [557, 601].
Four categories of shunt procedures have been reported [4, 552, 598, 601]. The limited available data preclude
any recommendation for one procedure over another based on outcomes (LE: 4).
Percutaneous distal (corpora-glanular) shunts

Winter’s procedure: this procedure uses a Trucut biopsy needle to create a fistula between the glans penis and
each corpora cavernosa [4, 552, 561, 602, 603] (LE: 3). Post-operative sequelae are uncommon [604]. Winter’s
shunt is easy to perform, but has been reported as the least successful operation to create a distal shunt [600].
Ebbehoj’s technique: this technique involves making multiple tunical incision windows between the glans and
each tip of the corpus cavernosum by means of a size 11 blade scalpel passed several times percutaneously
[4, 552, 602, 605, 606] (LE: 3).
T-Shunt: this technique involves performing a bilateral procedure using a scalpel with a size 10 blade inserted
through the glans just lateral to the meatus until it enters the tip of the corpus cavernosum. The blade is
then rotated 90° away from the urethral meatus and withdrawn [4, 552, 602, 607] (LE: 3). If unsuccessful the
procedure is repeated on the opposite side. This is followed by a tunneling procedure using a size 20 dilator
inserted through the glans and into the corpora which can also be performed using US for guidance, mainly in
order to avoid urethral injury [607]. The entry sites in the glans are sutured following detumescence.
Open distal (corpora-glanular) shunts

Al-Ghorab’s procedure: this procedure consists of an open bilateral excision of circular cone segments of the
distal tunica albuginea via the glans penis, along with a subsequent glans closure by means of a running suture
with absorbable material [4, 552, 602, 608, 609] (LE: 3).
Burnett’s technique (Snake manoeuvre): a modification of the Al-Ghorab corpora-glanular shunt involves
the retrograde insertion of a 7/8 Hegar dilator into the distal end of each corpus cavernosum through
the original Al-Ghorab glanular excision. After removal of the dilator from the corpus cavernosum, blood
evacuation is facilitated by manual compression of the penis sequentially from a proximal to distal direction.
After detumescence, the glans penis is closed as in the Al-Ghorab procedure [4, 552, 602, 610, 611] (LE: 3).
Reported complications include wound infection, penile skin necrosis and an urethrocutaneous fistula [611].
Open proximal (corporospongiosal) shunts

Quackles’s technique: through a trans-scrotal or perineal approach, a proximal open shunt technique creates a
communication between the corpus cavenosum and the corpus spongiosum. The most frequent complications
include an unwanted urethro-cavernous fistula and urethral stricture or the development of cavernositis [4, 552,
598, 612]. The risk of urethral injury is less with a perineal approach to the bulb of the corpus spongiosum (LE: 3).

Vein anastomoses/shunts
Grayhack’s procedure: this mobilises the saphenous vein below the junction of the femoral vein and
anastomoses the vein end-to-side onto the corpus cavernosum. Venous shunts may be complicated by
saphenofemoral thrombus formation and by pulmonary embolism [4, 552, 613-615] (LE: 3).
Immediate penile prosthesis implantation

Refractory, therapy-resistant, acute ischaemic priapism or episodes lasting more than 48-72 hours usually
result in complete ED, possibly along with significant penile deformity in the long term. In these cases,
immediate penile prosthesis surgery has been advocated [616-619] (LE: 3).
The immediate insertion of a malleable penile prosthesis has been recommended to avoid the difficulty and
complications of delayed prosthesis surgery in the presence of corporal fibrosis. Potential complications that
could compromise immediate penile prosthesis implantation include distal erosion and cavernositis [616, 618],
along with a small rate of revision surgery [616]. Early surgery also offers the opportunity to maintain penile
size, and prevent penile curvature due to cavernosal fibrosis. The prosthesis can be exchanged for an inflatable
prosthesis at a later date which also allows upsizing of the implant cylinders [620].
Currently, there are no clear indications for immediately implanting a penile prosthesis in a man with acute
ischaemic priapism [576]. Relative indications include [552] (LE: 4):
• ischaemia that has been presented for more than 36 hours [619];
• failure of aspiration and sympathomimetic intracavernous injections;
• failure of distal and proximal shunting (although in delayed cases, implantation might be considered
ahead of shunt surgery);
• MRI or corporal biopsy evidence of corporal smooth muscle necrosis [552, 616] (LE: 4).
Surgery for non-acute sequelae after ischaemic priapism

Structural changes may occur after ischaemic priapism including cavernosal tissue necrosis and fibrosis with
consequent penile scarring, megalophallic deformities, penile shortening, and occasional penile loss, [598, 616,
621, 622]. Erectile dysfunction is also often observed [552, 623]. Unfortunately, these outcomes can still occur
despite apparently successful first- or second-line treatment.
Penile prosthesis implantation is occasionally indicated in sickle cell patients with severe ED since other
therapeutic options such as PDE5Is and intracavernous injections are avoided as they may provoke a further
priapism event [552, 576]. In severe corporal fibrosis, narrow-based prosthetic devices are preferable since
they are easy to insert and need less dilatation [616] (LE: 3). Following severe priapism that has resulted in
penile destruction with complicated deformities or even loss of penile tissue, penile reconstruction using grafts
and concomitant prosthesis implant may be considered [624] (LE: 3).
3.4.1.5 Summary of evidence for the treatment of ischaemic priapism
Urgent intervention for ischaemic priapism is required as it is an emergency condition. 2b
Treatment aims to restore painless penile detumescence, in order to prevent chronic damage to the 3
corpora cavernosa.
Erectile function preservation is directly related to the duration of ischaemic priapism. 2b
Phenylephrine is the recommended drug due to its favourable safety profile on the cardiovascular 2b
system compared to other drugs. Phenylephrine is usually diluted in normal saline with a
concentration of 100-500 μg/mL and given in 200 μg doses every three to five minutes directly into
the corpus cavernosum. Maximum dosage is 1 mg within one hour. Patients at high cardiovascular
risk should be given lower doses. Patient monitoring is highly recommended.
The efficacy of shunt procedures for ischaemic priapism is questionable. Diagnose smooth muscle 3
necrosis when needed with a biopsy of the cavernosal smooth muscle. No clear recommendation on
one type of shunt over another can be given.
Erectile dysfunction is inevitable in prolonged cases or ischaemic priapism. Implantation of penile 2b
prosthesis at a later stage can be difficult due to severe corporal fibrosis.

3.4.1.6 Recommendations for the treatment of ischaemic priapism

Start management of ischaemic priapism as early as possible (within four to six hours) and Strong
follow a stepwise approach.
First, decompress the corpora cavernosa by penile aspiration until fresh red blood is Weak
obtained.
In priapism secondary to intracavernous injections of vasoactive agents, replace blood Strong
aspiration with intracavernous injection of a sympathomimetic drug as the first step.
In priapism that persists despite aspiration, proceed to the next step, which is Strong
intracavernous injection of a sympathomimetic drug.
In cases that persist despite aspiration and intracavernous injection of a sympathomimetic Strong
drug, repeat these steps several times before considering surgical intervention.
Treat ischaemic priapism due to sickle cell anaemia in the same fashion as idiopathic Strong
ischaemic priapism. Provide other supportive measures (intravenous hydration, oxygen
administration with alkalisation with bicarbonates, blood exchange transfusions), but do not
delay initial treatment to the penis.
Proceed to surgical treatment only when blood aspiration and intracavernous injection of Strong
sympathomimetic drugs have failed or for priapism events lasting < 72 hours.
Perform distal shunt surgical procedures first followed by proximal procedures in case of Strong
failure.
Consider insertion of a penile prosthesis if priapism episode is > 36 hours after onset, or in Strong
cases for which all other interventions have failed.
3.4.1.7 Follow-up
Follow-up of ischaemic priapism after successful treatment should include modification of risk factors (if any)
in order to avoid a further episode and assessment of erectile function since it may be severely compromised
especially after surgical treatment with a shunt. Penile fibrosis is usually easily identified with clinical
examination of the penis.
3.4.2 Non-ischaemic (high-flow or arterial) priapism

Epidemiological data on non-ischaemic priapism are almost exclusively derived from small case series [552,
572, 573, 625, 626]. The most frequent cause of non-ischaemic priapism is blunt perineal or penile trauma
[627]. The injury results in a laceration in the cavernosal artery leading to a fistula between the artery and the
lacunar spaces of the sinusoidal tissue [626]. This unregulated blood flow results in a persistent erection, and
has been proposed to occur via a mechanism that involves stimulation of endothelial NO synthase by the
turbulent blood flow [628]. Partial erections are enhanced after sexual stimulation, as the trabecular smooth
muscle fully relaxes, activating the corporal veno-occlusive mechanism [626, 629].
There is often a delay between the injury and the development of the priapism that may be up to two to three
weeks [629]. This has been suggested to reflect either spasm or ischaemic necrosis of the injured artery, with
the fistula only developing as the spasm resolves or when the ischaemic segment blows out.
Occasional cases are associated with metastatic malignancy to the penis [630, 631], acute spinal cord injury
[632] and occasionally following intracavernous injections or aspiration due to a lacerated cavernosal artery or
branch [633, 634]. Under these circumstances, it may complicate ischaemic priapism. It has also been reported to
occur following internal urethrotomy [635] and a Nesbit procedure [636]. Although sickle cell disease is usually
associated with ischaemic priapism, occasional cases of non-ischaemic priapism have been reported [637].
3.4.2.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of non-ischaemic priapism
Non-ischaemic priapism usually occurs after blunt perineal or penile trauma. 2
Non-ischaemic priapism is a persistent erection caused by unregulated cavernous arterial inflow [552]. The
patient typically reports an erection that is not fully rigid and is not associated with pain although fully rigid
erections may occur with sexual stimulation.

3.4.2.3.1 History
A comprehensive history is mandatory in non-ischaemic priapism diagnosis and follows the same principles as
described in Table 12. Non-ischaemic priapism is suspected when there is no pain and erections are not fully
rigid (Table 13). It can be associated with full erections under sexual stimulation and when there is a history
of coital trauma or blunt trauma to the penis. The onset of post-traumatic non-ischaemic priapism in adults
and children may be delayed by hours to weeks following the initial injury. Sexual intercourse is usually not
compromised.

In non-ischaemic priapism, the corpora are tumescent but not fully rigid (Table 13). Abdominal, penile and
perineal examination may reveal evidence of trauma.

Blood aspiration from the corpora cavernosa shows bright red arterial blood in non-ischaemic priapism, while
blood is dark in ischaemic priapism (Table 13) (LE: 2b). Blood gas analysis is essential to differentiate between
non-ischaemic and ischaemic priapism (Table 14).

Colour duplex US of the penis and perineum is recommended and can differentiate non-ischaemic from
ischaemic priapism as an alternative or adjunct to blood gas analysis [570-572] (LE: 2b). Examination of the
penile shaft and perineum is recommended. In non-ischaemic priapism US will show turbulent flow at the
fistula, which helps to localise the site of trauma since patients with non-ischaemic priapism have normal to
high blood velocities in the cavernous arteries.
A selective pudendal arteriogram can reveal a characteristic blush at the site of the injury to the cavernosal
artery in non-ischaemic priapism [638, 639]. However, due to its invasiveness it should be reserved for the
management of non-ischaemic priapism, when embolisation is being considered [552, 568] (LE: 3).
The role of MRI in the diagnostic evaluation of priapism is controversial. In non-ischaemic priapism, its role is
limited since the small penile vessels and arteriovenous fistulae cannot be easily demonstrated [640].
3.4.2.3.5 Recommendations for the diagnosis of non-ischaemic priapism

The same recommendations as in section 3.4.1.3.5 apply.

The management of non-ischaemic priapism is not an emergency because the corpus cavernosum does not
contain ischaemic blood. Definitive management can therefore be considered and should be discussed with
the patient so that they understand the risks and complications of treatment [552, 568] (LE: 3).
3.4.2.4.1 Conservative management

This may include applying ice to the perineum or site-specific perineal compression [572, 625, 641, 642]. It is
an option in all cases, particularly children [643] (LE: 3). The fistula occasionally closes spontaneously. Even
in those cases where the fistula remains patent, the response to sexual stimulation still allows intercourse to
be possible. Androgen deprivation therapy (leuprolide injections, bicalutamide and ketoconazole) has been
reported in case series to enable closure of the fistula reducing spontaneous and sleep-related erections [644].
However, sexual dysfunction due to these treatments must be considered. Very infrequently, patients may
develop ED or distal flaccidity whilst undergoing conservative treatment, earlier selective embolisation should
be considered [645].
Blood aspiration is not helpful for the treatment of non-ischaemic priapism and the use of α-adrenergic
antagonists is not recommended due to potential severe adverse effects, e.g. transfer of the drug into the
systemic circulation.
3.4.2.4.2 Selective arterial embolisation

Selective arterial embolisation can be performed using either an autologous clot [646-648], gel foam or
sponge [647, 649], or more permanent substances, such as coils [647, 649-651] or acrylic glue [652] (LE: 3).
Success rates of up to 89% have been reported [653] in relatively small, non-randomised studies. There are
no robust data to demonstrate the relative merits of the different substances. At least theoretically, the use of
an autologous clot has some attractions. It temporarily seals the fistula, but when the clot is lysed, the arterial

damage has usually resolved and the blood flow of the penis can return to normal. The use of a permanent
device, such as a coil, would permanently block an artery and may lead to adverse effects upon spontaneous
sexual function. Other potential complications include penile gangrene, gluteal ischaemia, cavernositis and
perineal abscess [552, 654].
Following percutaneous embolisation, a follow-up is appropriate within one to two weeks. Assessment by
clinical examination and by colour duplex US can determine whether the embolisation has been successful
[571]. If there is doubt, a repeat arteriogram is required. Recurrence rates of 7-27% after a single treatment
with embolisation have been reported [647, 648, 655] (LE: 3). In a few cases, repeat embolisation is necessary.
Sexual function following embolisation can be adversely affected although there is full restoration of potency in
around 80% of men [655, 656] (LE: 3).
Embolisation in children, although reportedly successful, is technically challenging and requires treatment
within a specialist paediatric vascular radiology department [580, 657].
3.4.2.4.3 Surgical management

Selective ligation of the fistula through a transcorporeal approach under the guidance of colour duplex US
is possible [4, 569, 658]. Surgery is technically challenging and may pose significant risks, mainly ED due
to accidental ligation of the cavernous artery instead of the fistula. It is rarely performed and should only be
considered when there are contraindications for selective embolisation, no availability of the technique or
embolisation failure (LE: 4).
3.4.2.5 Summary of evidence for the treatment of non-ischaemic priapism
Because non-ischaemic priapism is not an emergency, perform definitive management at the 2b
discretion of the treating physician and plan the treatment after a short period of conservative
treatment.
Conservative management with the use of ice applied to the perineum or site-specific perineal 3
compression may be successful particularly in children. The use of androgen deprivation therapy may
enable closure of the fistula reducing spontaneous and sleep-related erections.
Artery embolisation, using temporary or permanent substances, has high success rates. No 3
definitive statement can be made on the best substance for embolisation in terms of sexual function
preservation.
Repeat the procedure for the recurrence of non-ischaemic priapism following selective artery 2b
embolisation.
Reserve selective surgical ligation of the fistula as a last treatment option when embolisation has failed. 3
3.4.2.6 Recommendations for the treatment of non-ischaemic priapism

Because non-ischaemic priapism is not an emergency, perform definitive management at Weak
the discretion of the treating physician.
Manage conservatively with the use of site specific perineal compression as the first step, Weak
especially in children. Consider androgen deprivation therapy only in adults.
Perform superselective arterial embolisation, using temporary material. Strong
Repeat the procedure with temporary or permanent material for recurrent non-ischaemic Weak
priapism following selective arterial embolisation.
Reserve selective surgical ligation of a fistula as a final treatment option when embolisation Weak
has failed.
3.4.2.7 Follow-up
Follow-up after successful treatment of non-ischaemic priapism should include assessment of erectile function
and clinical examination to identify signs of recurrence especially after embolisation.
3.4.3 Stuttering (recurrent or intermittent) priapism

Robust epidemiological studies of stuttering priapism are lacking [8, 659]. However, recurrent priapism

episodes are common in men with sickle cell disease (42-64%) [660, 661] while in adolescents and young men
the incidence of priapism is 35%, of whom 72% have a history of stuttering priapism [8].
The aetiology of stuttering priapism is similar to that of ischaemic priapism. While sickle cell disease is the most
common cause, idiopathic cases and cases due to a neurological disorder have been reported. Moreover, men
who have suffered from an acute ischaemic priapism event, especially one which has been prolonged (more
than four hours) are at risk for developing stuttering priapism [623].
Recently, several studies have proposed alternative mechanisms including inflammation, cellular adhesion, NO
metabolism, vascular reactivity and coagulation [552, 564, 592, 662, 663].
3.4.3.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of stuttering priapism
Stuttering priapism is similar to ischaemic priapism in that it is low-flow, ischaemic and, if left 3
untreated would result in significant penile damage, with sickle cell disease being the most common
cause. But the cause can also be idiopathic and in rare cases may be due to a neurological disorder.
Stuttering priapism, also termed intermittent or recurrent priapism, is a distinct condition that is characterised
by repetitive and painful episodes of prolonged erections. Erections are self-limiting with intervening periods
of detumescence [592, 662]. These are analogous to repeated episodes of ischaemic priapism. In stuttering
priapism the duration of the erections is generally shorter than in ischaemic priapism [4]. The frequency and/
or duration of these episodes is variable and a single episode can sometimes progress into a prolonged
ischaemic priapism episode.

3.4.3.3.1 History
A comprehensive history is mandatory and follows the same principles as described in Table 12. There is a
history of recurrent episodes of prolonged erections. The onset of the priapism episodes usually occurs during
sleep and detumescence does not occur upon waking. These episodes can be painful and may be the reason
that the patient first seeks medical attention.

Erections are painful and the penis is rigid as in ischaemic priapism, but the duration of events is usually
shorter. Between erections the penis is usually normal, but in some cases signs of fibrosis can be found. Rarely,
the penis may become enlarged, a condition known as megalophallus.

Laboratory testing follows the same principles as in the two other types of priapism. It is recommended to
identify possible causes and should be directed by the history, clinical and laboratory findings.

There are no specific findings on imaging for stuttering priapism. Colour duplex US of the penis and perineum
and MRI are recommended and can differentiate non-ischaemic from ischaemic priapism.
3.4.3.3.5 Recommendations for the diagnosis of stuttering priapism

The same recommendations as described in section 3.4.1.3.5 apply. Stuttering priapism is a recurrent or
intermittent type of ischaemic priapism.

The primary goal in the management of patients with stuttering priapism is the prevention of further episodes
and limiting the chances of developing a prolonged ischaemic priapism which is refractory to conventional
treatment options. In the majority of cases, stuttering priapism can be managed with pharmacological
treatment. The management of each acute episode is similar to that for ischaemic priapism; aspiration/irrigation
in combination with intracavernous injections of α-adrenergic agonists. Unfortunately, the efficacy and safety
of the various treatment modalities reported in the medical literature are poorly characterised. Specifically,
most reports are from small case series and the Panel is not aware of any published, well-designed, controlled
studies on the efficacy and safety of these treatments [563, 592, 662].

3.4.3.4.1 α-adrenergic agonists
Studies of oral α-adrenergic agonists have suggested some benefit for daily dosing of these agents as effective
prevention [664]. Side-effects include tachycardia and palpitations. Pseudoephedrine, widely used as an oral
decongestant, can also be used as a first-line treatment option [589]. However, its effect on corporal smooth
muscle is not fully understood. Etilephrine has been used successfully to prevent stuttering priapism due to
sickle cell anaemia. It is taken orally at doses of 50-100 mg daily, with response rates of up to 72% [11, 665,
666]. In one randomised placebo-controlled clinical study looking at medical prophylaxis with etilephrine and
ephedrine, there was no difference in efficacy between the two drugs.
3.4.3.4.2 Hormonal manipulations of circulating testosterone

The aim of hormonal manipulation is to down-regulate circulating testosterone levels to suppress the action
of androgens on penile erection [563, 592, 667]. This can be achieved through the use of GnRH agonists
or antagonists, antiandrogens or oestrogens [668] (LE: 4). Potential side-effects may include hot flushes,
gynaecomastia, impaired erectile function, loss of libido and asthenia. All approaches have a similar efficacy
profile (LE: 4) while the potential cardiovascular toxicity of oestrogens limits their clinical use. Alternative
endocrine approaches that have been used with some success include 5-α-reductase inhibitors [669] (LE: 3)
and ketoconazole, an antifungal agent that reduces adrenal and testicular androgen production [667, 670]
(LE: 4).
Of the hormonal agents suggested for preventing priapism, GnRH agonists and anti-androgens appear to be
the most efficacious and safe. They are recommended as primary treatments for the management of stuttering
priapism in adult men (LE: 4).
The duration of hormonal treatment for effective suppression of recurrent priapism events is problematic.
It is not possible to make any conclusions on the efficacy, dose and the duration of treatment. Moreover,
hormonal agents have a contraceptive effect and interfere with normal sexual maturation and spermatogenesis.
Caution is therefore strongly advised when prescribing hormonal treatments to pre-pubertal boys, adolescents
or men who are trying with their female partner to conceive. Castrate levels of testosterone, which have a
contraceptive effect, interfere with growth, and significantly affect sexual function.
3.4.3.4.3 Digoxin
Digoxin (a cardiac glycoside and a positive inotrope) is used to treat patients with congestive heart failure.
Digoxin regulates smooth muscle tone through a number of different pathways leading to penile detumescence
[563, 592, 671]. The use of maintenance digoxin doses (0.25-0.5 mg daily) in idiopathic stuttering priapism
has been proven to reduce the number of hospital visits and to improve QoL [592]. A small, clinical, double-
blind, placebo-controlled study, using digoxin, produced a decrease in sexual desire and excitement with a
concomitant reduction in penile rigidity, regardless of any significant change in plasma levels of testosterone,
oestrogens and luteinising hormone [671] (LE: 2b). Side-effects may include a decreased libido, anorexia,
nausea, vomiting, confusion, blurred vision, headache, gynaecomastia, rash and arrhythmia.
3.4.3.4.4 Terbutaline
Terbutaline is a β-agonist that causes vasodilation, resulting in smooth muscle relaxation of the vasculature
[563, 592] and has been used to prevent stuttering priapism with detumescence rates of 36% in patients
with alprostadil-induced priapism [589] (LE: 3). The only randomised, placebo-controlled study (n = 68) in
patients with pharmacologically-induced priapism, showed detumescence in 42% of the terbutaline-treated
group compared to only 15% in the placebo-treated group [590] (LE: 1b). Side-effects include nervousness,
shakiness, drowsiness, heart palpitations, headache, dizziness, hot flashes, nausea and weakness.
3.4.3.4.5 Gabapentin
Gabapentin has anticonvulsant, antinociceptive and anxiolytic properties and is widely used as an analgesic
and antiepileptic agent. Its proposed mechanism of action is to inhibit voltage-gated calcium channels, which
attenuates synaptic transmission [667], and reduces testosterone- and FSH levels [672]. It is given at a dose of
400 mg, four times a day, up to 2,400 mg daily, until complete penile detumescence occurs, with subsequent
maintenance administration of gabapentin, 300 mg daily [673] (LE: 4). Side-effects include anorgasmia and
impaired erectile function.
3.4.3.4.6 Baclofen
Baclofen is a gamma-aminobutyric acid (GABA) derivative that acts as a muscle relaxant and anti-muscle
spasm agent. It can inhibit penile erection and ejaculation through GABA activity and prevents recurrent
reflexogenic erections or prolonged erections from neurological diseases [563]. Oral baclofen has little efficacy

and it is not usually used in stuttering priapism but intrathecal baclofen dosing is more effective [592, 674-676],
(LE: 4). Side-effects include drowsiness, confusion, dizziness, weakness, fatigue, headache, hypotension and
nausea.
3.4.3.4.7 Hydroxyurea
Hydroxyurea blocks the synthesis of deoxyribonucleic acid (DNA) by inhibiting ribonucleotide reductase,
which has the effect of arresting cells in the S-phase [667, 677]. It is an established treatment for ameliorating
sickle cell disease and improving patient life expectancy [591, 678]. For such patients with recurrent priapism
there is limited evidence to suggest a medical prophylactic role (LE: 3), [667, 677, 679]. Side-effects include
oligozoospermia and leg ulcers.
3.4.3.4.8 Phosphodiesterase type 5 inhibitors

Low doses of PDE5Is have a paradoxical effect in alleviating and preventing stuttering priapism, mainly in
patients with idiopathic and sickle cell disease-associated priapism [563, 592, 680-684] (LE: 3). It is important
to remember that therapy should be started when the penis is in its flaccid state and not during an acute
episode. There is a delay of one week before treatment is effective. There are no reported impairments in male
sexual function (LE: 3). Phosphodiesterase type 5 inhibitors use in stuttering priapism is possibly mediated
by and an increase in the concentration of cGMP in the smooth muscle in a NO dysfunctional state. This can
occur in priapism and may result in a change in the NO pathway, with down-regulation of cavernosal PDE5
thereby preventing the complete degradation of cGMP in the corpora cavernosa [563, 592, 680, 683].
3.4.3.4.9 Intracavernosal injections

Some patients with stuttering priapism, who have been started on systemic treatments to prevent recurrence of
unwanted erections, may not see therapeutic benefits immediately and may temporarily require intracavernous
self-injections at home with sympathomimetic agents [563, 592]. The most commonly used drugs are
phenylephrine and etilephrine (as described in the treatment of ischaemic priapism) [4, 552, 659, 666] (LE: 3).
Side-effects include hypertension, coronary ischaemia and cardiac arrhythmias.
Tissue plasminogen activator (TPA) is a secreted serine protease that converts the pro-enzyme plasminogen to
plasmin, which acts as a fibrinolytic enzyme. Limited clinical data have suggested that a single intracavernous
injection of TPA can successfully treat patients with recalcitrant priapism [667, 685] (LE: 3). Mild bleeding is the
most commonly observed side-effect.
3.4.3.5 Summary of evidence for the treatment of stuttering priapism
The primary goal in the management of patients with stuttering priapism is the prevention of future 2b
episodes, which can generally be achieved pharmacologically.
PDE5Is have a paradoxical effect in alleviating and preventing stuttering priapism, mainly in patients 3
with idiopathic and sickle cell disease associated priapism.
The evidence with other systemic drugs (digoxin, α-adrenergic agonists, baclofen, gabapentin, 3
terbutaline) is very limited.
3.4.3.6 Recommendations for the treatment of stuttering priapism

Manage each acute episode similar to that for ischaemic priapism. Strong
Use hormonal therapies (mainly gonadotropin-receptor hormone agonists or antagonists) Weak
and/or anti-androgens for the prevention of future episodes in patients with frequent
relapses. Do not use them before sexual maturation is reached.
Initiate treatment with phosphodiesterase type 5 inhibitors only when the penis is in its Weak
flaccid state.
Use digoxin, α-adrenergic agonists, baclofen, gabapentin or terbutaline only in patients with Weak
very frequent and uncontrolled relapses.
Use intracavernous self-injections at home of sympathomimetic drugs for the treatment of Weak
acute episodes on an interim basis until ischaemic priapism has been alleviated.

3.4.3.7 Follow-up
Follow-up for stuttering priapism include history and clinical examination to assess the efficacy of treatments in
preventing or alleviating erectile events as well as assessing erectile function and penile fibrosis.
4. REFERENCES
1. Lindau, S.T., et al. A study of sexuality and health among older adults in the United States. N Engl
J Med, 2007. 357: 762.
2. Rosenberg, M.T., et al. Identification and diagnosis of premature ejaculation. Int J Clin Pract, 2007. 61: 903.
3. Tekgül, S., et al. European Association of Urology guidelines on Paediatric Urology. Edn. presented at the EAU
Annual Congress London, 2017.
4. Montague, D.K., et al. American Urological Association guideline on the management of priapism.
J Urol, 2003. 170: 1318.
5. Eland, I.A., et al. Incidence of priapism in the general population. Urology, 2001. 57: 970.
6. Kulmala, R.V., et al. Priapism, its incidence and seasonal distribution in Finland. Scand J Urol Nephrol, 1995.
29: 93.
7. Furtado, P.S., et al. The prevalence of priapism in children and adolescents with sickle cell disease in Brazil.
Int J Hematol, 2012. 95: 648.
8. Adeyoju, A.B., et al. Priapism in sickle-cell disease; incidence, risk factors and complications - an international
multicentre study. BJU Int, 2002. 90: 898.
9. Emond, A.M., et al. Priapism and impotence in homozygous sickle cell disease. Arch Intern Med, 1980.
140: 1434.
10. Lionnet, F., et al. Hemoglobin sickle cell disease complications: a clinical study of 179 cases. Haematologica,
2012. 97: 1136.
11. Olujohungbe, A.B., et al. A prospective diary study of stuttering priapism in adolescents and young men with
sickle cell anemia: report of an international randomized control trial--the priapism in sickle cell study. J Androl,
2011. 32: 375.
12. Wespes, E., et al., EAU Guidelines Panel on Male Sexual Dysfunction. EAU Guidelines on Male Sexual
Dysfunction (Erectile Dysfunction and premature ejaculation). Edn. presented at the EAU Annual congress
Stockholm. 2009: Arnhem, The Netherlands.
13. Hatzimouratidis, K., et al., EAU Guidelines Panel on Male Sexual Dysfunction. EAU guidelines on Penile
Curvature. Edn. presented at the EAU Annual Congress Paris. 2012: Arnhem, The Netherlands.
14. Salonia, A., et al., EAU Guidelines Panel on Male Sexual Dysfunction. EAU guidelines on priapism. Edn.
presented at the EAU Annual Congress Stockholm. 2014: Arnhem, The Netherlands
15. Hatzimouratidis, K., et al., EAU Guidelines Panel on Male Sexual Dysfunction. EAU guidelines on Male Sexual
Dysfunction. Edn. presented at the EAU Annual Congress Munich 2016.
16. Hatzimouratidis, K., et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation.
Eur Urol, 2010. 57: 804.
17. Hatzimouratidis, K., et al. EAU guidelines on penile curvature. Eur Urol, 2012. 62: 543.
18. Salonia, A., et al. European Association of Urology guidelines on priapism. Eur Urol, 2014. 65: 480.
19. Wespes, E., et al. EAU Guidelines on erectile dysfunction: an update. Eur Urol, 2006. 49: 806.
20. Wespes, E., et al. Guidelines on erectile dysfunction. Eur Urol, 2002. 41: 1.
21. Guyatt, G.H., et al. What is “quality of evidence” and why is it important to clinicians? Bmj, 2008. 336: 995.
22. Guyatt, G.H., et al. GRADE: an emerging consensus on rating quality of evidence and strength of
recommendations. Bmj, 2008. 336: 924.
23. Phillips, B. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by Jeremy Howick March
2009. 1998.
24. Guyatt, G.H., et al. Going from evidence to recommendations. Bmj, 2008. 336: 1049.
25. Van den Broeck T, et al. What are the benefits and harms of testosterone treatment for male sexual dysfunction?
PROSPERO: International prospective register of systematic reviews, 2015.
26. Gratzke, C., et al. Anatomy, physiology, and pathophysiology of erectile dysfunction. J Sex Med, 2010. 7: 445.
27. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA, 1993.
270: 83.
28. Feldman, H.A., et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male
Aging Study. J Urol, 1994. 151: 54.
29. Fisher, W.A., et al. Erectile dysfunction (ED) is a shared sexual concern of couples I: couple conceptions of ED.
J Sex Med, 2009. 6: 2746.

Tulburarile de Dinamica Sexuala - EAU Guidelines

Uploaded by

Copyright:

Available Formats

Tulburarile de Dinamica Sexuala - EAU Guidelines

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Tulburarile de Dinamica Sexuala - EAU Guidelines

Uploaded by

Copyright:

Available Formats

EAU Guidelines on

© European Association of Urology 2018

16 Male Sexual Dysfunction_2018_print.indd 1 22-02-18 15:57

3. MALE SEXUAL DYSFUNCTION 7

2 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

16 Male Sexual Dysfunction_2018_print.indd 2 22-02-18 15:57

MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 3

16 Male Sexual Dysfunction_2018_print.indd 3 22-02-18 15:57

4 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

16 Male Sexual Dysfunction_2018_print.indd 4 22-02-18 15:57

MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 5

16 Male Sexual Dysfunction_2018_print.indd 5 22-02-18 15:57

1.2 Publication history

1.3 Available Publications

1.4 Panel composition

6 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

16 Male Sexual Dysfunction_2018_print.indd 6 22-02-18 15:57

2.3 Future goals

3. MALE SEXUAL DYSFUNCTION

MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 7

16 Male Sexual Dysfunction_2018_print.indd 7 22-02-18 15:57

3.1.1.2 Risk factors

8 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

16 Male Sexual Dysfunction_2018_print.indd 8 22-02-18 15:57

3.1.1.3.1 Post-radical prostatectomy ED, post-radiotherapy ED & post-brachytherapy ED

MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 9

16 Male Sexual Dysfunction_2018_print.indd 9 22-02-18 15:57

3.1.1.3.2 Summary of evidence on the epidemiology/aetiology/pathophysiology of ED

3.1.3 Diagnostic evaluation

3.1.3.1.1 Sexual history

10 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

16 Male Sexual Dysfunction_2018_print.indd 10 22-02-18 15:57

3.1.3.1.2 Physical examination

3.1.3.1.3 Laboratory testing

MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 11

16 Male Sexual Dysfunction_2018_print.indd 11 22-02-18 15:57

Paent with ED (self-reported)

Medical and psychosexual history (use of validated instruments, e.g. IIEF)

Idenfy other than Idenfy common Idenfy reversible Assess psychosocial

Focused physical examinaon

Signs of Cardiovascular and

Total testosterone (morning sample)

ED = erectile dysfunction; IIEF = International Index of Erectile Function.

3.1.3.1.4 Cardiovascular system and sexual activity: the patient at risk

12 MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018

16 Male Sexual Dysfunction_2018_print.indd 12 22-02-18 15:57

Low-risk category Intermediate-risk category High-risk category

Sexual inquiry of all men

Low risk Intermediate risk High risk

Low risk High risk

Advice, treat ED Cardiologist

MALE SEXUAL DYSFUNCTION - LIMITED UPDATE MARCH 2018 13

16 Male Sexual Dysfunction_2018_print.indd 13 22-02-18 15:57

3.1.3.1.4.2 Intermediate- or indeterminate-risk category

3.1.3.1.4.3 High-risk category

3.1.3.2 Specialised diagnostic tests

3.1.3.2.1 Nocturnal penile tumescence and rigidity test

3.1.3.2.2 Intracavernous injection test

Paent with ED (self-reported)

Idenfy other than Idenfy common Idenfy reversible Assess psychosocial

Focused physical examinaon

Management of erecle dysfuncon

Idenfy and treat Lifestyle changes and Provide educaon

Idenfy paent needs and expectaons

Assess therapeuc outcomes

• Assess adequate use of treatment opons

Assess therapeuc outcomes

Assess therapeuc outcomes