E UROP E AN U RO LO GY 8 0 (2 021) 333 –357

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Review – Andrology

European Association of Urology Guidelines on Sexual and

Reproductive Health—2021 Update: Male Sexual Dysfunction

Andrea Salonia a,b,*, Carlo Bettocchi c, Luca Boeri d, Paolo Capogrosso e, Joana Carvalho f,
Nusret Can Cilesiz g, Andrea Cocci h, Giovanni Corona i, Kostantinos Dimitropoulos j,k,
Murat Gül l, Georgios Hatzichristodoulou m, T. Hugh Jones n, Ates Kadioglu o,
Juan Ignatio Martı´nez Salamanca p, Uros Milenkovic q, Vaibhav Modgil r, Giorgio Ivan Russo s,
Ege Can Serefoglu t, Tharu Tharakan u,v, Paolo Verze w, Suks Minhas u,
on behalf of the EAU Working Group on Male Sexual and Reproductive Health
a b
Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; University Vita-Salute San Raffaele, Milan, Italy;
c d
Department of Urology, University of Foggia, Foggia, Italy; Department of Urology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico,
e
University of Milan, Milan, Italy; Department of Urology and Andrology, Ospedale di Circolo and Macchi Foundation, Varese, Italy; f CPUP: Center for
Psychology of Porto University, Faculty of Psychology and Educational Sciences, Porto University, Porto, Portugal; g Department of Urology, Taksim Training &
Research Hospital, Istanbul, Turkey; h Department of Minimally Invasive and Robotic Urologic Surgery and Kidney Transplantation, University of Florence,
Florence, Italy; i Endocrinology Unit, Medical Department, Maggiore-Bellaria Hospital, Bologna, Italy; j Academic Urology Unit, Institute of Applied Health
k
Sciences, University of Aberdeen, Aberdeen, UK; Department of Urology, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK; l School of Medicine,
m
Department of Urology, Selcuk University, Konya, Turkey; Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany; n Centre for
Diabetes and Endocrinology, Barnsley Hospital NHS Trust, Barnsley, UK; o Department of Urology, Istanbul
_ _
University Istanbul _
School of Medicine, Istanbul,
Turkey; p Department of Urology, Hospital Universitario Puerta de Hierro-Majadahonda, Lyx Institute of Urology, Universidad Francisco de Vitoria, Madrid,
q
Spain; Department of Urology, University Hospitals Leuven, Leuven, Belgium; r Manchester Andrology Centre, Manchester Royal Infirmary, Manchester
University Hospitals NHS Foundation Trust, Manchester, UK; s Urology Section, Department of Surgery, University of Catania, Catania, Italy; t Department of
Urology, Biruni University School of Medicine, Istanbul, Turkey; u Department of Urology, Imperial Healthcare NHS Trust, Charing Cross Hospital, London, UK;
v w
Section of Investigative Medicine, Department of Medicine, Imperial College London, London, UK; Department of Medicine and Surgery "Scuola Medica
Salernitana", University of Salerno, Fisciano, Campania, Italy

* Corresponding author. Division of Experimental Oncology/Unit of Urology, URI-Urological Research

Institute, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Tel. +39 02 26435506.
E-mail address: [email protected] (A. Salonia).

https://doi.org/10.1016/j.eururo.2021.06.007
0302-2838/© 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.
334 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Article info Abstract

Article history: Context: The present summary of the European Association of Urology (EAU) guidelines
Accepted June 9, 2021 is based on the latest guidelines on male sexual health published in March 2021, with a
last comprehensive update in January 2021.
Associate Editor: Objective: To present a summary of the 2021 version of the EAU guidelines on sexual and
James Catto reproductive health.
Evidence acquisition: A literature review was performed up to January 2021. The guide-
lines were updated, and a strength rating for each recommendation was included based on
Keywords: either a systematic review of the evidence or a consensus opinion from the expert panel.
Guidelines Evidence synthesis: Late-onset hypogonadism is a clinical condition in the ageing male
combining low levels of circulating testosterone and specific symptoms associated with
Male
impaired hormone production and/or action. A comprehensive diagnostic and thera-
Testosterone peutic work-up, along with screening recommendations and contraindications, is
Hypogonadism provided. Erectile dysfunction (ED) is the persistent inability to attain and maintain
Sexual dysfunction an erection sufficient to permit satisfactory sexual performance. Along with a detailed
Erectile dysfunction basic and advanced diagnostic approach, a novel decision-making algorithm for treating
ED in order to better tailor therapy to individual patients is provided. The EAU guidelines
Ejaculatory disorders have adopted the definition of premature ejaculation (PE), which has been developed by
Premature ejaculation the International Society for Sexual Medicine. After the subtype of PE has been defined,
Haemospermia patient’s expectations should be discussed thoroughly and pharmacotherapy must be
considered as the first-line treatment for patients with lifelong PE, whereas treating the
underlying cause must be the initial goal for patients with acquired PE. Haemospermia is
defined as the appearance of blood in the ejaculate. Several reasons of haemospermia
have been acknowledged; the primary goal over the management work-up is to exclude
malignant conditions and treat any other underlying cause.
Please visit www.eu-acme.org/ Conclusions: The 2021 guidelines on sexual and reproductive health summarise the
europeanurology to answer questions on- most recent findings, and advise in terms of diagnosis and treatment of male hypogo-
line. The EU-ACME credits will then be at- nadism and sexual dysfunction for their use in clinical practice. These guidelines reflect
tributed automatically. the multidisciplinary nature of their management.
Patient summary: Updated European Association of Urology guidelines on sexual and
reproductive health are presented, addressing the diagnosis and treatment of the most
prevalent conditions in men. Patients must be fully informed of all relevant diagnostic
and therapeutic options and, together with their treating physicians, decide on optimal
personalised management strategies.
© 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1. Introduction 2. Evidence acquisition

The most recent summary of the European Association of The panel performed a broad and comprehensive literature
Urology (EAU) guidelines on male sexual health were search, covering all sections of the guidelines. Databases
published in 2010 [1] and 2012 [2]. The present summary is searched included Medline, EMBASE, and the Cochrane
based on the latest guidelines published in March 2021 [3], Libraries, covering a time frame between 2013 and 2020 and
with the last comprehensive update in January 2021. The restricted to English-language publications.
2021 version of the EAU guideline document is a further A strength rating has been provided for each recommen-
comprehensive update of the 2020 guidelines, which dation according to the EAU Guideline Office methodology
already includes an update of the 2018 versions of male (modified from the Grading of Recommendations Assessment,
sexual dysfunction, Male infertility, and male hypogonad- Development and Evaluation [GRADE] methodology) [4].
ism, along with several new topics. It must be emphasised
that guidelines present the best evidence available to the 3. Evidence synthesis
experts, who have participated fully in the evaluation of all
the material revised systematically for individual chapters. 3.1. Male hypogonadism
This article summarises the EAU guideline recommen-
dations on male sexual health management (namely, late- 3.1.1. Definition and epidemiology
onset hypogonadism [LOH], erectile dysfunction [ED], Male hypogonadism is a disorder associated with decreased
premature ejaculation [PE], and recurrent haemospermia). functional activity of the testes, with decreased production
The panel presents a summary of these latter conditions and/or action of androgens and/or impaired sperm produc-
because of their epidemiological importance, and a number tion [5]. This is caused by poor testicular function or as a
of innovative updates in terms of their management and result of inadequate stimulation of the testes by the
their relevance to men's health. Moreover, the full text on hypothalamic-pituitary-gonadal (HPG) axis. Likewise, sev-
male sexual health management can be found in the EAU eral congenital or acquired disorders causing impaired
guideline textbook and at uroweb.org [3]. action of androgens have also been described [5].
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 335

LOH is a clinical condition in the ageing male, which, by hypogonadism, allows the clinician to select appropriate
definition, must comprise specific symptoms and biochem- treatment adequately. Organic hypogonadism is charac-
ical evidence of testosterone deficiency [5,6]. It is a terised by any proven pathology affecting the HPG axis and
condition diagnosed in the absence of an identifiable should be treated with conventional medications (ie,
classical cause of hypogonadism, which becomes more gonadotropins or testosterone therapy). Conversely, func-
prevalent with age, occurring usually, but not exclusively, in tional hypogonadism is based on the absence of any
men over 40 yr of age. The present guideline summary will recognised organic alterations in the HPG axis and should
specifically address the management of LOH. be treated first by resolving or improving the associated
In men aged between 40 and 79 yr, the incidence of comorbidities; therefore, the need for testosterone therapy
symptomatic hypogonadism varies between 2.1% and 5.7% has been questioned [17,18].
[7,8]. The incidence of hypogonadism has been reported to be
12.3 and 11.7 cases per 1000 people per year [9]. Testosterone 3.1.3. Diagnostic evaluation of male hypogonadism
production declines as a function of age, and the prevalence Potential aetiology and risk factors associated with male
of hypogonadism increases with ageing; moreover, there is a hypogonadism are shown in Supplementary Table 1. The
higher prevalence of hypogonadism within specific popula- phenotype of the hypogonadal patient appears to be
tions, including men with type 2 diabetes (T2DM), metabolic independent of the aetiology underlying the problem but
syndrome (MetS), obesity, cardiovascular disease (CVD), is more often affected by the age of onset of hypogonadism.
chronic obstructive pulmonary disease (COPD), renal disease, When hypogonadism occurs in adulthood, especially in the
and cancer [9–12]. Klinefelter syndrome, a trisomy associated case of functional hypogonadism, symptoms can often be
with a 47,XXY karyotype, is the most prevalent genetic cause relatively mild, difficult to recognise, and frequently
of primary hypogonadism, with a global prevalence of 1/500– confused with the ageing process [5,14] or with comorbid
1000 live male births [13]. chronic conditions. Several nonspecific clinical features (eg,
fatigue, weakness, and decreased energy) as well as sexual
3.1.2. Classification and causes of male hypogonadism impairment may be clinical manifestations. The European
Male hypogonadism can be classified according to the origin Male Ageing Study (EMAS) showed that a triad of sexual
of the underlying aetiology into primary, if a consequence of symptoms, including low libido, reduced spontaneous
testicular dysfunction, and secondary, if due to a pituitary or erections, and ED, are typically associated with a decrease
hypothalamic dysfunction (Supplementary Table 1). Prima- in serum testosterone levels [7]. Conversely, psychological
ry hypogonadism is also called hypergonadotropic hypo- and physical symptoms were less informative (Supplemen-
gonadism, since the pituitary tries compensating the tary Table 2) [7]. As detailed, the mainstay of an LOH
dysfunctional testis by increasing central stimulation. diagnosis includes the presence of signs and symptoms
Conversely, in secondary hypogonadism (also called hypo- consistent with hypogonadism, coupled with biochemical
gonadotropic hypogonadism), the testis is inadequately evidence of low morning serum total testosterone levels on
stimulated by gonadotropins, usually with inappropriately two or more occasions, measured with a reliable assay.
normal or reduced gonadotropin levels [6,14]. A compen- Testosterone levels show a circadian variation, which
sated or subclinical form of hypogonadism, characterised by persists in ageing men [19]. Likewise, testosterone levels
normal testosterone serum levels and elevated luteinising are potentially influenced by food intake [5,20]; hence,
hormone (LH) production, has also been reported [15]; the serum total testosterone should be measured in fasting
clinical significance of the latter condition is unclear conditions and in the morning (between 7.00 and
[16]. Finally, hypogonadism can also result from a group 11.00 hours). Moreover, a confirmatory measurement
of several conditions leading to reduced sensitivity/insen- should always be undertaken in the case of a primary
sitivity to testosterone and its metabolites (Supplementary pathological value and certainly before starting any
Table 1) [5,14]. This classification, based on the aetiology of testosterone therapy. Liquid chromatography–tandem mass

Table 1 – Recommendations for screening and diagnostic evaluation of late-onset hypogonadism

Recommendations

Check for concomitant diseases, drugs, and substances that can interfere with testosterone production/action.
Total testosterone must be measured in the morning (07.00 and 11.00 hours) and in the fasting state, with a reliable method.
Repeat total testosterone on at least two separate occasions when <12 nmol/l and before starting testosterone therapy.
A total testosterone level of 12 nmol/L (3.5 ng/ml) represents a reliable threshold to diagnose LOH.
Consider SHBG and free testosterone calculation when indicated.
Free testosterone <225 pmol/l has been suggested as a possible cut-off to diagnose LOH.
Analyse LH and FSH serum levels to differentiate between primary and secondary hypogonadism.
Consider prolactin measurement if low sexual desire (or other suggestive signs/symptoms) and low or low-to-normal testosterone are present.
Perform pituitary MRI in secondary hypogonadism, with elevated prolactin or specific symptoms of a pituitary mass and/or presence of other anterior pituitary
hormone deficiencies.
Perform pituitary MRI in secondary severe hypogonadism (total testosterone <6 nmol/l).

FSH = follicle-stimulating hormone; LH = luteinising hormone; LOH = late-onset hypogonadism; MRI = magnetic resonance imaging; SHBG = sex hormone–
binding globulin.
336 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Fig. 1 – Diagnostic evaluation of late-onset hypogonadism. cFT = calculated free testosterone; LH = luteinising hormone; MRI = magnetic resonance
imaging; PRL = prolactin; SHBG = sex hormone–binding globulin; T = testosterone; TT = total testosterone.

spectrometry (LC-MS/MS) represents the gold standard and testosterone (fT); therefore, direct fT evaluation with these
most accurate method for sex steroid evaluation; however, methods is not recommended and should be avoided
standardised automated platform immune assays for total [5]. Free testosterone can be derived from specific
testosterone assessment demonstrate a good correlation mathematical calculations taking into account serum sex
with LC-MS/MS [21]. Conversely, available immunoassays hormone–binding globulin (SHBG) and albumin levels
are not able to provide an accurate estimation of free (http://www.issam.ch/freetesto.htm) [22].
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 337

Data derived from meta-analyses have shown that Table 2 – Main contraindications of testosterone therapy
testosterone therapy is ineffective when baseline levels Absolute contraindications Locally advanced or metastatic
are above 12 nmol/l (3.5 ng/ml) [23]. Positive outcomes are prostate cancer
documented when testosterone levels are below 12 nmol/l Male breast cancer
and higher in symptomatic patients with more severe forms Men with an active desire to have
children
of hypogonadism (testosterone <8 nmol/l). Hence, Haematocrit !54%
12 nmol/l should be considered a threshold to start with Uncontrolled or poorly controlled
testosterone therapy in the presence of hypogonadal congestive heart failure
Relative contraindications Severe lower urinary tract symptoms
symptoms (Table 1) [23,24]. In the presence of clinical
(IPSS score >19)
conditions that may potentially interfere with SHBG levels Baseline haematocrit 48–50%
(Supplementary Table 3), the evaluation of fT should be Familial history for venous
considered in order to better estimate actual testosterone thromboembolism

levels (Fig. 1 and Table 1). Unfortunately, despite its IPSS = International Prostate Symptom Score.
potential clinical value [25], no validated thresholds for fT
are available from clinical studies, and this represents an
area of uncertainty; however, some data indicate that fT
levels below 225 pmol/l (<6.5 ng/dl) are associated with site of origin of the disease. Conversely, the age of onset of
hypogonadal symptoms (Table 1) [7,26,27]. hypogonadism can deeply influence the clinical phenotype
The determination of LH must be performed along with [35]. In patients with secondary hypogonadism, both
prolactin (PRL) when low total testosterone levels are fertility and testosterone normalisation can be achieved
detected, in order to define the underlying conditions theoretically with an adequate treatment, whereas in
correctly and exclude possible organic forms (Fig. 1 and primary hypogonadism, only testosterone therapy can be
Table 1). Owing to its negative influence on libido, PRL can considered, which will suppress gonadotropins and
also be considered as first-line screening in patients with endogenous testosterone secretion as well as spermato-
reduced sexual desire. In addition, pituitary magnetic genesis (Supplementary Table 1) [5,14]. Hence, testoster-
resonance imaging (MRI) scanning, as well as other one therapy is contraindicated in individuals who desire
pituitary hormone evaluation, is required in the presence fertility [36].
of specific symptoms such as visual disturbances, headache,
or when hyperprolactinemia is confirmed [28]. In addition, 3.1.4.1. Testosterone therapy outcomes
limited evidence suggests performing pituitary MRI also in
cases of severe hypogonadism (<6 nmol/l; 1.75 ng/ml) with 3.1.4.1.1. Sexual dysfunction. Sexual concerns are the main
inadequate gonadotropin levels (Fig. 1 and Table 1) [28]. symptoms of the hypogonadal patient [7]. A consistent
A number of self-reported questionnaires or structural body of evidence shows that testosterone therapy in
interviews have been developed for the screening of hypogonadal men may have a beneficial effect on several
hypogonadism [29]. Although these case-history tools have aspects of sexual function (Fig. 1); in contrast, there is no
demonstrated clinical utility in supporting the biochemical evidence of benefits in using testosterone therapy for
diagnosis of hypogonadism, or in the assessment of treating sexual dysfunction in eugonadal men (Table 3)
testosterone therapy outcomes, their specificity remains [23,24,37,38]. The beneficial effect on sexual function seems
relatively poor and they should not be used for systematic to be more related to testosterone level normalisation
screening of hypogonadal men [30]. rather than the specific testosterone formulations used
Since obesity is frequently associated with hypogonad- [33,39]. Men with comorbidities such as diabetes usually
ism (mostly functional) [31,32], determination of body mass show modest improvements in terms of sexual function
index (BMI) and measurement of waist circumference are after testosterone therapy and may potentially require
strongly recommended in all individuals. Testicular and concomitant phosphodiesterase type 5 inhibitors (PDE5Is)
penile size, as well as the presence of sexual secondary to improve effectiveness [5,38]. Overall, the specific
characteristics, can provide useful information regarding beneficial effect derived from the combined use of
overall androgen status. Finally, digital rectal examination testosterone therapy and PDE5Is is still not completely
(DRE) should be performed in all patients to exclude clear (Table 3) [24]. Similarly, information related to the
prostate abnormalities before testosterone therapy (any combined use of testosterone therapy with other ED
type) or support the suspicion of hypogonadism [33,34]. pharmacotherapies is lacking.

3.1.4. Treatment of LOH 3.1.4.1.2. Body composition and metabolic profile. LOH is associated
Patients with symptomatic hypogonadism without specific with a greater percentage of fat mass and a lower lean mass
contraindications are suitable candidates for receiving than testosterone-repleted men [40]. A substantial amount
testosterone therapy (Table 2). A detailed explanation of of published data have suggested that testosterone therapy
absolute and relative contraindications to testosterone reduces percentage body fat and increases lean mass
therapy can be found in the complete EAU guidelines [3]. It [41,42]. However, it should be recognised that these results
should also be recognised that symptoms and signs of are mainly derived from registry and observational trials,
hypogonadism can be relatively similar independent of the which have important limitations due to the risk of
338 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Table 3 – Recommendations for testosterone therapy outcome (TTrials; one of the largest placebo-controlled trials on
Recommendations Strength testosterone therapy), which evaluated the effect of
rating testosterone therapy in 493 individuals with age-associated
memory impairment in order to assess possible improve-
The use of testosterone therapy in eugonadal men is Strong
not indicated. ment of several aspects of cognitive function, failed to
Use testosterone as first-line treatment in patients Strong demonstrate any beneficial effect of testosterone therapy in
with symptomatic hypogonadism and mild ED. improving cognitive function (Table 3) [50].
Use combination of PDE5Is and testosterone therapy Weak
in more severe forms of ED as it may result in better
outcomes. 3.1.4.1.5. Bone. The possible association between mild hypo-
Use conventional medical therapies for severe Strong gonadism and osteopenia/osteoporosis is weak, whereas
depressive symptoms and osteoporosis. severe hypogonadism (total testosterone <3.5 nmol/l) is
Do not use testosterone therapy to improve body Weak
frequently associated with bone loss and osteoporosis,
composition, reduce weight, and benefit
cardiometabolic profile. independent of patient age [51]. Although two independent
Do not use testosterone therapy to improve cognition Strong meta-analyses and data derived from TTrials confirmed that
vitality and physical strength in ageing men. testosterone therapy increased bone mass density in
ED = erectile dysfunction; PDE5Is = phosphodiesterase type 5 inhibitors. hypogonadal ageing men, particularly at the lumbar level
[50,52,53], available data are insufficient to determine the
effect of testosterone therapy alone on the risk of bone
selection bias for the nonrandom assignment of testoster- fractures [51]. In addition, the use of testosterone therapy as
one exposure (Table 3). an adjunct to antiresorptive treatment in hypogonadal
patients at a high risk of fractures is not established.
3.1.4.1.3. MetS and T2DM. A number of randomised controlled Therefore, antiresorptive therapy must be the first-choice
trials (RCTs) have shown that testosterone therapy might treatment in hypogonadal men at a high risk for bone
improve insulin resistance and hyperglycaemia, and lower fractures. The combination of antiresorptive treatment and
cholesterol and low-density lipoprotein cholesterol testosterone therapy should be offered only in conjunction
[43]. Testosterone therapy in hypogonadal T2DM improved with hypogonadal-related symptoms (Table 3).
glycaemic control in some RCTs and registry trials [3]. A
recent large placebo-controlled RCT, including 1007 patients 3.1.4.1.6. Vitality and physical strength. The role of testosterone
with impaired glucose tolerance or newly diagnosed T2DM therapy in older men with mobility limitations remains
and total testosterone <14 nmol/l, showed that testoster- unclear [50,54].
one therapy for 2 yr reduced the proportion of patients with
T2DM regardless of a lifestyle programme [44]. Similarly, a 3.1.4.2. Testosterone therapy—medical preparations. Several testos-
previously published registry study reported that in men terone formulations are available; a detailed explanation of
with T2DM, total testosterone "12.1 nmol/l, and symptoms available preparations can be found in the complete EAU
of hypogonadism, testosterone therapy was associated in guidelines [3]. The final choice should be based on the
time with improved glycaemic control and insulin resis- clinical situation, availability of testosterone formulations,
tance, and even remission of T2DM in one-third of the and patient needs and expectations [55]. Table 4 provides
patients [45]. guideline recommendations for the choice of treatment for
LOH.
3.1.4.1.4. Mood and cognition. Several observational studies
have documented a relationship between depressive 3.1.4.3. Testosterone therapy—safety and follow-up in hypogonadism
symptoms, reduced quality of life (QoL), and hypogonadism management. As detailed, testosterone therapy is contra-
[42,46], despite the specific relationship between hypogo- indicated in hypogonadal men seeking fertility treatment
nadism and the incidence of depression still being unclear [36]. When secondary hypogonadism is present, gonado-
[46]. Only a few placebo-controlled RCTs have investigated tropin therapy can maintain normal testosterone levels and
the role of testosterone therapy in improving depressive restore sperm production [5]. Available meta-analyses did
symptoms. The largest meta-analysis of available studies, not find significant changes in lower urinary tract symp-
including 1890 hypogonadal (baseline total testosterone toms (LUTS) in men using testosterone therapy compared
<12 nmol/l or fT <225 pmol/l) men from 27 RCTs, docu- with placebo [56,57]. Likewise, according to the most recent
mented that the positive effect of testosterone therapy was literature, there are no grounds to discourage testosterone
particularly evident in patients with milder depressive therapy in hypogonadal patients with benign prostatic
symptoms [47]. Robust data on the effect of testosterone hyperplasia (BPH)/LUTS. The only concern is related to
therapy on QoL are limited. Although recent meta-analyses patients with severe LUTS (International Prostate Symptom
suggest a significant effect of testosterone therapy over Score >19), as these patients are usually excluded from
placebo, the magnitude is low and the heterogeneity high, RCTs, therefore limiting the long-term safety data of
therefore reducing the scientific value of the effect testosterone therapy in this specific setting [33]. As for
[39,48]. The role of testosterone therapy in patients with the association between circulating higher testosterone
cognitive impairment is even more uncertain [49]. Data levels and prostate cancer (PCa), the most recent meta-
from the Sexual Function Trial of the Testosterone Trials analyses found no evidence of increased prostate-specific
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 339

Table 4 – Recommendations for choice of treatment for late-onset Table 5 – Recommendations on risk factors in testosterone
hypogonadism treatment

Recommendations Strength Recommendations Strength

rating rating

Treat, when indicated, organic causes of hypogonadism (eg, Strong Fully counsel symptomatic hypogonadal men who have Weak
pituitary masses, hyperprolactinemia, etc.). surgically treated for localised PCa and who are currently
Improve lifestyle and reduce weight (eg, obesity); withdraw, Weak without evidence of active disease considering testosterone
when possible, concomitant drugs that impair testosterone therapy, emphasising the benefits and lack of sufficient
production; treat comorbidity before starting testosterone safety data on long-term follow-up.
therapy. Restrict treatment to patients with a low risk for recurrent Weak
Fully inform patients about expected benefits and adverse Strong PCa (ie, preoperative PSA<10 ng/ml, Gleason score <7
effects of any treatment option. Select the testosterone [International Society for Urological Pathology grade 1], cT1–
preparation in a joint decision process, only with fully 2a), a and treatment should start after at least 1 yr of follow-
informed patients. up with PSA level <0.01 ng/ml.
The aim of testosterone therapy is to restore serum Weak Safety data on the use of testosterone therapy in men treated Strong
testosterone concentration to the average normal range for for breast cancer are unknown.
young men. Assess CV risk factors before commencing testosterone Strong
Use testosterone gels rather than long-acting depot Weak therapy.
administration when starting initial treatment, so that Assess men with known CVD for CV symptoms before Strong
therapy can be adjusted or stopped in case of treatment- testosterone therapy and with close clinical assessment and
related adverse effects. evaluation during treatment.
Treat men with hypogonadism and pre-existing CVD, venous Weak
thromboembolism, or chronic cardiac failure, who require
testosterone therapy with caution, by careful clinical
antigen (PSA) levels following testosterone therapy for no monitoring and regular measurement of haematocrit (not
less than 1 yr [58–60]. With regard to PCa survivors, exceeding 54%) and testosterone levels.
Exclude a family history of venous thromboembolism before Strong
because of the limited data available in the literature, safety
starting testosterone therapy.
in terms of the risk of recurrence and progression has not Monitor testosterone and haematocrit at 3, 6, and 12 mo Strong
yet been established. Recently, meta-analyses suggested after testosterone therapy initiation, and thereafter annually.
that testosterone therapy did not increase the risk of Haematocrit >54% should require testosterone therapy
withdrawal and phlebotomy. Reintroduce testosterone
biochemical recurrence [60,61]. It is important to recognise
therapy at a lower dose once the haematocrit has normalised
that the vast majority of studies analysed included low-risk and consider switching to topical testosterone preparations.
patients with a Gleason score of <8 [60]. In conclusion, CV = cardiovascular; CVD = cardiovascular disease; EAU = European
while the EAU guidelines recommend to avoid testosterone Association of Urology; PCa = prostate cancer; PSA = prostate-specific
administration in men with advanced PCa, insufficient long- antigen.
a
term prospective data on the safety of androgen adminis- As for EAU risk groups for biochemical recurrence of localised or locally
advanced prostate cancer (see EAU guidelines 2020 on prostate cancer).
tration in PCa survivors [61] should prompt caution in
choosing to treat symptomatic hypogonadal men in this
setting. Patients should be fully counselled that the long-
term effects of testosterone therapy in this setting are still evidence that testosterone therapy can result in the onset or
unknown and require further investigation. worsening of sleep apnoea.
Published data show that LOH is associated with an Table 5 summarises the recommendations on risk factors
increase in all-cause and CVD-related mortality [62]. There for testosterone therapy.
are no RCTs that provide a clear answer on whether Testosterone therapy alleviates symptoms and signs of
testosterone therapy affects cardiovascular (CV) outcomes hypogonadism in men. In terms of follow-up, testosterone
[63]. As a whole, as for major adverse cardiovascular events, therapy in hypogonadal men has been proved to be effective
current available data from interventional studies suggest in alleviating symptoms and signs in a specific time-
that there is no increased risk with testosterone therapy dependent manner [50]. Hence, the first evaluation should
with up to 3 yr of therapy [64–67]. An elevated haematocrit be planned after 3 mo of treatment. Further evaluation may
is the most common side effect of testosterone therapy be scheduled at 6 or 12 mo, according to patient
[68,69]. There is no evidence that an increase of haematocrit characteristics, as well as results of biochemical testing.
up to and including 54% causes any adverse effects on Table 6 summarises the clinical and biochemical parame-
health. If the haematocrit exceeds 54%, there is a testoster- ters that should be monitored during testosterone therapy.
one-independent but weak associated rise in CV events and
mortality [70], although there have been no specific studies 3.2. Erectile dysfunction
including men with only testosterone-induced erythrocy-
tosis. An elevated haematocrit in the absence of any 3.2.1. Definition and epidemiology of ED
comorbidities, or acute CV or venous thromboembolism ED is defined as the persistent inability to attain and
can be managed by a reduction in testosterone dose—a maintain an erection sufficient to permit satisfactory sexual
change in formulation; conversely, if the elevated haema- performance [71]. ED may affect psychosocial health and
tocrit is very high, it can be managed by venesection have a significant impact on the QoL of patients and their
(500 ml), even repeated if necessary, with usually no need partners. ED is commonly classified into three groups based
to stop the testosterone therapy. There is also no clear on aetiology. These include organic, psychogenic, and mixed
340 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Table 6 – Clinical and biochemical parameters to be checked during testosterone therapy

Parameters Year 1 of treatment After year 1 of treatment

Baseline 3 mo 6/12 mo Annually 18–24 mo

Clinical
Symptoms # # # #
BMI
Waist circumference # # # #
DRE # # # #
Blood pressure # # # #

BMI = body mass index; DRE = digital rectal examination.

ED. However, this classification should be used with caution men with ED [85,86]. Meta-analytic data reveal a positive
as most cases are actually of mixed aetiology. Therefore the effect of lipid-lowering therapy with statins on erectile
use of the term “primary organic” or “primary psychogenic” function [87].
has been suggested. ED is also frequently associated with a number of
Epidemiological data have shown a high prevalence and urological conditions and procedures [3,88]. Epidemiologi-
incidence of ED worldwide [72]; detailed available data on cal studies have demonstrated consistent evidence for an
ED incidence and prevalence can be found in the complete association between LUTS/BPH and sexual dysfunction,
EAU guidelines [3]. regardless of age, other comorbidities, and lifestyle factors
There is established evidence that the presence of ED [89]. Regardless of the technique used, surgery for BPH/
increases the risk of future CV events including myocardial LUTS had no significant impact on erectile function. In fact,
infarction, cerebrovascular events, and all-cause mortality, even an improvement was found depending on the degree
with a trend towards an increased risk of CV mortality of improvement of urinary symptoms [90,91]. An associa-
[73]. Therefore, ED can be an early manifestation of tion between ED and chronic prostatitis/chronic pelvic pain
coronary artery and peripheral vascular disease, and should syndrome, and bladder pain syndrome/interstitial cystitis
not be regarded only as a QoL issue, but also as a potential has been confirmed, mostly in younger men [92,93]. An
warning sign of CVD [73–75]. increased risk of ED is reported following transrectal
ultrasound (TRUS)-guided prostate biopsy [94] and after
3.2.2. Risk factors for ED open urethroplasty, especially for correction of posterior
ED is associated with unmodifiable and modifiable common strictures [3,95]. Pelvic surgery, especially for oncological
risk factors, including age, diabetes mellitus, dyslipidaemia, disease (eg, radical prostatectomy or RP [96,97] or radical
hypertension, CVD, BMI/obesity/waist circumference, MetS, cystectomy [98], and colorectal surgery [99]), may have a
hyperhomocysteinemia, lack of exercise, and smoking negative impact on erectile function and overall sexual
[73,74,76]. Furthermore, an association between ED status health [3]. The most relevant causal factor is a lesion (any)
and pharmacotherapeutic agents for CVD (eg, thiazide occurring to the neurovascular bundles that control the
diuretics and b-blockers, except nebivolol) exerts detri- complex mechanism of the cavernous erectile response, the
mental effects on erectile function, whereas other drugs (ie, preservation (either partial or complete) of which during
angiotensin-converting enzyme inhibitors, angiotensin surgery constitutes the so-called nerve-sparing (NS) ap-
receptor blockers, and calcium channel blockers) have proach [100]. Thus, surgery resulting in damage of the
neutral or even beneficial effects [3,71,77]. Atrial fibrillation, neurovascular bundles will result in ED, although NS
hyperthyroidism, vitamin D deficiency, hyperuricaemia, approaches have been adopted over the last few decades
depression, chronic renal disease, rheumatic disease, and [100]. A significant amount of data have been reported,
COPD have also been associated with ED [3]. Available data outlining various treatment outcomes in men operated with
do not confirm a clear association between ED and a variety of NS approaches. In terms of the effects of surgical
hypothyroidism [78–80] and hyperprolactinemia [80– interventions (eg, robot-assisted RP vs other types of
82]. Further epidemiological data have also highlighted surgery), data are still conflicting [3,101–105]. Of note,
other potential risk factors associated with ED, including despite the advancements in surgical techniques and the
sleep disorders, obstructive sleep apnoea, psoriasis, gouty advent of minimally invasive approaches, the rates of post-
arthritis and ankylosing spondylitis, nonalcoholic fatty liver RP ED are still high and ranging between 25% and 75%
disease, other chronic liver disorders, chronic periodontitis, [3,101–105]. Even nonsurgical treatments of PCa (ie,
open-angle glaucoma, inflammatory bowel disease, chronic radiotherapy and brachytherapy) can be associated with
fatigue syndrome, and allergic rhinitis [3]. Insufficient data significant impairment of erectile function [106,107]. Over-
are currently available to correlate a primarily organic or a all, potential therapeutic options in patients with clinically
primarily psychogenic ED problem with SARS-CoV-2 localised PCa (eg, high-intensity focused ultrasound [US],
infection–associated disease (COVID-19) [83,84]. A number cryoablation of the prostate [cryotherapy], focal padelipor-
of studies have shown that lifestyle modification, including fin-based vascular-targeted photodynamic therapy, and
physical activity, weight loss, and pharmacotherapy for CVD focal radiation therapy by brachytherapy or CyberKnife)
risk factors, may be of help in improving sexual function in have been shown to have a less negative impact on erectile
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 341

function, although all these treatment approaches lack about previous and current sexual relationships, current
robust long-term oncological outcomes, and prospective emotional status, onset and duration of the erectile
RCTs are needed to compare functional and oncological problem, and previous consultations and treatments. The
outcomes between these surgical treatment modalities sexual health status of the partner(s), when available, can
[3,108]. The concept of an active surveillance (AS) strategy also be useful. A detailed description should be made of the
for the treatment of PCa was developed to avoid overtreat- rigidity and duration of both sexually stimulated and
ment of nonsignificant localised low-risk diseases, while morning erections and of problems with sexual desire,
limiting potential functional side effects (including ED). arousal, ejaculation, and orgasm [111]. Validated psycho-
However, it is interesting that data suggest that even AS may metric questionnaires (such as the International Index of
have a detrimental impact on erectile function (and sexual Erectile Function or IIEF [112] or its shortened version, ie,
well-being as a whole) [3,109]. Sexual Health Inventory for Men [SHIM]) or structured
interviews help assess the different sexual function
3.2.3. Diagnostic evaluation (basic work-up) domains (ie, sexual desire, erectile function, orgasmic
3.2.3.1. Medical and sexual history. Figure 2 lists the minimal function, intercourse satisfaction, and overall satisfaction),
diagnostic evaluation (basic work-up) in patients with ED. as well as the potential impact of a specific treatment
The first step in evaluating ED is always a detailed medical modality. Psychometric analyses also support the use of the
and sexual history of patients and, when available, their Erectile Hardness Score (EHS) [113] for the assessment of
partners [110]. The sexual history must include information penile rigidity in practice and in clinical trial research, or the

Fig. 2 – Minimal diagnostic evaluation (basic work-up) in patients with ED. ED = erectile dysfunction; IIEF = International Index of Erectile Function.
342 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Beck Depression Inventory [114] in cases of depressive Peyronie’s disease (PD), premalignant or malignant genital
mood. Patients should always be screened for symptoms of lesions, prostatic enlargement or irregularity/nodularity, or
possible hypogonadism, as well as for LUTS [3]. signs and symptoms suggestive of hypogonadism (ie, small
Of clinical relevance, patients who seek treatment for testes, alterations in secondary sexual characteristics, etc.).
sexual dysfunction have a high prevalence of CVDs. ED Overall, assessing previous or concomitant penile abnor-
increases significantly the risk of CVD, coronary heart malities (eg, hypospadias, congenital curvature, or PD with
disease, and stroke [115,116]. Furthermore, ED is an preserved rigidity) during the medical history and the
independent predictor of incident atrial fibrillation physical examination is mandatory. Blood pressure and
[117]. All these increase mortality and are probably heart rate should be measured if these have not been
independent of conventional CV risk factors [73]. The assessed in the previous 3–6 mo. Likewise, either a BMI
EAU guidelines for diagnosing and treating men with ED calculation or a waist circumference measurement should
have been adapted from previously published recommen- be undertaken to assess patients for comorbid conditions
dations from the Princeton Consensus conferences on (Fig. 2).
sexual dysfunction and cardiac risk [118]. Accordingly,
patients with ED can be stratified into three CV risk 3.2.3.3. Laboratory testing. Laboratory testing must be tailored
categories, which can be used as the basis for a treatment to the patient’s complaints and risk factors. Patients should
algorithm for initiating or resuming sexual activity (Fig. 3). undergo fasting blood glucose, HbA1c, and lipid profile tests
if these have not been assessed in the previous 12 mo.
3.2.3.2. Physical examination. Every patient must undergo a Hormonal tests should include an early morning total
physical examination focused on the genitourinary, endo- testosterone in a fasting state. The bioavailable or calculated
crine, vascular, and neurological systems [119]. A physical fT value can be used to corroborate total testosterone
examination may reveal unsuspected diagnoses, such as measurements after considering SHBG evaluation. Addi-

Fig. 3 – Treatment algorithm for determining level of sexual activity according to cardiac risk in ED (based on the third Princeton Consensus).
ED = erectile dysfunction. a Sexual activity is equivalent to walking 1 mile on the flat in 20 min or briskly climbing two flights of stairs in 10 s. b
Sexual
activity is equivalent to 4 min of the Bruce treadmill protocol.
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 343

Table 7 – Recommendations for the diagnostic evaluation of in those conditions where a potential vasculogenic aetiol-
erectile dysfunction
ogy of ED (eg, diabetes mellitus, renal transplantation,
Recommendations Strength multiple concomitant CV risk factors and/or overt periph-
rating eral vascular disease, poor responders to oral therapy, etc.)
Take a comprehensive medical and sexual history in every Strong is suspected [3]. Recent data have suggested that duplex
patient presenting with ED. Consider psychosexual scanning as a haemodynamic study may be better at
development, including life stressors, cultural aspects, and tailoring therapy for ED, such as for low-intensity shock-
cognitive/thinking style of the patient regarding their sexual
wave therapy (LI-SWT) and for diagnosing vasculogenic ED
performance.
Use a validated questionnaire related to ED to assess all Strong [126]. Further vascular investigation is unnecessary if a
sexual function domains (eg, IIEF) and the effect of a specific duplex US examination is normal.
treatment modality.
Include a focused physical examination in the initial Strong
3.2.4.4. Arteriography and dynamic infusion cavernosometry or
assessment of men with ED to identify underlying medical
conditions and comorbid genital disorders that may be cavernosography. Pudendal arteriography should be per-
associated with ED. formed only in patients who are being considered for
Assess routine laboratory tests, including glucose and lipid Strong penile revascularisation [127]. Nowadays, dynamic infusion
profile and total testosterone, to identify and treat any
reversible risk factors and lifestyle factors that can be
cavernosometry or cavernosography are infrequently used
modified. diagnostic tools aimed at diagnosing venogenic ED [3].
Include specific diagnostic tests in the initial evaluation of ED Strong
in the presence of specific conditions (presented in 3.2.4.5. Psychiatric and psychosocial assessment. When clinically
Supplementary Table 3).
indicated, patients with psychiatric disorders should be
ED = erectile dysfunction; IIEF = International Index of Erectile Function.
referred to a psychiatrist [3]. In younger patients (<40 yr)
with long-term primary ED, psychiatric assessment may be
helpful before any clinical assessment is carried out. Mental
tional laboratory tests may be considered in selected health issues are frequently comorbid with ED; this is most
patients with specific signs and associated symptoms (eg, evident for depression- and anxiety-related disorders, but
PSA), PRL, and LH [120]). Although physical examination may also include transitory states of altered mood (ie,
and laboratory evaluation of most men with ED may not dysfunctional affective states resulting from a specific life
reveal the exact diagnosis, clinical and biochemical stressor) [3,128].
evaluations present an opportunity to identify comorbid Table 7 details the recommendations for the diagnostic
conditions [119]. evaluation of patients presenting with ED.

3.2.4. Diagnostic evaluation (advanced work-up) 3.2.5. Treatment of ED

Most patients with ED can be managed on the basis of ED can be treated successfully with a number of therapeutic
medical and sexual history; conversely, some patients may options, but it cannot be cured. The only exceptions are
need specific diagnostic tests (Supplementary Table 4). psychogenic ED, post-traumatic arteriogenic ED in young
patients, and hormonal causes (eg, hypogonadism) [3,120],
3.2.4.1. Nocturnal penile tumescence and rigidity test. For the which can potentially be cured with specific treatments.
nocturnal penile tumescence and rigidity (NPTR) test, Most men with ED will be treated with therapeutic options
nocturnal monitoring devices are used to measure the that are not cause specific. Based on the currently available
number of erectile episodes, tumescence (circumference evidence and the consensus of the panel, a novel
change by strain gauges), maximal penile rigidity, and comprehensive therapeutic and decision-making algorithm
duration of nocturnal erection(s) [121–123]. NPTR monitor- for treating ED has been presented (Fig. 4). This novel
ing is considered an additional test for even more treatment algorithm was discussed extensively within the
objectively differentiating between organic and psychogen- guideline panel as an alternative to the traditional three-
ic ED (patients with psychogenic ED usually have normal level concept, in order to better tailor personalised therapy
findings in the NPTR test), but many potential confounding to individual patients, according to invasiveness, tolerabili-
factors (eg, situational) may limit its routine use solely for ty, and effectiveness of the different therapeutic options,
diagnostic purposes [121,124]. along with patients’ needs and expectations. In this context,
patients should be counselled fully with respect to all
3.2.4.2. Intracavernous injection test. The intracavernous injec- available treatment modalities.
tion test gives limited information about the vascular ED may be associated with modifiable or reversible risk
status; overall, the test is inconclusive as a diagnostic factors, including lifestyle or drug-related factors [3]. These
procedure, and a duplex Doppler study of the penis should factors may be modified either before or at the same time as
be requested, if clinically warranted. specific therapies are used. Likewise, ED may be associated
with concomitant and underlying conditions (such as
3.2.4.3. Dynamic duplex US of the penis. Dynamic duplex US of endocrine disorders and metabolic disorders—eg, diabetes,
the penis is a test specifically aimed to study the and some CV problems—eg, hypertension), which should
haemodynamic pathophysiology of erectile function always be well controlled as the first step of any ED
[125]. Therefore, in clinical practice, it is usually applied treatment [129]. Major clinical potential benefits of lifestyle
344 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Fig. 4 – Management algorithm for erectile dysfunction. ED = erectile dysfunction; LI-SWT = low-intensity shockwave therapy;
PDE5I = phosphodiesterase type 5 inhibitor.

changes may be achieved in men with specific comorbid CV 3.2.5.1. Oral pharmacotherapy for ED. Four potent selective
or metabolic disorders, such as diabetes or hypertension PDE5Is have currently been approved by the European
[129]. An educational intervention is often the first Medicines Agency (EMA) for the treatment of ED (ie,
approach to sexual dysfunction and consists of informing sildenafil, tadalafil, vardenafil, and avanafil) [3,129]. A
patients about the psychological processes involved in the detailed summary of their key pharmacokinetic data, along
individual’s sexual response, in ways they can understand. with their effectiveness and safety profiles can be found in
This first-level approach was shown to favour sexual the EAU guidelines, which also details potential strategies to
satisfaction in men with ED [130]. manage nonresponders to PDE5Is, thus including combina-
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 345

tion therapies [3]. Overall, since they are not initiators of order to facilitate absorption of alprostadil (200 and
erection, PDE5Is require sexual stimulation to facilitate an 300 mg) via the urethral meatus [135]. Clinical data in
erection. Efficacy is defined as an erection, with rigidity, patients with mild-to-severe ED are still limited. Side effects
sufficient for satisfactory intercourse. To date, no data are include penile erythema, penile burning, and pain that
available from double- or triple-blind multicentre studies usually resolve within 2 h of application. Systemic side
comparing the efficacy and/or patient preference for the effects (eg, dizziness and hypotension) are very rare. The
four available PDE5Is. The choice of drug will depend on the second method of delivery is by the intraurethral insertion
frequency of intercourse (occasional use or regular therapy, of a specific formulation of alprostadil (125–1000 mg) in a
three to four times weekly) and the patient’s personal medicated pellet (MUSE). Topical alprostadil (Vitaros) at the
experience. Patients need to know whether a drug is short- dose of 300 mg is available in some European countries
or long-acting, its possible disadvantages, and how to use it [3]. Recently a randomised cross-over clinical trial showed
[3,129]. Most frequent treatment-related side effects (ie, that, compared with the standard administration route,
headache, flushing, dyspepsia, nasal congestion, dizziness, direct delivery of the drug within the urethral meatus is able
abnormal vision, back pain, and myalgia) are generally mild to increase the level of treatment efficacy and confidence
in nature and self-limited [129]. among patients, without increasing the incidence of side
effects [136].
3.2.5.1.1. CV safety. Clinical trial results for the four PDE5Is and
postmarketing data of sildenafil, tadalafil, and vardenafil 3.2.5.3. Intracavernous injection therapy. Intracavernous admin-
have demonstrated no increase in myocardial infarction istration of vasoactive drugs was the first medical treatment
rates in patients receiving PDE5Is, as part of either RCTs or introduced for ED. According to invasiveness, tolerability,
open-label studies, or compared with expected rates in age- effectiveness, and patients’ expectations (Fig. 4), patients
matched male populations [131]. None of the PDE5Is had an may be offered intracavernous injections. Overall, the
adverse effect on total exercise time or time to ischaemia success rate is high (85%) [137]. Alprostadil (Caverject
during exercise testing in men with stable angina and Edex/Viridal) was the first and only drug approved for
[131]. Chronic or on-demand use is well tolerated with a intracavernous treatment of ED [138]. Intracavernous
similar safety profile. The prescription of all PDE5Is in alprostadil is most efficacious as a monotherapy at a dose
patients with CVD or in those with a high CV risk should be of 5–40 mg (of note, 40 mg dose may be offered off-label in
based on the recommendations of the third Princeton some European countries). An office-training programme is
Consensus Panel [118]. required for the patient to learn the injection technique. The
In general, the adverse event profile of a PDE5I is not use of an automatic pen that avoids a view of the needle
worsened by a background of antihypertensive medication, may be useful to resolve fear of penile puncture and
even when the patient is taking several antihypertensive simplifies the technique. Efficacy rates for intracavernous
agents. Coadministration of PDE5Is with antihypertensive alprostadil of >70% have been found in the general ED
agents (eg, angiotensin-converting enzyme inhibitors, population, as well as in patient subgroups (eg, men with
angiotensin-receptor blockers, calcium blockers, b-block- diabetes or CVD), with reported satisfaction rates of 87–
ers, and diuretics) may result in small additive decreases in 93.5% in patients and 86–90.3% in partners after the
blood pressure, which are usually minor [118]. All PDE5Is injections, respectively [139,140]. Complications of intra-
show some interaction with a-blockers. A recent meta- cavernous alprostadil include penile pain (1–11%), exces-
analysis concluded that a concomitant treatment with sively prolonged undesired erections, priapism (0.25–1%),
a-blockers and PDE5Is may produce changes in haemody- and persisting (tunical) fibrosis (5–7%) [137,141]. Systemic
namic parameters, but it does not increase the rate of side effects (ie, mild hypotension) are uncommon. Contra-
adverse events due to hypotension [132]. In everyday indications include men with a history of hypersensitivity to
clinical practice, a patient presenting for ED should be stable alprostadil, men at risk of priapism, and men with bleeding
on one medication before starting a PDE5I, and the use of disorders. Careful counselling of patients during the office-
uroselective a-blockers should strongly be preferred. training phase as well as close follow-up is important in
Absolute contraindication to PDE5Is is represented by addressing patient withdrawal from an intracavernous
patients who are using any form of organic nitrate (eg, injection programme [138].
nitroglycerine, isosorbide mononitrate, and isosorbide
dinitrate) or nitric oxide donors (eg, other nitrate prepara- 3.2.5.4. Low-intensity shockwave therapy. The use of LI-SWT has
tions used to treat angina, such as nicorandil, an antianginal increasingly been proposed as a treatment for vasculogenic
vasodilator drug that acts by increasing nitric oxide ED over the last decade [142], being the only currently
bioavailability and opening of the KATP channel, as well as marketed treatment that might offer a cure, which is the
amyl nitrite or amyl nitrate such as “poppers” that are used most desired outcome for most men suffering from ED
for recreation) [3,133,134]. [126]. Overall, several single-arm trials have shown benefit
of LI-SWT in patient-reported erectile function scores, but
3.2.5.2. Topical/intraurethral alprostadil. The vasoactive agent data from prospective randomised trials are conflicting, and
alprostadil can be administered per urethra with two many questions remain to be answered especially because
different formulations. The first compound is the topical of the heterogeneity in shockwave generators (ie, electro-
route using a cream that includes a permeation enhancer in hydraulic, electromagnetic, piezoelectric, and electropneu-
346 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

matic), type of shockwaves delivered (ie, focused, linear, treatment for ED has received empirical support and is
semifocused, and unfocused), set-up parameters (eg, considered an optimal procedure [149].
energy flux density and number of pulses per session),
and treatment protocols (ie, duration of treatment course, 3.2.5.8. Vascular surgery for ED. In young patients with pelvic or
number of sessions per week, total number of shockwave perineal trauma, surgical penile revascularisation has a 60–
pulses delivered, and penile sites of application) [143]. As a 70% long-term success rate [127]. The stenosis must be
whole, most of the studies suggest that LI-SWT can confirmed by penile pharmacoarteriography. Corporeal
significantly increase the IIEF and EHS, especially in patients veno-occlusive dysfunction is a contraindication to revas-
with mild vasculogenic ED, although this improvement cularisation and must be excluded by dynamic infusion
appears modest [126]; indeed, a pooled data analysis of cavernosometry or cavernosography [3]. Venous ligation
RCTs has shown a mean IIEF-EF score improvement from surgery for veno-occlusive dysfunction is no longer
baseline ranging from 2 to 4 points [126]. Moreover, few recommended because of poor long-term results [3].
studies have shown an improvement in terms of penile
haemodynamic parameters after LI-SWT, with a meta- 3.2.5.9. Penile prostheses. Surgical implantation of a penile
analysis showing a mean peak systolic velocity improve- prosthesis may be considered in patients who (1) are not
ment of 4.12 (95% confidence interval: 2.3–5.9) after suitable for different pharmacotherapies or prefer a
treatment [143], but the clinical meaning of this improve- definitive therapy and (2) do not respond to pharmacologi-
ment remains unclear [143]. Likewise, data suggest that LI- cal therapies (Fig. 4). The vast majority of men receiving
SWT could ameliorate erection quality even in patients with penile prosthesis for ED have organic causes, with vascular
severe ED who are either nonresponders or inadequate disease, diabetes, and previous pelvic surgery/trauma being
responders to PDE5Is [144,145], thus reducing the immedi- most common [150,151]. The two currently available classes
ate need for more invasive treatments. Further clarity is also of penile implants include inflatable (two and three pieces)
needed in defining treatment protocols that can result in and semirigid devices (malleable, mechanical, and soft
greater clinical benefits [146]. As a whole, according to the flexible) [3]. There are two main surgical approaches for
available data and the novel treatment decision algorithm, penile prosthesis implantation: penoscrotal and infrapubic.
LI-SWT may be offered to patients with vasculogenic ED, A recent systematic review comparing the satisfaction and
although they should be counselled fully before treatment. complication rates of the different surgical approaches
showed that there is no specific advantage between the two,
3.2.5.5. Vacuum erection devices. Published data report that the but rather it is recommended that the surgeon has
efficacy of vacuum erection devices, in terms of erections knowledge of both techniques and is capable of tailoring
satisfactory for intercourse, is as high as 90%, regardless of the incision strategy for complex cases [152]. Regardless of
the cause of ED, and satisfaction rates range between 27% the indication, prosthesis implantation has one of the
and 94% [147]. The most common adverse events include highest satisfaction rates among the treatment options for
pain, inability to ejaculate, petechiae, bruising, and numb- ED with appropriate counselling [3,153,154]. Structured
ness. Serious adverse events (skin necrosis) can be avoided psychosexual counselling may improve sexuality and sexual
if patients remove the constriction ring within 30 min. well-being in both patients and their partners after penile
Vacuum erection devices are contraindicated in patients implant surgery [155]. A detailed summary of the types of
with bleeding disorders or those on anticoagulant therapy prostheses currently available, along with their effective-
[127,147]. ness and complication profiles, can be found in the EAU
guidelines [3]. Of note, currently there are also no head to
3.2.5.6. Hormonal treatment. When clinically indicated [3,5], head studies comparing the different manufacturers’
testosterone therapy (intramuscular or transdermal) can be implants, demonstrating superiority of one implant type
considered for men with low or low-normal testosterone over another [156].
levels and concomitant problems with their sexual desire, Table 8 details the recommendations for the treatment of
erectile function, and dissatisfaction derived from inter- patients presenting with ED.
course and overall sexual life. The advice of an endocrinol-
ogist should be sought for managing patients with certain 3.2.6. Follow-up in patients with ED
hormonal abnormalities or endocrinopathies [120]. Follow-up is important in order to assess efficacy and safety
of the treatment provided. It is also essential to assess
3.2.5.7. Psychosexual counselling and therapy. For patients with a patient satisfaction since successful treatment for ED goes
recognised psychological problem [3,148], psychosexual beyond efficacy and safety. Physicians must be aware that
therapy may be given either alone or with another there is no single treatment that fits all patients or all
therapeutic approach in order to improve couple’s sexual situations, as described in detail in the previous section.
satisfaction and partner’s sexual function. Despite this
psychological treatment including different modalities (eg, 3.3. Disorders of ejaculation
training of sexual skills, marital therapy, and psychosexual
education) [130], cognitive and behaviour therapy (CBT), Ejaculation is a complex physiological process that is
including group or couple format, has been recommended composed of emission and expulsion processes and is
[149]. The CBT approach combined with the medical mediated by neurological and hormonal pathways. Any
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 347

Table 8 – Recommendations for the treatment of erectile that always or nearly always occurs prior to or within about
dysfunction
1 min of vaginal penetration (lifelong PE) or a clinically
Recommendations Strength significant and bothersome reduction in latency time, often
rating to about "3 min (acquired PE); (2) the inability to delay
Assess all patients for inadequate/incorrect information Weak ejaculation in all or nearly all vaginal penetrations; and (3)
about the mechanism of action and the ways in which drugs negative personal consequences, such as distress, bother,
should be taken, as they are the main causes of a lack of frustration, and/or the avoidance of sexual intimacy.
response to PDE5Is.
Two more PE syndromes have been proposed [158]:
Use CBT as a psychological approach (include the partner) Strong
combined with medical treatment to maximise treatment
outcomes.
Discuss with patients undergoing RP (any technique) about Strong 1 “Variable PE” is characterised by inconsistent and
the risk of sexual changes other than ED, including libido
reduction, changes in orgasm, anejaculation, Peyronie-like
irregular early ejaculations, representing a normal varia-
disease, and penile size changes. tion in sexual performance.
Initiate lifestyle changes and risk factor modification prior to, Strong 2 “Subjective PE” is characterised by subjective perception
or at the same time as, initiating ED treatments. of consistent or inconsistent rapid ejaculation during
Treat a curable cause of ED first, when found. Weak
Use PDE5Is as a first-line therapeutic option. Strong
intercourse, while ejaculation latency time is in the
Use topical/intraurethral alprostadil as an alternative first- Weak normal range or can last even longer. It should not be
line therapy in well-informed patients who do not wish to regarded as a symptom or manifestation of true medical
have or are not suitable for oral vasoactive therapy.
pathology.
Use topical/intraurethral alprostadil as an alternative first- Weak
line therapy in well-informed patients who do not wish to
have intracavernous injections or in patients who prefer a The addition of these new types may help in overcoming the
less invasive therapy. limitations of each individual definition, and it may support
Use LI-SWT in patients with mild vasculogenic ED or as an Weak
a more flexible view of PE for patient stratification,
alternative first-line therapy in well-informed patients who
do not wish to have or are not suitable for oral vasoactive diagnosis, and treatment [158].
therapy or who desire a curable option. The major problem in assessing the prevalence of PE is
Use LI-SWT in vasculogenic ED patients who are poor the lack of a universally recognised definition at the time
responders to PDE5Is.
the surveys were conducted [158]. For instance, historical
Use VEDs as a first-line therapy in well-informed patients Weak
with infrequent sexual intercourse and comorbidity data from the PE Prevalence and Attitudes (PEPA) survey of
requiring noninvasive, drug-free management of ED. 12 133 participants suggested that the prevalence of PE was
Use intracavernous injections as an alternative first-line Strong 22.7% and did not vary significantly with age among men
therapy in well-informed patients or as a second-line
over the age of 24 yr [159]. Two separate observational,
therapy.
Use implantation of a penile prosthesis if other treatments Strong cross-sectional surveys from different continents found the
fail or based upon patient preference. overall prevalence of the complaint of PE to be 19.8% and
Data are inadequate to support the use of any specific Strong 25.80% [160,161]. An approximately 5% prevalence of
regimen for penile rehabilitation after radical prostatectomy.
Proerectile treatments should start at the earliest Weak
acquired PE and lifelong PE in general populations is
opportunity after radical prostatectomy/pelvic surgery and consistent with epidemiological data indicating that around
other curative treatments for PCa. 5% of the population have an ejaculation latency of <2 min
CBT = cognitive and behaviour therapy; ED = erectile dysfunction; LI- [162].
SWT = low-intensity shockwave treatment; PCa = prostate cancer;
PDE5Is = phosphodiesterase type 5 inhibitors; RP = radical
3.3.1.2. Diagnostic evaluation of PE. Diagnosis of PE is based on
prostatectomy; VED = vacuum erection device.
the patient’s medical and sexual history [3]. History should
classify PE as lifelong or acquired, and determine whether
PE is situational (under specific circumstances or with a
interference with these pathways may cause a wide specific partner) or consistent. Specific attention should be
spectrum of ejaculatory disorders (ie, PE, retarded or given to the duration time of ejaculation, degree of sexual
delayed ejaculation, anejaculation, painful ejaculation, stimulus, impact on sexual activity and QoL, and drug use or
retrograde ejaculation, anorgasmia, and haemospermia). abuse. It is also important to distinguish PE from ED. Many
A detailed discussion of the EAU recommendations for the patients with ED develop secondary PE caused by the
entire spectrum of ejaculatory disorders can be found in the anxiety associated with difficulty in attaining and main-
EAU guidelines [3]. Here, PE and haemospermia will be taining an erection [163].
discussed in more detail. Although it has been suggested as an objective diagnostic
criterion and treatment outcome measure [3], the use of
3.3.1. Premature ejaculation intravaginal ejaculatory latency time (IELT) alone is not
3.3.1.1. Definition and epidemiology of PE. The EAU guidelines sufficient to define PE, as there is a significant overlap
have adopted the definition of PE that has been developed between men with and without PE [164]. Moreover, some
by the International Society for Sexual Medicine (ISSM) as men may experience PE in their noncoital sexual activities
the first evidence-based definition [157]. According to this (eg, during masturbation, oral sex, or anal intercourse);
definition, PE (lifelong and acquired) is a male sexual thus, measuring IELT will not be suitable for their
dysfunction characterised by the following: (1) ejaculation assessment. Moreover, perceived control over ejaculation
348 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

has a significant direct effect on both ejaculation-related Table 9 – Recommendations for the diagnostic evaluation of
premature ejaculation
personal distress and satisfaction with sexual intercourse
(each showing direct effects on interpersonal difficulty Recommendations Strength
related to ejaculation) [165]. In everyday clinical practice, rating
self-estimated IELT is sufficient [166]. Conversely, measure- Perform the diagnosis and classification of PE based on Strong
ment of IELT with a calibrated stopwatch is mandatory in medical and sexual history, which should include assessment
clinical trials [3,167]. of IELT (self-estimated), perceived control, distress, and
interpersonal difficulty due to ejaculatory dysfunction.
The need to assess PE objectively has led to the
Use of stopwatch-measured IELT is not compulsory in clinical Weak
development of several questionnaires based on the use practice.
of patient-reported outcomes. Only two questionnaires can Use patient-reported outcomes in daily clinical practice. Weak
discriminate between patients who have PE and those who Include physical examination in the initial assessment of PE Strong
to identify anatomical abnormalities that may be associated
do not: (1) Premature Ejaculation Diagnostic Tool—a total with PE or other sexual dysfunctions, particularly ED.
score of >11 suggests a diagnosis of PE, and a score of 9 or Do not perform routine laboratory or neurophysiological Strong
10 suggests a probable diagnosis of PE [168], and (2) Arabic tests. They should only be directed by specific findings from
Index of Premature Ejaculation—a cut-off score of 30 (range history or physical examination.

of scores 7–35) discriminated PE diagnosis best [169]. Ques- ED = erectile dysfunction; IELT = intravaginal ejaculatory latency time;
PE = premature ejaculation.
tionnaires are a significant step in simplifying the method-
ology of PE drug studies, although further cross-cultural
validation is needed [161].
Physical examination may be a part of the initial (TEAEs) in both patients and partners has been reported,
assessment of men with PE. It may include a focused including genital hypoesthesia (4.5% and 1.0% in partners of
examination of the urological, endocrine, and neurological males and females, respectively), ED (4.4%), and vulvova-
systems to identify underlying medical conditions associ- ginal burning sensation (3.9%), but is unlikely to be
ated with PE or other sexual dysfunctions, such as associated with systemic TEAEs [181].
endocrinopathy, PD, urethritis, or prostatitis. Laboratory All other medications used in PE are off-label indications
or physiological testing should be directed by specific [172]. Daily or on-demand use of selective serotonin
findings from history or physical examination, and is not reuptake inhibitors (SSRIs) and clomipramine, and on-
recommended routinely [3]. demand topical anaesthetic agents have consistently shown
Table 9 details the EAU guideline recommendations for efficacy in PE [172]. Of all, several systematic reviews and
the diagnostic evaluation of PE. meta-analyses of drug treatment studies showed that,
despite methodological problems in most studies, daily
3.3.1.3. Therapeutic management of PE. After the subtype of PE SSRIs are significantly effective for PE [3,176,182]. Paroxetine
has been defined, patient’s expectations should be dis- was found to be superior to fluoxetine, clomipramine, and
cussed thoroughly [3]. Pharmacotherapy must be consid- sertraline [3,183–186]. Likewise, tramadol, a mild opioid
ered as the first-line treatment for patients with lifelong PE, receptor agonist that also promotes reuptake inhibition of
whereas treating the underlying cause (eg, ED, prostatitis, serotonin and noradrenaline, has been demonstrated to be
LUTS, anxiety, hyperthyroidism, etc.) must be the initial goal effective as an off-label on-demand oral therapy in men
for patients with acquired PE (Fig. 5) [162,170]. with a history of lifelong PE [3,187,188]. Side effects were
Dapoxetine (30 and 60 mg) is the first on-demand oral reported at doses used for analgesic purposes (up to 400 mg
pharmacological agent approved for lifelong and acquired daily) and include constipation, sedation, and dry mouth.
PE in many countries, except for the USA [171–173]. Dapox- The efficacy and safety of tramadol have been confirmed in
etine has shown a similar efficacy profile in men with systematic reviews and meta-analyses [182,189–191]. As a
lifelong and acquired PE [3,171,172,174,175]. Treatment- whole, long-term outcomes of pharmacological treatments
related side effects were dose dependent and included are unknown [3,176,182,192]. Figure 5 provides a treatment
nausea, diarrhoea, headache, and dizziness [3,176]. More- algorithm for PE management.
over, the eutectic metered-dose aerosol spray of lidocaine Overall, PDE5Is were found to be significantly more
(150 mg/ml) and prilocaine (50 mg/ml) combination is the effective than placebo in the treatment of patients with PE
first topical formula to be officially approved for the on- and without ED [192]. Moreover, some meta-analyses
demand treatment of lifelong PE by the EMA in the demonstrated that the combined use of SSRIs and PDE5Is
European Union [177]. Compared with topical creams, the may be more effective than SSRI or PDE5I monotherapy
metered-dose spray delivery system has been proved to [3,193,194].
deposit the drug in a dose-controlled, concentrated film In lifelong PE, behavioural techniques are not recom-
covering the glans penis, maximising neural blockage and mended alone, and pharmacotherapy must be considered as
minimising the onset of numbness [178], without absorp- the basis of treatment [162]. Accordingly, psychosexual
tion through the penile shaft skin [179]. Based on available interventions, irrespective of whether these are beha-
data, the recommended dose of lidocaine/prilocaine spray is vioural, cognitive, or focused on the couple, are aimed at
one dose (namely, three sprays) to be applied on the glans teaching techniques to control/delay ejaculation, gaining
penis at least 5 min before sexual intercourse [180]. A low confidence in sexual performance, reducing anxiety, and
incidence of local treatment-emergent adverse events promoting communication and problem solving within the
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 349

Table 10 – Recommendations for the treatment of premature

ejaculation

Recommendations Strength
rating

Treat ED, other sexual dysfunction, or genitourinary infection Strong

(eg, prostatitis) first.
Use either dapoxetine or the lidocaine/prilocaine spray as Strong
first-line treatments for lifelong PE.
Use off-label topical anaesthetic agents as a viable Strong
alternative to oral treatment with SSRIs.
Use tramadol on demand as a weak alternative to SSRIs. Weak
Use PDE5Is alone or in combination with other therapies in Strong
patients with PE (without ED).
Use psychological/behavioural therapies in combination Weak
with pharmacological treatment in the management of
acquired PE.

ED = erectile dysfunction; PE = premature ejaculation;

PDE5Is = phosphodiesterase type 5 inhibitors; SSRIs = selective serotonin
reuptake inhibitors.

anxiety in many men and may be indicative of underlying

pathology [199]. The exact incidence and prevalence of
haemospermia are difficult to elucidate due to a number of
factors, including its covert presentation, usually self-
limiting nature, and patient embarrassment. The symptom
represents approximately 1–1.5% of all urological referrals
and occurs in all age groups, with a mean age of 37 yr
[199,200]. Several reasons of haemospermia have been
acknowledged and can be classified into the following
subcategories: idiopathic, congenital malformations, in-
flammation/infections, obstruction, malignancies (eg, gen-
itourinary cancers: prostate and testis), vascular
abnormalities, iatrogenic/trauma, and systemic causes
(Supplementary Table 5) [201,202]. The risk of malignancy
Fig. 5 – Management of premature ejaculation. ED = erectile in patients presenting with haemospermia is approximately
dysfunction; IELT = intravaginal ejaculatory latency time;
PE = premature ejaculation; SSRI = selective serotonin receptor 3.5% (0–13.1%) [209,210].
inhibitor. Adapted from Lue et al [170].
3.3.2.2. Investigations for haemospermia. As with other clinical
conditions, a systematic clinical history and assessment to
help identify the reason of haemospermia is undertaken.
couple [195]. It is worth noting, however, that psychosexual Although the differential diagnosis is extensive, most cases
interventions alone regarding PE lack empirical support. are caused by infections or other inflammatory processes
Yet, recent evidence suggested that start-stop exercises, [199,202]. A sexual history should be taken to identify those
combined with psychoeducation and mindfulness techni- whose haemospermia may be as a consequence of a
ques, improved PE symptoms as well as PE-associated sexually transmitted disease. Recent foreign travel to areas
distress, anxiety, and depression [196,197]. Behavioural affected by schistosomiasis or tuberculosis should also be
therapy may be most effective when used to “add value” to considered. A urinalysis should be performed along with
medical interventions (eg, dapoxetin) [198]. Validated sending the urine for culture and sensitivities as well as
assessment instruments need to be used as an end-point. microscopy. If tuberculosis or schistosomiasis is the
Longer follow-up periods are necessary to confirm these suspected cause, the semen or prostatic secretions should
findings [3]. be sent for analysis. A full sexually transmitted disease
Table 10 lists the EAU guideline recommendations for the screen should include assessment for Chlamydia, Urea-
treatment of PE. plasma, and herpes simplex. Using this strategy, it may be
possible to find an infectious agent among patients who
3.3.2. Haemospermia would have been labelled to have idiopathic haemospermia
3.3.2.1. Definition, classification, and epidemiology of haemospermia. [203]. The possibility of coexisting systemic disease such as
Haemospermia is defined as the appearance of blood in the hypertension, liver disease, and coagulopathies should be
ejaculate. Although it is often regarded as a symptom of investigated along with systemic features of malignancy.
minor significance, blood in the ejaculate causes great Examination of the patient should also include measure-
350 E U RO P EAN UROL OGY 80 ( 2021 ) 333 – 357

Table 11 – Recommendations for the management of recurrent diseases. A serum PSA measurement should be performed
haemospermia
in men over the age of 40 yr who have been counselled
Recommendations Strength appropriately. DRE should also be performed and the
rating meatus re-examined after DRE for the presence of bloody
Perform a full medical and sexual history with detailed Strong discharge [206].
physical examination. TRUS and MRI are increasingly used as a definitive means
Men aged !40 yr with persistent haemospermia should be Weak to investigate haemospermia (Table 11) [211–213]. The use
screened for PCa.
of cystoscopy has been included in the majority of
Consider noninvasive imaging modalities (TRUS and MRI) in Weak
men aged !40 yr or men of any age with persistent or suggested investigation protocols in patients with high-
refractory haemospermia. risk features (patients who are refractory to conservative
Consider invasive methods such as cystoscopy and Weak treatments and those with persistent haemospermia)
vesiculoscopy when noninvasive methods are inconclusive.
[200]. With the advancement of optics, it has been made
MRI = magnetic resonance imaging; PCa = prostate cancer;
possible to create ureteroscopes of diameters small enough
TRUS = transrectal ultrasound.
to allow insertion into the ejaculatory duct and seminal
vesicles (seminal vesiculoscopy) [3].

ment of the blood pressure, as there have been several case 3.3.2.3. Disease management. The primary goal of the treatment
reports suggesting an association between uncontrolled is to exclude malignant conditions such as prostate and
hypertension and haemospermia [204,205]. Blood work bladder cancer, and treat any other underlying cause.
including a full blood count, liver function tests, and a Conservative management is generally the primary treat-
clotting screen should be taken to identify systemic ment option when the patients are younger than 40 yr of

Fig. 6 – Management algorithm for haemospermia. DRE = digital rectal examination; MRI = magnetic resonance imaging; PSA = prostate-specific
antigen; STI = sexually transmitted infections; TRUS = transrectal ultrasonography; US = ultrasonography.
 E U ROP E AN URO LO GY 8 0 (20 21) 333– 357 351

age and have a single episode of haemospermia Financial disclosures: Andrea Salonia certifies that all conflicts of
[199]. Patients with recurrent haemospermia and those interest, including specific financial interests and relationships and
who are middle aged warrant a more aggressive interven- affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
tion. Appropriate antibiotic therapy should be given to
cies, honoraria, stock ownership or options, expert testimony, royalties,
patients who have urogenital infections or sexually
or patents filed, received, or pending), are the following: None.
transmitted infections. Urethral or prostate varices or
angiodysplastic vessels can be fulgurated, whereas cysts Funding/Support and role of the sponsor: This work was supported by
of either the seminal vesicles or the prostatic urethra can be European Association of Urology.
aspirated transrectally [199]. Ejaculatory duct obstruction is
Acknowledgements: The authors acknowledge Julie Darraugh and Karin
managed by a transurethral incision at the duct opening Plass, for their constant support from the EAU Guidelines Office, and
[207]. Systemic conditions should be treated appropriately Edoardo Pozzi, MD, for the great support during the preparation of the
[208]. Based on the literature, a management algorithm is manuscript.
proposed (Fig. 6).
Table 11 lists the EAU guideline recommendations for the
management of recurrent haemospermia. Appendix A. Supplementary data

4. Conclusions Supplementary material related to this article can be

found, in the online version, at doi:https://doi.org/10.1016/j.
The present text represents a summary of the 2021 EAU eururo.2021.06.007.
guidelines on sexual and reproductive health, dealing with
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