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Advances in understanding and treating premature ejaculation

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 REVIEWS
Advances in understanding and treating
premature ejaculation
Theodore R. Saitz and Ege Can Serefoglu
Abstract | Over the past several years, many advances have been made in our understanding of the
epidemiology, pathophysiology, and management of premature ejaculation. Newly developed definitions of
premature ejaculation are now available, and our perception of the classification, prevalence, aetiological
factors, and treatment options for premature ejaculation have evolved. Despite ongoing research, there
remains much to be learned about all aspects of this common sexual disorder, in particular effective clinical
diagnosis and treatment options.
Saitz, T. R. & Serefoglu, E. C. Nat. Rev. Urol. advance online publication 27 October 2015; doi:10.1038/nrurol.2015.252

Introduction
Ejaculatory dysfunction, especially premature ejacula­
tion, is considered the most common type of male sexual
disorder.1,2 The first report regarding premature ejacu­
lation was published more than 100 years ago,3 yet our
understanding of the epidemiology, pathophysiology and
management of this disorder remain limited.4 Over the
past two decades, our knowledge of premature ejacula­
tion has improved as a result of studies that have reported
high prevalence rates, detrimental psychosocial con­
sequences, and possible pharmacological management
options.5 In 2014 the International Society for Sexual
Medicine (ISSM) provided evidence-based definitions to
aid in the diagnosis and treatment of patients who suffer
from either lifelong or acquired premature ejaculation.6
These definitions will help establish a more accurate
understanding of the prevalence of premature ejacula­
tion and enable the conduction of sound and method­
ologically rigorous clinical trials. As expected, debates
surrounding the definition, classification, prevalence,
aetiological factors, and effective t­reatment options for
premature ejaculation are ongoing.
Evidenced-based definitions
Numerous authors and various medical organizations
Department of Urology,
Oregon Health & have proposed their own definitions of premature ejacu­
Science University, lation over the years, and no consensus has existed with
3303 SW Bond Avenue,
CH10U, Portland,
regards to what truly constitutes this sexual problem. The
OR 97239, USA early definitions were criticized for being vague, open to
(T.R.S.). Department of multiple interpretations, and for lacking operational cri­
Urology, Bagcilar
Training & Research teria.7 In order to overcome the limitations of these defi­
Hospital, Merkez nitions, the ISSM convened a meeting in Amsterdam in
Mahallesi Mimar
Sinan Caddesi 6,
2007 with the goal of developing the first contemporary,
Sokak, Bagcilar, evidence-based definition of premature ejaculation.7
Istanbul 34200, Turkey After critical evaluation of all published data, the com­
(E.C.S.).
mittee unanimously agreed that the constructs necessary
Correspondence to:
E.C.S.
egecanserefoglu@ Competing interests
hotmail.com The authors declare no competing interests.
to define premature ejaculation included a number of
factors: time from penetration to ejaculation, inability
to delay ejaculation, and negative personal consequences
from premature ejaculation. At this time, the commit­
tee was unable to identify sufficient published objective
data to craft an evidence‑based definition of acquired
premature ejaculation.7
During April 2013, the ISSM ad hoc committee met
again in Bangalore, India, with the goal of evaluating up-
to-date data and developing an evidence-based defini­
tion for acquired premature ejaculation. The committee
concluded that patients with lifelong premature ejacula­
tion and those with acquired premature ejaculation both
suffer from short ejaculatory latency, reduced or absent
perceived ejaculatory control, and negative personal
consequences. Study findings consistently demonstrated
that about 90% of men who seek treatment for lifelong
premature ejaculation ejaculate within 1 min of penetra­
tion, so the committee agreed that 1 min is an appropri­
ate time criterion for the diagnosis of lifelong premature
ejaculation.8,9 Findings from studies in patients with
acquired premature ejaculation showed that an intra­
vaginal ejaculatory latency time (IELT) of <3 min was
most common.10–12 After consideration of these new data,
a unified definition of lifelong and acquired premature
ejaculation was established (Box 1).6
The unified evidence-based definition of premature
ejaculation provides ample guidance in identifying
patients who suffer from the disorder, and should, in
turn, help improve our understanding of the disease.
We believe that the definition should not only be applied
in the diagnosis of lifelong and acquired premature
ejaculation, but should also be used in the design of
o­bservational and interventional clinical trials.
Of note, in May 2013 the American Psychiatric
Association published The Diagnostic and Statistical
Manual for Mental Disorders, 5th edition (DSM‑5),
in which they defined premature ejaculation as

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Key points
■■ Premature ejaculation is extremely prevalent and can have substantial effects
on quality of life
■■ In 2014, the ISSM provided standard evidence-based definitions of lifelong
and acquired premature ejaculation
■■ The aetiologies of lifelong and acquired premature ejaculation are different;
the former suggests an underlying neurobiological functional disturbance,
while the latter is more likely related to underlying medical, psychological,
or interpersonal causes
■■ The pathophysiological mechanisms of premature ejaculation have not yet been
entirely elucidated, but 5-hydroxytryptamine, dopamine, and various hormonal
factors have been suggested to have a role
■■ Current treatment options include behavioural therapies, topical therapies and
oral medications, such as antidepressants and phosphodiesterase-5 inhibitors
■■ Modafinil, silodosin and botulinum toxin might offer potential therapeutic
options in the future, but require further research
“A persistent or recurrent pattern of ejaculation occur­
ring during partnered sexual activity within approxi­
mately 1 minute following vaginal penetration and
before the individual wishes it. The symptoms must
have been present for at least 6 months and must
be experi­e nced on almost all or all (approximately
75–100%) occasions of sexual activity (in identified situ­
ational contexts or, if generalized, in all contexts).” The
definition also states “The symptoms cause clinically
significant distress in the individual” and “the sexual
dysfunction is not better explained by a n­onsexual
mental disorder or as a consequence of severe relation­
ship distress or other significant stressors and is not
attributable to the effects of a substance/medication or
another medical condition.”13 Unlike the most recent
definition of the ISSM,6 the DSM‑5 definition does not
provide different cut-off IELT values for lifelong or
acquired forms of the disorder, although it does recog­
nize the two different forms. Moreover, the DSM‑5
further classifies premature ejaculation to a ‘general­
ized’ form in which premature ejaculation occurs with
different partners and situations, or to a ‘situational’
form in which premature ejaculation only occurs with
a specific partner and situation. Unlike any other pre­
vious definition, the DSM‑5 categorizes the severity
of premature ejaculation as being mild, moderate, or
severe. Mild premature ejaculation is defined as ejacu­
lation occurring within approximately 30 seconds to
1 minute of vaginal penetration, moderate premature
ejaculation is defined as ejaculation occurring within
approximately 15–30 seconds of vaginal penetration
and severe premature ejaculation is defined as ejacu­
lation occurring before sexual activity, at the start of
Box 1 | ISSM unified definition of lifelong and acquired premature ejaculation6
■■ Ejaculation that always or nearly always occurs before or within about 1 min of
vaginal penetration (lifelong premature ejaculation), or a clinically significant
and bothersome reduction in latency time, often to about 3 min or less
(acquired premature ejaculation)
■■ 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
2  |  ADVANCE ONLINE PUBLICATION
© 2015 Macmillan Publishers Limited. All rights reserved
sexual activity, or within approximately 15 seconds of
vaginal penetration. It must be noted that this categor­
ization is based on authority opinion and not clinical
data. Thus, future studies are warranted to assess if
these IELT cut-off values truly match the severity of
the disorder. The DSM‑5 definition does demonstrate
an increased understanding of the characteristics and
variety of patients suffering from premature ejaculation,
as both a time criterion and definitions for lifelong and
acquired premature ejaculation were included in the
updated definition, although parts of the definition lack
support based on current evidence.
Epidemiology of premature ejaculation
The lack of standardized definitions and specific
operational criteria for premature ejaculation has pre­
viously limited the ability to conduct evidence-based
research into its true epidemiology. As a result, reported
prevalence rates of premature ejaculation are conflict­
ing.2,9–11,14–57 In an attempt to remedy these discordant
data, Waldinger and Schweitzer 58–60 emphasized the
importance of distinguishing the ‘complaint’ of prema­
ture ejaculation from the ‘syndrome’ of premature ejacu­
lation, and stated that the prevalence of patients seeking
medical treatment was actually much less than that
reported in previous population-based epidemiologi­
cal studies. In an attempt to improve the vagueness of
the existing definitions, in 2008 they proposed a new
classifi­cation system identifying four subtypes of pre­
mature ejaculation; these subtypes are categor­ized by
the IELT, the frequency of complaints, and the course of
premature ejaculation throughout life (Box 2). In addi­
tion to previously defined lifelong premature ejaculation
and acquired premature ejaculation, this classification
system included definitions for variable premature
ejaculation and subjective premature ejaculation. 33
Men with variable premature ejaculation occasion­
ally experi­ence early ejaculation, and it should not be
regarded as a disorder, but as a natural variation of ejacu­
lation time. A patient with the syndrome of subjective
prema­ture ejaculation was defined as a man who feels
he ejaculates early, while he actually has normal or even
extended ejaculation time. The complaint of premature
ejaculation in these men is most likely related to various
psychological or cultural factors.61 The persistent early
ejaculation of lifelong premature ejaculation suggests
an underlying neuro­biological functional disturbance,
whereas the early ejacu­l ation of acquired prema­ture
ejaculation is more likely related to underlying medical,
psychological, or inter­p ersonal causes. 61 Unlike the
ISSM definition, these definitions are opinion based;
however, they have provided an interesting perspective
and enabled further evaluation and better understanding
of p­remature ejaculation.
Serefoglu et  al. 10 investigated the prevalence of
premature ejaculation in 17 provinces in Turkey in a
noninterventional, observational, cross-sectional field
survey applying the definitions from Waldinger and
Schweitzer 58–60 and reported that the overall preva­
lence of a premature ejaculation complaint was 19.8%,
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Box 2 | Diagnostic criteria for four subtypes of premature ejaculation58–61
Lifelong premature ejaculation
■■ Early ejaculation occurs almost every time the patient has intercourse
■■ Occurs with nearly all women
■■ Begins at approximately the first sexual encounter
■■ Ejaculation occurs, in the majority of cases, within 30 s (70%), 60 s (90%),
or 1–2 min (10%)
■■ Persists throughout life (70%) and can even be aggravated with age (30%)
■■ Ability to delay imminent ejaculation is diminished or absent
Acquired premature ejaculation
■■ Early ejaculation occurs at some point in a man’s life
■■ The man has usually had normal ejaculatory experience before the first
complaint
■■ Either a sudden or a gradual onset
■■ Dysfunction might be due to urological dysfunction (for example, erectile
dysfunction or prostatitis), thyroid dysfunction, or psychological or
relationship problems
■■ Ability to delay imminent ejaculation is diminished or absent
Variable premature ejaculation
■■ Early ejaculations are inconsistent and occur irregularly
■■ The ability to delay imminent ejaculation is diminished or absent
■■ Diminished ability to ejaculate is accompanied by either a short or normal
ejaculation time
Subjective premature ejaculation
■■ Subjective perception of consistent or inconsistent early ejaculation during
intercourse
■■ Preoccupation with an imagined early ejaculation, or lack of ability to delay
ejaculation
■■ Actual intravaginal ejaculation latency time is in the normal range or can even
be of longer duration (that is, occurs after 3–25 min)
■■ Ability to delay imminent ejaculation is diminished or absent
■■ Preoccupation is not better explained by another mental disorder
comprising lifelong premature ejaculation (2.3%),
acquired premature ejaculation (3.9%), variable prema­
ture ejaculation (8.5%) and subjective premature ejacu­
lation (5.1%). Gao et al.11 investigated the prevalence
of these four syndromes of premature ejaculation in
a Chinese population and reported that 25.80% of
3,016 Chinese men reported premature ejaculation,
and found the prevalence of the different forms to be
similar to those reported by Serefoglu10 and co-work­
ers: lifelong premature ejaculation (3.18%), acquired
premature ejacu­l ation (4.84%), variable premature
ejaculation (11.38%) and subjective premature ejacu­
lation (6.4%). Of note, Serefoglu et al.10 reported that
men with acquired premature ejaculation are more
likely to seek medical treatment than men with life­
long premature ejaculation (26.53% versus 12.77%).
This finding was also confirmed by Gao et al.11 who
demonstrated that patients with acquired premature
ejaculation were more likely than men with lifelong
premature ejaculation to seek treatment (17.12% versus
14.58%) or plan to seek treatment (36.30% versus
27.08%). The reasons for increased treatment-seeking
behaviour in men with acquired premature ejacula­
tion are unclear. It is possible that men with lifelong
prema­ture ejaculation come to terms with the problem,
whereas the additional psychological burden of an
un­expected shorten­ing in ejaculatory latency in the case
of acquired premature ejaculation might prompt more
NATURE REVIEWS | UROLOGY ADVANCE ONLINE PUBLICATION  |  3
© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
frequent treatment seeking.35 However, the severity of
the early ejaculation complaints of men with variable
premature ejaculation and subjective premature ejacu­
lation might be so mild that patients rarely consult a
physician for their problems which might explain the
difference of the distribution of premature ejaculation
syndromes observed in outpatient clinics; the major­
ity of patients seeking treatment have either lifelong or
acquired premature ejaculation.12,14 Continuing research
into the diverse phenomenology, aetiology and patho­
genesis of premature ejaculation using the new ISSM
definition along with the application of Waldinger’s sub­
types is expected to provide a better understanding of
p­remature ejaculation.
Pathophysiology of premature ejaculation
In order to determine the pathophysiology of pre­
mature ejaculation, it is necessary to understand the
physiological ejaculatory reflex (Figure 1). The spinal
ejaculatory generator (SEG) coordinates sympathetic,
parasympathetic, and motor outflow for the two phases
of ejaculation: emission and expulsion. Somatosensory,
visceral, and proprioceptive inputs to the SEG during
sexual activity can all trigger the ejaculatory mech­
anism. 62–64 The SEG integrates these inhibitory and
excitatory influences from supra-spinal sites, as well as
inputs conveying biochemical or mechanical informa­
tion from the accessory sex organs.65 Emission of semen
involves the sympathetic efferent fibres of the ‘secretory
centre’ (T10–L2) coordinating sequential contractions
of the epididymis, vas deferens, seminal vesicles, and
prostate with associated closure of the bladder neck.66
Expulsion of semen is then initiated somatically by the
‘mechanical centre’ of the sacral spinal cord (S2–S4)
via the pudendal nerve, which induces contractions
of the bulbospongiosus, bulbocavernous and perineal
muscles, which in turn, rhythmically force the ejaculate
through the distal urethra.67
The mechanisms contributing to the pathophysio­logy
of premature ejaculation have not yet been entirely eluci­
dated. Waldinger et al.68 hypothesized that hyposensitiv­
ity of the 5‑HT2C and/or hypersensitivity of the 5‑HT1A
receptors located in the neuronal centres is a possible
aetiology for lifelong premature ejaculation. They sug­
gested that men with low 5-­hydroxytryptamine neuro­
transmission, probable 5‑HT2C receptor hypo­sensitivity
and/or hypersensitivity of the 5‑HT1A receptors might
have a lower ejaculatory threshold and, therefore,
ejaculate more rapidly and with less stimulation. By
contrast, men with a genetically determined higher
threshold could undergo more prolonged and intense
sexual stimu­lation with better control of ejacu­lation.
Finally, men with a very high set point might experi­ence
delayed or absent ejaculation despite p­rolonged sexual
s­timulation and achieving a full erection.69
Investigations in both animal models and humans
have demonstrated that ejaculatory latency is normally
distributed among populations and constitutionally
influenced, supporting that there is likely a genetic com­
ponent to this disorder.70,71 Waldinger et al.72 confirmed
REVIEWS
SSRIs reduce serotinin
Medial preoptic area
Paraventricular nucleus
inhibition, increasing activity
Nucleus paragigantocellularis
T10–L2: Secretory centre
Topical anaesthetics Sequential contractions of epididymis,
inhibit penile vas deferens, seminal vesicles and prostate
sensory receptors Closure of the bladder neck
Emission
Sensory afferents L3–L4: Spinal
Pudendal
nerve ejaculatory generator
Ejaculation
Expulsion
S2–S4: Mechanical centre
Contractions of bulbospongiosus, Botulinum toxin inhibits
bulbocavernosus and perineal muscles rhythmic contractions
Figure 1 | The ejaculation reflex and ejaculatory control. Ejaculation
Nature Reviews Urology
is the |result of
the coordinated contractile activity involving different ejaculatory organs organized
by the spinal ejaculatory generator, located at the T12–L1–L2 level of the spinal
cord. Afferent information is received by the spinal ejaculatory generator, which
coordinates sympathetic, parasympathetic, and motor outflow for the two phases
of ejaculation—emission and expulsion. The SEG integrates these inhibitory and
excitatory influences from supraspinal sites, as well as inputs conveying
biochemical or mechanical information from the accessory sex organs. Emission
of semen involves the sympathetic efferent fibres of the ‘secretory centre’
(T10–L2) coordinating sequential contractions of the epididymis, vas deferens,
seminal vesicles, and prostate with associated closure of the bladder neck.
Expulsion of semen is then initiated somatically by the ‘mechanical centre’ of the
sacral spinal cord (S2–S4) via the pudendal nerve, which induces contractions of
the bulbospongiosus, bulbocavernous and perineal muscles, which, in turn,
rhythmically force the ejaculate through the distal urethra. Abbreviation: SSRI,
selective 5-hydroxytryptamine reuptake inhibitor.
a genetic component by surveying family members of
men with a lifelong IELT of <1 min, and found that 88%
of their first-degree male relatives also reported lifelong
premature ejaculation. In 2009, Janssen et al.73 pub­
lished the first DNA-based study of premature ejacula­
tion, in which they compared IELTs (confirmed using
a stopwatch) in 89 Dutch men with lifelong premature
ejaculation and a cohort of white Dutch men in good
mental and physical health. This study assessed a gene
poly­morphism for the 5-­hydroxytryptamine transporter
protein (5-HTTLPR) and determined that the allele
that resulted in reduced synaptic 5-­hydroxytryptamine
was more prevalent in men with lifelong prema­
ture ejaculation than in controls, which is consistent
with our current understanding of the influences of
5-­hydroxytryptamine on ejaculation.73 They described
that human 5‑HTT is encoded by a single gene
(SLC6A4) on chromo­some 17q12. A polymorphism in
the transcriptional region is composed of a 44 bp inser­
tion (‘long allele’ [L]) or deletion (‘short allele’ [S]). They
found the LL genotypes had significantly shorter IELTs
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than the SS and SL genotypes.73 Follow-up studies on
this same gene locus by other investigators have shown
mixed results, with one study reporting findings con­
sistent with those of Janssen and colleagues,74 another
study reporting no association between the 5‑HTTLPR
polymorphism and premature ejaculation,75 and another
study finding patients with primary premature ejacula­
tion had a significantly higher frequency of the short
allele of the 5‑HTTLPR gene.76
Studies have been performed to investigate the
function of 5-hydroxytryptamine receptors, and have
demonstrated that 5‑HT2C, 5‑HT1A and 5‑HT1B recep­
tors affect the speed of ejaculation. Studies involving
the administration of nonselective 5‑HT2C agonists
suggest that stimulation of 5‑HT2C receptors delays
ejaculation. 77 Compounds that equally stimulate
5‑HT2A and 5‑HT2C receptors also increase ejaculation
latency,78 whereas selective 5‑HT2A receptor agonists
have a different effect. 77 On the other hand, activa­
tion of post­s ynaptic 5‑HT1A receptors by a selective
5‑HT1A receptor agonist actually results in reduced
ejaculatory latency. 77 The application of this under­
standing of 5-­hydroxytryptamine receptors has led
to the use of selective 5-hydroxytryptamine-reuptake
inhibitors (SSRIs) in the treatment of premature ejacu­
lation. Use of these agents results in increased levels of
5-­hydroxytryptamine in the synapse owing to the active
blockade of 5-hydroxytryptamine transporters in the
presynaptic membrane.68 5-hydroxytryptamine levels
are only mildly increased at first, but after the eventual
desensitization of 5‑HT1A and 5‑HT1B/1D autoreceptors,
5-hydroxytryptamine levels in the synapse increase
greatly. The increased levels of 5-hydroxytryptamine
activate the postsynaptic 5‑HT2C and 5‑HT1A receptors
and consequently delay ejaculation.68,79
Investigations into whether tandem-repeat poly­
morphisms of the dopamine transporter gene (DAT1)
modulate ejaculation latency have also been con­
ducted.80–82 It has been proposed that men with longer
tandem repeat lengths in the DAT1 gene have increased
transcription of the dopamine transporter protein—a
protein that is responsible for the reuptake of dopa­
mine back into the presynaptic neuron—and hence
reduced synaptic dopamine activity.80 Santilla et al.80
reported that men with longer tandem repeats in the
DAT1 gene were more likely to have symptoms consis­
tent with early ejaculation. Other studies, mainly male
twin studies in the general population, have investi­
gated polymorphisms in genes encoding receptors for
5-hydroxytryptamine, oxytocin, and vasopressin. 83,84
Preliminary findings have not indicated a marked pre­
ponderance of any one genetic polymorphism of the
genes encoding these receptors in men with symptoms
of early ejaculation.83,85,86 A multi­factorial genetic com­
ponent likely contributes to the degree of symptoms in
men with premature ejaculation; however, apart from
the previously discussed data, we do not have strong
reproducible evidence supporting the involvement of all
of the exact genes involved in the pathogenesis of human
premature ejaculation.
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Hormones might also have a role in the pathophysio­
logy of premature ejaculation. Erection, ejaculation and
penile detumescence have been postulated to be associ­
ated with increased central and peripheral oxytocin
release.87 In a large sample of men (n = 1,517), 12 oxy­
tocin receptor gene single nucleotide polymorphisms
(SNPs) had no effect on ejaculatory function; however,
researchers found that men who were hetero­zygous for
one SNP in the oxytocin receptor gene (rs75775) had
a significantly increased risk of symptoms of prema­
ture ejaculation compared with those who were homo­
zygous.83 Prolactin might also have a hormonal role
in the ejaculatory mechanism: low prolactin levels
have been associ­ated with an increased risk of prema­
ture ejaculation, even after adjusting for confounding
variables.88 The prevalence of premature ejaculation
has been reported to be increased in men with hyper­
thyroidism compared with those who were hypo­thyroid
or e­uthyroid.89 In addition, men with premature ejacu­
lation have been shown to have increased levels of
testosterone compared with those without premature
ejaculation.90 However, the interaction between hor­
mones and ejaculatory dis­orders is a controversial issue91
and cannot explain the p­athophysiology of l­i felong
p­remature ejaculation.
In addition to hormonal disruptions, some urological
conditions might contribute to premature ejaculation.
For example, symptoms of prostatitis have been found
to be associated with acquired premature ejaculation.92,93
The successful eradication of the causative bacteria in
patients with chronic prostatitis and comorbid prema­
ture ejaculation was found to lead to marked improve­
ment in IELT and ejaculatory control.94 Moreover, it has
also been postulated that varicocele can lead to intra­
pelvic venous congestion with development of prostatic
venous congestion and, eventually, prostatitis-related
premature ejaculation.34 Interestingly, one study has
demonstrated that varicocelectomy might improve the
symptoms of premature ejaculation through eradication
of this venous congestion.95 Further research into the role
of hormones and other conditions in premature ejacula­
tion will enable improved neurobiological understanding
of all the subtypes of this disorder.
Social and psychological associations
Premature ejaculation can exert a considerable psycho­
logical burden on men, their partners, and their relation­
ships in general.96 Conversely, any type of anxiety, as well
as relationship and life stressors, can result in increased
sympathetic activity, which could in turn lead to more
prompt induction of smooth-muscle contractions and
subsequent premature ejacu­lation.97 Empirical studies
have demonstrated that men with any sexual dysfunc­
tion are more likely to report decreased sexual satisfac­
tion.41,98 Compared to men without sexual dysfunction,
men with premature ejaculation have increased levels
of embarrass­ment, guilt, worry, tension, and fear of
failure associated with sexual situations.99,100 Premature
ejaculation can result in decreased self-confidence,
increased distress and interpersonal difficulties, and
NATURE REVIEWS | UROLOGY ADVANCE ONLINE PUBLICATION  |  5
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REVIEWS
mental preoccupation with the condition. 98,100 As
patients who suffer from premature ejaculation often
feel less secure in sexual situations when compared to
men without premature ejaculation, it is not surprising
that relationship dysfunction is reported as a negative
effect of premature ejaculation.100,101 Premature ejacula­
tion can also be associated with marital discord102 and a
patient’s insecurity regarding their partner’s satisfaction
can serve as an obstacle to initiating and maintaining
new relationships.101,103
Further evidence of the negative impact of premature
ejaculation on psychological wellbeing in men and rela­
tionship functioning with their partners was documented
in a community-based study of 1,587 men (207 of whom
had premature ejaculation) and their female partners.96
Women in a relationship with men with premature ejacu­
lation were well aware of their partner’s lack of control
over ejaculation. These couples reported reduced sexual
satisfaction, increased personal distress and increased
interpersonal difficulty compared with couples without
the disorder. However, sexual expectations might vary
among women of different cultures. A study of 1,463 sex­
ually active women from Mexico, South Korea and Italy,
who reported being in or having been in a relationship
with a man with premature e­jaculation, reported differ­
ences in the importance of ejaculatory control, as well
as the degree of distress caused by premature ejacula­
tion between countries.104 A lack of control was the most
commonly reported reason for distress for Mexico and
South Korea, yet short latency was the most common
reason in Italy. A partner’s expectations and understand­
ing of the disease clearly influences overall satisfaction of
the couple. The Female Sexual Distress Scale—Revised—
Premature Ejaculation questionnaire has been used in a
large-scale internet-based population survey comparing
1,361 women in a stable relationship with a partner with
premature ejaculation and 748 controls.105 The revised
questionnaire was found to fulfil psychometric require­
ments for measuring sexual distress related to a part­
ner’s sexual dysfunction.105 Application of this revised
question­naire will shed further light on the interpersonal
consequences of premature ejaculation, and it could also
be used as a tool to evaluate effective treatment. Our
understanding of the social and psychological burden of
premature ejaculation will continue to evolve as further
well designed studies uncover its true effect on the lives
of both men and their partners.
Current therapeutic options
A number of treatment options for premature ejacu­
lation are available (Table  1). 106–108 SSRIs, topical
anaesthetic creams, and phosphodiesterase type 5
(PDE‑5) inhibitors are widely used, and psychological
therapies and b­ehavioural techniques have not been
completely abandoned.5
Behavioural interventions
Four randomized controlled studies evaluating the use
of psychological therapies as a treatment of prema­
ture ejaculation have provided weak and inconsistent
REVIEWS

Table 1 | Medical treatment options for premature ejaculation cream.115 Another topical agent containing extracts of
nine different herbs is severance secret (SS) cream.116
Treatment Class Dose
SS cream has been shown to increase mean IELT from
Dapoxetine 135
SSRI 30–60 mg on demand 1.37 min to 10.92 min in a double-blind, randomized,
Clomipramine133,191,192 TCA 12.5–50 mg/day or placebo-controlled study involving 106 men with life­
12.5–50 mg on demand long premature ejaculation, and improved sexual satis­
Fluoxetine193 SSRI 20–40 mg/day faction was reported by 82% of patients who used the
Paroxetine133,134 SSRI 10–40 mg/day or cream.117 However, SS cream is manufactured in Korea
10–40 mg/day on demand and its availability in other countries might be limited.
Sertraline194 SSRI 50–200 mg/day Topical agents seem to have successful outcomes (with
Citalopram195 SSRI 20–40 mg/day
limited adverse effects)118 in terms of increasing IELT
in patients with premature ejaculation, and their use is
Tramadol154 Opiate analgesic 62 mg ODT on demand or
89 mg ODT on demand
r­ecommended in current guidelines.5,118
Sildenafil148 PDE-5 inhibitor 100 mg on demand
Oral therapies
Lidocaine cream196 Topical local anaesthetic 25 mg/g SSRIs
Prilocaine cream196 Topical local anaesthetic 25 mg/g Serotonergic antidepressants are the best studied of the
Abbreviations: ODT, oral dissolving tablet; PDE-5, phosphodiesterase type 5; SSRI, selective currently available oral treatments for premature ejacula­
5-hydroxytryptamine reuptake inhibitor; TCA, tricyclic antidepressant.
tion. The therapeutic benefits of daily SSRI therapy are
supported by results of numerous well-designed, double-
blind, placebo-controlled trials.106 This evidence has led
evidence regarding their efficacy.109 On the other hand, to guidelines recommending medical SSRI therapy as the
sexual counseling and other psychological interven­ first-line treatment for lifelong premature ejaculation.5,119
tions are advocated as an adjunct to pharmacotherapy When commonly available SSRIs have been compared,
in patients who are suffering from a clear psychologi­ paroxetine has been shown to produce superior outcomes
cal problem in addition to premature ejaculation.108,109 in terms of increasing the IELT to fluoxetine, clomipra­
Although relevant psychological issues should clearly mine and sertraline.120,121 In a 2015 study that compared
not be discounted when evaluating patients with life­ a 1‑month course of daily duloxetine therapy with a
long or acquired premature ejaculation, on the basis of 1‑month course of daily paroxe­tine therapy in 80 patients
current evidence, pharmacotherapy is more effective with lifelong premature ejaculation, the mean IELT
than psychological treatment alone.109 For the treatment increase was 117% in the duloxetine group (P <0.001)
of patients with variable or subjective premature ejacula­ and 126% in the p­aroxetine group (P <0.001).122
tion, it is our opinion that psychological therapies should SSRI use is associated with a number of adverse effects
be considered a potential treatment,109 even though no and is contraindicated in some patients. Men with
strong evidence exists to support such treatment, as these infertility should seek a different treatment modality,
forms of premature ejaculation have not previously been as chronic SSRI treatment seems to impair spermato­
universally defined. genesis and sperm transportation, compromise the
The ‘stop–start’ method described by Semans110 in sperm cell membrane, change sperm DNA and affect
1956 and the ‘squeeze’ technique suggested by Masters hormonal homeo­stasis.123–126 The mechanisms by which
and Johnson in 1970 111 are examples of behavioural daily SSRI treatment causes these adverse effects are not
approaches to managing premature ejaculation. Gradual fully understood, and additional investigations are nec­
exposure of the patient to higher degrees of stimula­ essary. Several animal studies have suggested that SSRI
tion is hypothesized to attenuate various stimulus– use is associated with impaired erectile function owing to
response connections with repetition of these methods. reduced nitric oxide (NO) production, reduced NO bio­
Masturbation before sexual intercourse has also been availability and reduced neuronal nitric oxide synthase
studied, and seems to have an efficacy comparable to (nNOS) expression.127,128 A further study performed on
that of the ‘stop–start’ method.112 A small, randomized, rats demonstrated that SSRI treatment might impair
prospective study comparing pelvic floor rehabilitation erectile function by decreasing NO bioavailability via
exercises with on-demand SSRI therapy found similar increased NADPH oxidase activity and increased reac­
efficacy in treatment of lifelong premature ejaculation.113 tive oxygen species production.129 Other sexual adverse
Combining behavioural modifications with medica­ effects of serotonergic anti­depressants include decreased
tions might be beneficial in the overall manage­ment of libido and anorgasmia, which can continue beyond ces­
p­remature ejaculation, but further study is necessary.114 sation of treatment.130,131 An additional concern is the
slight increase in the risk of suicidal ideation seen in
Topical therapies young adolescents receiving SSRI treatment for depres­
Topical anaesthetic creams, which reduce the sensitiv­ sive or anxiety disorders.132 Although this increased risk
ity of the penis, are a simple, locally applied treatment was not detected in adult men using SSRIs for treat­
option for premature ejaculation. Significant increases ment of premature ejaculation,133–136 physicians should
in IELT have been reported in randomized, double- still be aware of this potential risk when p­rescribing
blind, placebo-controlled trials of lidocaine–prilocaine a­ntidepressants to patients with premature ejaculation.

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© 2015 Macmillan Publishers Limited. All rights reserved

Dapoxetine was the first approved oral medication
for the treatment of premature ejaculation in many
countries. 5 It is a rapidly acting SSRI with a short
half-life that enables on-demand use. 135,137–140 Several
well-controlled studies have demonstrated the effi­
cacy of dapoxetine, 30 mg or 60 mg, taken orally 1–2 h
before intercourse. These studies reported mean IELT
increases of 2.5–3.0-fold, as well as improvements in
other patient-reported outcome measures to include
all Premature Ejaculation Profile (PEP) items and
clinical global impression of change score. 135,141,142
Adverse effects, including nausea, diarrhoea, head­
ache and dizzi­ness, were uncommon and seemed to be
dose dependent.135,140 A recent observational study of
6,712 patients with premature ejaculation treated with
dapoxetine over a 12-week period confirmed its good
safety profile and demonstrated a slight—but signifi­
cant—decrease in the occurrence of adverse events in
dapoxetine-treated patients compared with 1,515 men
treated with oral ‘alternative care,’ which included
treatment with clomipramine, paroxetine, fluoxetine,
or sertraline, while there was a significant increase in
adverse events when dapoxetine-treated patients were
compared to a group of 2,928 men who underwent non-
oral therapy options, to include topical m­e dication,
condoms and behavioural therapy.143
However, dapoxetine might not be the treatment of
choice for every man with premature ejaculation. In a
study performed by Waldinger et al.144 it was demon­
strated that 81% of men with premature ejaculation
preferred a daily scheduled medication, as they felt
that on-demand treatment interfered with the spon­
taneity of sexual encounters. Another study reported
that 20% of patients with premature ejaculation who
were prescribed on-demand dapoxetine did not start
the medication, either owing to fear of using a new drug
or because of the cost of the treatment.145 Interestingly,
among 120 patients with premature ejaculation who
were prescribed dapoxetine, 90% who initiated dapox­
etine therapy discontinued the treatment within 1 year.
The main reasons for discontinuation included an effi­
cacy below expectations (24.4%), cost (22.1%), adverse
effects (19.8%) and loss of interest in sex (19.8%).145
Another study found that discontinuation rates were
high between different SSRIs, ranging from 28.8% to
70.6%. Dapoxetine was associated with the highest
dropout rate, and paroxetine the lowest dropout rate.146
Dapoxetine is effective and well tolerated in patients
with lifelong or acquired premature ejaculation;
however, further studies must be conducted in order
to determine the true effectiveness and adverse effects
of SSRIs for the treatment of premature e­jaculation in
a clinical setting.147
PDE‑5 inhibitors
PDE‑5 inhibitors are another class of medications that
have potential therapeutic benefits in patients with
concomitant premature ejaculation and erectile dys­
function.5,119 The PDE‑5 inhibitor sildenafil has been
shown to increase confidence, perception of ejaculatory
NATURE REVIEWS | UROLOGY ADVANCE ONLINE PUBLICATION  |  7
© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
control and overall sexual satisfaction, and to decrease
the refractory time to achieving a second erection after
ejaculation in men with premature ejaculation, in spite
of no significant change in IELT.148 Thus, PDE‑5 inhibi­
tors remain a treatment for which further evidence is
required to support their efficacy and mechanism of
action.149 When addressing premature ejaculation in
patients with comorbid erectile dysfunction, expert
opinion supported by a critical review of the litera­
ture supports that PDE‑5 inhibitors should be used
before dapoxetine.150
Tramadol
Tramadol is an opiate analgesic used to treat moderate-
to-severe pain. Results from several placebo-controlled
studies have supported the use of tramadol as an on-
demand treatment option for patients with premature
ejaculation.151–153 A large, multicentre, multinational,
double-blind, placebo-controlled trial demonstrated a
significant 2.4-fold increase in mean IELT with appli­
cation of on-demand tramadol in men with premature
ejaculation.154 Almost no adverse effects or tolerability
issues were reported to be associated with administra­
tion of the medication.154 However, it is important to
note that the combination of tramadol with an SSRI can
pose a potentially fatal risk of 5-­hydroxytryptamine syn­
drome, which comprises a triad of cognitive, autonomic,
and somatic effects, ensuing rapidly after the medica­
tion is administered.155 Thus, although tramadol seems
to be effective in the treatment of premature ejacula­
tion, its long-term adverse effects are not established
and—given the observed levels of hetero­geneity between
trials included in recent meta-analyses—caution should
be used when i­nterpreting the data.156–158
Combining therapeutic approaches
The pathology of premature ejaculation is multi­
factorial and some patients require a combination of
treatment approaches. 159 The physician should con­
sider the degree of impairment that the symptoms are
causing and the potential adverse effects of each treat­
ment modality when considering management options.
A combination of pharmacological, psychological, and
behavioural approaches for both partners are currently
used in most clinical practices that manage patients
with premature ejaculation.160 Follow-up studies with
combination therapies that provide quantitative results
can help to determine optimal management of patients
with premature ejaculation.161 Improved understanding
of the complex pathophysiology of premature ejacu­
lation and further study of the numerous treatment
options available will continue to shape the clinical
management of patients (Table 1).
Future perspectives
Several in vitro and animal studies have demonstrated
that the desensitization of 5‑HT1A receptors, increased
activation of postsynaptic 5‑HT2C receptors, and the
resultant higher increase in synaptic 5-hydroxytrypta­
mine neurotransmission can be acutely achieved
REVIEWS
through blockade of these receptors using adminis­
tration of an on-demand SSRI and a 5‑HT1A recep­
tor antagonist. 162,163 One randomized, double-blind,
placebo-controlled study reported that patients with
premature ejaculation who are refractory to daily par­
oxetine therapy show increases in IELT and improved
intercourse satisfaction following combination therapy
with continued paroxetine therapy and the addition of
daily high-dose pindolol, a nonselective β‑blocker that
has partial β‑agonist activity and also functions as a
5‑HT1A receptor antagonist.164 Another potent SSRI,
DA‑8031, is also emerging as a potential therapeu­
tic agent in the treatment of premature ejaculation:
this agent has been shown to significantly inhibit ejacu­
lation in several animal models,165,166 and does not seem
to affect the initiation of mounting behaviour or post­
ejaculatory interval in rats.167 Human clinical trials are
currently being conducted with DA‑8031 as a treatment
for premature ejaculation (NCT01798667).168 The com­
plete mechanism of action of 5‑HT receptors and their
contribution to the pathogenesis of premature ejacula­
tion is still not completely understood. Further study of
these mechanisms will enable improved understanding
of premature ejaculation and will provide great insight
into additional potential therapies.
Modafinil also represents a novel treatment option
for men with premature ejaculation. First identified
as a wakefulness-promoting agent and used for the
treatment of narcolepsy, its mechanism of action is
complex and remains poorly understood. 169,170 Male
sexual behaviour and ejaculation are influenced by
variations of 5-hydroxytryptamine release in the brain
and spinal cord, as well as action of the dopamine
system.171 Modafinil’s mechanism of action is likely via
modification of these pathways. Low doses of modafinil
that normally do not alter serotonergic neurotransmis­
sion have been shown to increase SSRI-induced central
5-hydroxytryptamine release, suggesting that modafinil
works through common pathways that alter mood.172
A study of male rats that received oral modafinil
(30 mg/kg and 100 mg/kg) showed a significant delay in
ejaculation, accompanied by an increase in the number
of intromissions without any change in their mount or
intromission latency.173 Modafinil has been reported to
be effective in the treatment of a patient with lifelong
premature ejaculation,174 but well controlled clinical
trials are warranted to further evaluate the feasibility
of this promising t­reatment option.
Silodosin is a highly selective α 1A-adrenoceptor
antagonist that has shown clinical efficacy and safety
in the management of lower urinary tract symp­
toms.175–177 Interestingly, reduced or absent ejaculation
during orgasm due to the blockage of α 1A receptors
involved in the ejaculation process is a common side
effect of this medication. 176–179 Sato et al. 180 reported
that in eight men with premature ejaculation who took
silodosin (4 mg) 2 h before sexual intercourse, mean
IELT improved significantly (from 3.4 min to 10.1 min,
P = 0.003); significant improvements were also seen in
validated questionnaires to include the Clinical Global
8  |  ADVANCE ONLINE PUBLICATION
© 2015 Macmillan Publishers Limited. All rights reserved
Impression of Change and the PEP. Another study com­
pared the efficacy of daily silodosin 4 mg, tamsulosin
hydrochloride 0.4 mg, alfuzosin 10 mg, terazosin 5 mg
and doxazosin mesylate 4 mg in men with premature
ejaculation. The findings revealed that IELT, PEP, and
quality of life responses were statistically improved with
each of the drugs, with the most effective improvements
noted with silodosin when compared to the other
drugs with regards to statistical increase in IELT and
decrease in PEP (P <0.05).181 These results support the
possible use of α1-adrenoceptor antagonists, in particu­
lar silodosin, as a new treatment option for premature
ejaculation; however, further placebo-controlled trials
assessing this application are needed.
An increasing number of studies report the involve­
ment of central oxytocinergic neurotransmission in
the ejaculatory process. In men, plasma oxytocin levels
are elevated during penile erection and at the time of
orgasm.182,183 Electrical stimulation of the dorsal penile
nerve produced excitation in about half of the oxytocin-­
producing cells in the paraventricular nucleus of the
hypothalamus and supraoptic nucleus in rats. 184,185
In a rat model, systematic administration of oxytocin
facilitated ejaculation by reducing the number of intro­
missions required for ejaculation, ejaculation latencies,
and postejaculation intervals.186,187 Oxytocin receptor
antagonists might also have a potential use, but there
have been no reports of their efficacy in the treatment
of premature ejaculation.188
A slightly more invasive option for treatment of pre­
mature ejaculation includes injection of botulinum‑A
toxin into the bulbospongiosus and ischiocavernosus
muscles, as ejaculation is a spinal cord reflex in which
these muscles play a primary role. Inhibiting the rhyth­
mic contractions of these muscles with botulinum‑A
toxin might increase ejaculatory latency (Figure 1).189
Injection of botulinum‑A toxin into the bulbospongio­
sus muscle in rats has been shown to extend the ejacu­
latory latency without affecting the ability to engage in
sexual activity or achieve ejaculation.190 Botulinum‑A
toxin represents another potential therapy that could
provide relief to men who experience significantly
severe premature ejaculation.
Conclusions
The new ISSM unified evidence-based definition of
premature ejaculation produced in 2014 could be a
critical step in improving our understanding of the
scope and process of this disorder, as it provides con­
crete oper­ational criteria to include as limitations in
future studies. Much remains to be learned with regards
to the mechanisms of pathophysiology and manage­
ment options for premature ejaculation; however,
credible progress has been made and the future seems
bright. Current medical therapy offers several effective
options, with many more in development and trial. As
our understanding of the pathophysiology continues
to evolve and new therapies are developed, the options
available for men with p­r emature ejaculation can
only increase.
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Author contributions
E.C.S. made substantial contributions to discussion
of content and reviewed/edited the manuscript before
submission. T.R.S. researched data for article and
wrote the manuscript.
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