Escolar Documentos
Profissional Documentos
Cultura Documentos
ISSN: 2047-2919
REVIEW ARTICLE
Correspondence:
Serap Gur, Department of Pharmacology, Faculty
of Pharmacy, Ankara University, 06100, Tandogan,
Ankara, Turkey.
E-mail: serapgur@ankara.edu.tr
Keywords:
dapoxetine, intravaginal ejaculation latency time,
pathophysiology, premature ejaculation, selective
serotonin reuptake inhibitors, serotonin
Received: 6-Sep-2014
Revised: 3-Feb-2015
Accepted: 21-Feb-2015
doi: 10.1111/andr.12032
SUMMARY
Premature ejaculation (PE) is the most prevalent male sexual dysfunction. This is associated with negative personal and interpersonal psychological outcomes. The pharmacologic treatment of PE includes the use of antidepressants, local anesthetic agents, and
phosphodiesterase type 5 inhibitors. While numerous treatments can control PE, only antidepressants and topical anesthetic creams
and sprays have recently been shown to be more effective. This review focuses on the physiology and pharmacology of ejaculation,
the pathophysiology of PE and the most effective pharmacological treatment of PE. Pharmacotherapy of PE with off-label shortacting selective serotonin reuptake inhibitors (SSRIs) is common, effective, and safe. Dapoxetine, a SSRI with a short half-life, has
been recently evaluated for the treatment of PE by several countries and results are promising. In clinical practice, follow-up side
effects are an important part of the management strategy for PE. The understanding of etiology, pathophysiology, and treatment
modalities of PE would be beneficial to clinician in helping patients with this disappointing sexual problem.
INTRODUCTION
PREVALANCE OF PE
424
PHYSIOLOGY OF EJACULATION
Ejaculation is the interaction between the nervous system and
specialized peripheral organs.
Brain areas and spinal control center
Various brain areas are involved in ejaculatory behavior (Coolen et al., 1997) and comprise of a complex interconnected network. Spinal ejaculation generator (SEG) which is important
area for ejaculation is located lateral to the central canal in lamina X and the medial portion of lamina VII of L3 and L4 of the
lumbar spinal cord (Fig. 1). These lumbar spinothalamic (LSt)
neurons project to the medial parvocellular subparafascicular
nucleus of the posterior thalamus and are specifically activated
during ejaculation but not with other components of male sexual behavior. Lesions of these neurons cause dramatic disruption in ejaculatory response (Truitt & Coolen, 2002). The sensory
information is then transmitted via the dorsal nerve of the penis
(S4) to the lumbosacral spinal cord and is joined by sympathetic
afferents from the hypogastric plexus conveying biochemical
and/or mechanical information from the accessory sex organs
(Carro-Juarez & Rodriguez-Manzo, 2005). Traveling up the spinal
cord (and joined by visual, auditory, and olfactory cerebral afferents), the impulses are integrated by cerebral structures specifically activated during ejaculation to form a tightly
interconnected network comprising hypothalamic, diencephalic,
and pontine areas. The regulation of the ejaculatory reflex
requires neurochemically coordinated interrelationships at various levels of the neuraxis.
The physiologic ejaculatory reflex is mediated by a spinal control center, referred to as SEG which induces coordination of
ANDROLOGY
WHAT IS IELT?
Intravaginal ejaculation latency time is defined as the time
between the start of vaginal intromission and the start of intravaginal ejaculation. Furthermore, assessment of IELTs with stopwatch time has more accuracy compared with retrospective
questionnaire and spontaneous reported latency. In clinical trials, it is commonly measured by the female partner utilizing a
Figure 1 Ejaculatory organs involved in ejaculatory activity. Organs shown are brain, spinal
cord, peripheral genital organs, and many
nerves. It is the result of coordination between
contractile activity involving different ejaculatory organs and the SEG. The population of LSt
neurons has important role as a component of
SEG. SEG, spinal ejaculatory ganglion; MPOA,
medial
preoptic
area;
LSt,
lumbar
spinothalamic.
425
ANDROLOGY
Serotonin is released from pre-synaptic neurons into the synapse and activates the 5-HT1B receptors resulting in reduced
release of serotonin in the synapse. This in turn, activates 5HT1A and 5-HT1B receptors resulting in sustained mild stimulation of all post-synaptic 5-HT receptors. After several days to
weeks of SSRI treatment, the receptors become desensitized and
there is a reduction in the inhibitory action on serotonin release.
The overall effect is more serotonin released into the synapse
(Wylie & Ralph, 2005). Any short-term increase in the 5-HT
release into the synapse is immediately followed by activation of
pre-synaptic 5-HT1A autoreceptors on the cell bodies of serotonergic neurons. Activation of these 5-HT1A autoreceptors
decreases firing of the serotonin neuron and consequently lowers release of serotonin from the pre-synaptic neuron into the
synaptic cleft with negative feedback mechanism. Acute administration of SSRIs also leads to stimulation of the 5-HT1A receptors. However, during chronic administration of SSRIs, 5-HT1A
autoreceptors are thought to desensitize over time (Haensel
et al., 1991; Barnes & Sharp, 1999). This negative feedback mechanism can be reduced by a selective 5-HT1A antagonist, for
example, WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridyl)cyclohexanecarboxamide;
Clement
et al., 2006). Acute and chronic SSRI citalopram slightly inhibited ejaculation, which was strongly increased by coadministration of WAY 100635 (de Jong et al., 2005). It would be of interest
if these autoreceptors could be blocked (i.e., immediately desensitized), allowing marked increases in 5-HT levels.
5-HT1B receptors are located on pre- and post-synaptic
axon terminals in several brain areas, including the raphe
nuclei, lateral hypothalamic area, the nucleus of the stria terminalis, and nucleus accumbens, and in the spinal cord (de
Jong et al., 2005). These receptors may play a role as autoreceptors controlling the 5-HT release into the synaptic cleft
(Waldinger, 2007a), as heteroreceptors by inhibiting the
release of various neurotransmitters that facilitate ejaculation,
such as acetylcholine, GABA, dopamine, glutamate or perhaps
galanin (de Jong et al., 2005), or may mediate the inhibition
of ejaculation induced by serotonin possibly through a postsynaptic action (Giuliano & Clement, 2006). Although theoretically interesting, the 5-HT1B receptors have not yet been
shown to be an important target for drugs to be used for PE
treatment. 5-HTT are present on the somata and dendrites of
5-HT neurons where they facilitate the re-uptake of 5-HT after
cell firing-induced 5-HT release. Inhibition of these transporters causes enhanced 5-HT levels in the synaptic cleft leading
to enhanced serotonergic neurotransmission. The SSRIs block
5-HTT mechanisms and so increase 5-HT within the synapse.
Consequently, 5-HTT became a rational target for therapeutic
intervention and SSRI became the most widely prescribed
drugs.
Dopamine receptors
Dopamine plays a key role in ejaculation (Hull & Dominguez,
2007; Peeters & Giuliano, 2008). Dopamine stimulates two subfamilies of receptors, D1-like including D1 and D5 receptors,
and D2-like, consisting of D2, D3, and D4 receptors (Beaulieu &
Gainetdinov, 2011). Dopamine receptors are distributed on the
soma and across the dendritic tree of dopaminergic neurons
(Kitrey et al., 2007). When a D3 receptor antagonist (Clement
et al.) was microinjected into the MPOA of rats, an ejaculation
2015 American Society of Andrology and European Academy of Andrology
between the sympathetic and the parasympathetic system activity. The sympathetic action was high in patients with lifelong PE,
resembling in autonomic imbalance that might trigger lifelong
PE (Zorba et al., 2012).
Most of the patients who seek treatment for the PE at a urology
clinic suffer from lifelong PE (Serefoglu et al., 2010). Lifelong PE
can be best managed by pharmacotherapy.
Acquired PE
In a mans life, early ejaculation can occur at any time.
Acquired PE is accompanied by medical and psychological
causes and also involves short IELT, which is mostly between 1
and 2 min (Waldinger & Schweitzer, 2008). The men had normal
ejaculation responses before and the onset of PE usually occurs
at a later age. Rapid ejaculation may result from comorbid diseases, for example, urological, thyroid, or psychological problems. The management of acquired PE is etiology specific and
may include pharmacotherapy for comorbid ED. Behavioral
therapy is indicated when psychogenic or relationship factors
are present and are often best combined with PE pharmacotherapy in an integrated treatment program.
Variable PE
Formerly variable PE has been described as natural variable
PE (Waldinger, 2008b). In this PE condition, men occasionally
suffer from early ejaculations and have a normal ejaculatory performance unlike those with established EjD (Waldinger &
Schweitzer, 2008). The IELT may be diminished or lacking. Psychotherapy as first-line therapy should be considered.
Subjective EjD
Subjective EjD is related to psychological, cultural, or interrelationship factors and does not involve neurobiological or
genetic factors. Although having a normal or even a long IELT
duration of 520 min, men under this category complain subjectively about early ejaculation which is not based on real ejaculation duration (Waldinger, 2007b, 2008a; Waldinger & Schweitzer,
2008). As availability to delay ejaculation may be diminished or
ANDROLOGY
Figure 3 Schematic diagram of pre-synaptic 5-hydroxytryptamine (HT1B and 5HT1D) and post-synaptic (5HT1A and 5HT2C) receptors of serotonin (5-HT)
involved in ejaculation. PE, premature ejaculation; SSRI, selective serotonin re-uptake inhibitors; HTT, serotonin transporter.
427
ANDROLOGY
Serotonin is released from pre-synaptic neurons into the synapse and activates the 5-HT1B receptors resulting in reduced
release of serotonin in the synapse. This in turn, activates 5HT1A and 5-HT1B receptors resulting in sustained mild stimulation of all post-synaptic 5-HT receptors. After several days to
weeks of SSRI treatment, the receptors become desensitized and
there is a reduction in the inhibitory action on serotonin release.
The overall effect is more serotonin released into the synapse
(Wylie & Ralph, 2005). Any short-term increase in the 5-HT
release into the synapse is immediately followed by activation of
pre-synaptic 5-HT1A autoreceptors on the cell bodies of serotonergic neurons. Activation of these 5-HT1A autoreceptors
decreases firing of the serotonin neuron and consequently lowers release of serotonin from the pre-synaptic neuron into the
synaptic cleft with negative feedback mechanism. Acute administration of SSRIs also leads to stimulation of the 5-HT1A receptors. However, during chronic administration of SSRIs, 5-HT1A
autoreceptors are thought to desensitize over time (Haensel
et al., 1991; Barnes & Sharp, 1999). This negative feedback mechanism can be reduced by a selective 5-HT1A antagonist, for
example, WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridyl)cyclohexanecarboxamide;
Clement
et al., 2006). Acute and chronic SSRI citalopram slightly inhibited ejaculation, which was strongly increased by coadministration of WAY 100635 (de Jong et al., 2005). It would be of interest
if these autoreceptors could be blocked (i.e., immediately desensitized), allowing marked increases in 5-HT levels.
5-HT1B receptors are located on pre- and post-synaptic
axon terminals in several brain areas, including the raphe
nuclei, lateral hypothalamic area, the nucleus of the stria terminalis, and nucleus accumbens, and in the spinal cord (de
Jong et al., 2005). These receptors may play a role as autoreceptors controlling the 5-HT release into the synaptic cleft
(Waldinger, 2007a), as heteroreceptors by inhibiting the
release of various neurotransmitters that facilitate ejaculation,
such as acetylcholine, GABA, dopamine, glutamate or perhaps
galanin (de Jong et al., 2005), or may mediate the inhibition
of ejaculation induced by serotonin possibly through a postsynaptic action (Giuliano & Clement, 2006). Although theoretically interesting, the 5-HT1B receptors have not yet been
shown to be an important target for drugs to be used for PE
treatment. 5-HTT are present on the somata and dendrites of
5-HT neurons where they facilitate the re-uptake of 5-HT after
cell firing-induced 5-HT release. Inhibition of these transporters causes enhanced 5-HT levels in the synaptic cleft leading
to enhanced serotonergic neurotransmission. The SSRIs block
5-HTT mechanisms and so increase 5-HT within the synapse.
Consequently, 5-HTT became a rational target for therapeutic
intervention and SSRI became the most widely prescribed
drugs.
Dopamine receptors
Dopamine plays a key role in ejaculation (Hull & Dominguez,
2007; Peeters & Giuliano, 2008). Dopamine stimulates two subfamilies of receptors, D1-like including D1 and D5 receptors,
and D2-like, consisting of D2, D3, and D4 receptors (Beaulieu &
Gainetdinov, 2011). Dopamine receptors are distributed on the
soma and across the dendritic tree of dopaminergic neurons
(Kitrey et al., 2007). When a D3 receptor antagonist (Clement
et al.) was microinjected into the MPOA of rats, an ejaculation
2015 American Society of Andrology and European Academy of Andrology
related response was induced. However, no anatomical or functional connections have been found between the MPOA and the
spinal ejaculation centers. Hence, these structures may be indirectly linked through other nuclei like the paraventricular
nucleus and the nucleus paragigantocellularis, which have been
shown to possess direct connections with spinal autonomic and
somatic nuclei (Giuliano & Clement, 2005). Behavioral studies
have shown that the dopamine D3 receptor-preferring agonist, 7hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT), decreases
the number of intromissions preceding ejaculation and the
latency of ejaculation in rats (Clement et al., 2007). This effect of
intracerebroventricular administration of the 7-OH-DPAT
(Clement et al., 2007), targeted brain D3 receptors that may provide a therapeutic approach for treating ejaculatory disorders in
humans. Further supporting this, a selective dopamine D3
receptor antagonist (SB-277011), delayed ejaculation by specifically and dose-dependently inhibiting the expulsion phase without impairing either emission or erection (Clement et al., 2009).
The dopamine transporter gene (DAT1) polymorphism is associated with PE (Santtila et al., 2010). Targeting dopamine D3
receptors would be an interesting therapeutic approach.
Oxytocin receptors
Oxytocin plays an important role in the control of ejaculation
(Arletti et al., 1985). When oxytocin was infused into the cerebral
ventricle of male rats, it facilitated ejaculatory behavior by shortening ejaculation latency, and the post-ejaculatory refractory
period (Arletti et al., 1985). 7-OH-DPAT in anesthetized rats
increases sexual responses, whereas L6 spinal oxytocin receptors
only impair the occurrence of ejaculation. Furthermore, a selective oxytocin receptor antagonist inhibited sexual behavior,
including ejaculation, and reversed the pro-sexual effect of the
non-selective dopamine-receptor agonist, apomorphine in the
mating test in rats (Argiolas et al., 1988). Oxytocin, when administered via the intracerebroventricular route, increased latencies
of mount and intromission in rats (Stoneham et al., 1985).
Blockade of L6 spinal oxytocin receptors only impaired the
occurrence of ejaculation. It has been found a heterozygote
effect of one polymorphism (rs75775) in the oxytocin receptor
gene leading to increased risk for PE (Jern et al., 2012).
Clement et al. (2008), using a selective oxytocin receptor
antagonist, demonstrated that brain oxytocin receptors mediate
male sexual response elicited by 7-OH-DPAT in anaesthetized
rats. Peripheral oxytocin receptors were found to be only marginally involved in 7-OH-DPAT induced sexual responses. However, 7-OH-DPAT-induced ejaculation takes place via blockade
of brain oxytocin receptors. These findings should be considered
for the development of potential pharmacologic treatment of PE
in man (Clement et al., 2008). GSK557296 is a highly selective,
non-peptide oxytocin antagonist that increases seminal vesicle
pressures and reduces the occurrence of ejaculation (Clement
et al., 2013). This antagonist interferes with ejaculation induced
by stimulation of dopamine D3 receptors in anesthetised rats
possibly by acting at multiple levels with different modalities
(Clement et al., 2013). For the treatment of PE central oxytocin
receptors can be targeted with a highly selective antagonist. This
is a promising and interesting approach. Interestingly, epelsiban
(selective oxytocin receptor antagonist), at 50 and 150 mg doses
did not result in a clinically significant change in IELT in men
with PE (Shinghal et al., 2013). In addition to oxytocin, serotonin
2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
429
ANDROLOGY
(Carani et al., 2005; Sadeghi-Nejad & Watson, 2008). The presence of thyroid hormone receptor isoforms in the male genital
tract may be a further mechanism of action of that relationship.
Carosa et al. (2010) demonstrated the presence of TRa1, TRa2,
and TRb in rat and human corpus cavernosum. TRa1 and TRa2
both expressed in the penis and smooth muscle cells during
ontogenesis without-dependent changes TRb remained high in
adulthood and its expression is regulated by development. Thyroid hormone may also influence the ejaculatory process by
estrogen metobolism. Hyperthyroidism enhances SHBG, which
binds androgens with higher affinity than estrogens resulting in
hyperestrogenism (Carani et al., 2005). However, in recent study
prolactin on male accessory glands from animals to humans had
trophic effect and a positive association among prolactin and
ejaculate and seminal vesicles volume, before and after ejaculation was observed (Lotti et al., 2013). It was suggested that low
prolactin is associated with a lessened ability to control ejaculation (Lotti et al., 2013). Men with prolactin levels at the lowest
quartile are at increased risk of developing the metabolic syndrome, arteriogenic ED, PE, and associated anxiety symptoms
(Corona et al., 2009). As hypoprolectinemia is more associated
with ED, it is not clear which patient will develop PE secondary
to ED or vice-versa. Hypothyroidism is also frequently associated with high prolactin levels that correlated with TSH but
dropped when adequate T4 replacement was given in hypothyroid patients (Carani et al., 2005). The higher prolaction levels in
hypothyroid subjects may be influenced by the central pathways
of sexual drive (Cohen et al., 1984) as shown in earlier data
(Corona et al., 2004).
EARLY TREATMENT OF PE
The use of anesthetics to diminish the sensitivity of the glans
penis is probably the oldest known treatment of PE. Schapiro
(1943) described the use of topical anesthetic ointment to delay
ejaculation. In 1973, the first double-blind, placebo-controlled
studies of successful ejaculatory delay by clomipramine, the
serotonergic tricyclic antidepressant, was published (Goodman,
1980; Assalian, 1998; McMahon, 1998a,b).
Over the past 15 years, an increasing number of wellcontrolled, evidence-based studies have demonstrated the efficacy and safety of SSRIs in delaying ejaculation, confirming their
role as first-line treatment of lifelong and acquired PE (Waldinger et al., 2004a). The introduction of the serotonergic tricyclic
clomipramine and the SSRIs paroxetine, sertraline, fluoxetine,
and citalopram showed great potential in the treatment of PE.
These drugs block axonal reuptake of serotonin from the synaptic cleft of central and peripheral serotonergic neurons by
5-HTT, resulting in enhanced 5-HT neurotransmission and stimulation of post-synaptic 5-HT2C receptors. Although, the methodology and the protocol of initial drug treatment studies was
not adequate, later double-blind and placebo-controlled studies
confirmed the ejaculation-delaying effect of clomipramine and
SSRIs (Kim & Seo, 1998; Waldinger et al., 2004a).
ANDROLOGY
Oral pharmacotherapy
Opioid analgesic
Drugs
Mechanism of action
Efficacy on PE
Dosage
Citation
Tramadol
25 and 50 mg
Eassa &
El-Shazly (2013)
2550 mg
Waldinger
et al. (2004a,b)
3060 mg
McMahon
et al. (2013a,b)
10, 20 and
40 mg/day
Salonia
et al. (2002)
10 mg
Safarinejad
(2007)
Haensel
et al. (1998)
McMahon
(1998a,b)
Tricyclic antidepressants
Clomipramine
SSRI
Dapoxetine
Paroxetine
Fluoexetine
Sertraline
Sildenafil
Vardenafil
Tadalafil
Escitalopram
PDE5-inhibitors
Silodosin
Topical treatments
Sodium
sulfacetamide
(SS) cream
Lignocaine spray
50100 mg
Wang
et al. (2007)
20 mg
Aversa
et al. (2009)
20 mg
Mattos
et al. (2008)
Basar
et al. (2005)
and Cavallin
i (1995)
Sato
et al. (2012)
48 mg
Tian
et al. (2004)
9.6%
Linton &
Wylie (2010)
Dinsmore
et al. (2007)
Dyclonine and
alprostadil
combination
520 mg/day
Cream- mixture
spray-7.5 mg of
lidocaine and 2.5
mg of prilocaine
0.5% dyclonine
Morales
and 0.4% alprostadil et al. (2007)
PE, premature ejaculation; 5-HT, 5-hydroxytryptamine; IELT, intravaginal ejaculation latency time; SSRI, selective serotonin reuptake inhibitors; NA, noradrenaline;
PDE, phosphodiesterase.
tendency in any of these trials. The multicenter trial was the only
individual trial to show a statistically significant risk ratio. The
overall risk ratio for SSRIs in depression trials was 1 compared to
1.95 for in this category. The overall risk difference for all drugs
across all indications was 0.02 (Hammad et al., 2006). In addition looking at adult data from FDA reviews, Khan et al. (2000)
reported that the risk of completed suicide was the same for
antidepressant drugs and placebo. In the analysis of proprietary
data submitted to US FDA (Stone et al., 2009), risk of suicidality
associated with use of antidepressants is strongly age-dependent. Compared with placebo the increased risk for suicidal
2015 American Society of Andrology and European Academy of Andrology
behavior among adults under 25 approaches that seen in children and adolescents. The net effect appears to be neutral on
suicidal behavior but likely protective for suicidal ideation in
adults aged 2564 and to diminish the risk of both suicidality
and suicidal behavior in those aged 65 (Stone et al., 2009).
Dapoxetine: Dapoxetine (Priligy Johnson & Johnson) is a novel,
well-tolerated, efficacious short-acting SSRI and probably better
suited as an on-demand treatment for PE (Giuliano & Clement,
2012). Dapoxetine is similar to the other SSRIs in that it exerts its
effects through the inhibition of the serotonin reuptake transporter (Modi et al., 2009; Razzak, 2013). It is currently the only
Andrology, 2015, 3, 424442
431
drug approved (in limited numbers of countries) for PE treatment. Elimination of the drug is rapid, the half-life is 1.31.4 h,
and there appears to be very little accumulation (Modi et al.,
2006). This is in contrast to the other SSRIs that have half-lives
in the order of 14 days and chronic use results in important
accumulation. In several placebo-controlled clinical trials, dapoxetine has been shown to improve the IELT and is effective
from the first dose when taken 13 h before intercourse (Pryor
et al., 2006; McMahon et al., 2013a; Mirone et al., 2014). This
agent is rapidly absorbed and eliminated, resulting in minimal
accumulation, and has dose proportional pharmacokinetics
which are unaffected by multiple dosing. Dapoxetine (30 and
60 mg) has been evaluated on demand in men with PE and ED
in five industry-sponsored randomized, double-blind, placebocontrolled studies in 6081 men aged at least 18 years and
showed an increase in IELT (McMahon et al., 2011). High dose
(60 mg) dapoxetine taken 13 h before intercourse displayed a
higher post-treatment IELT increase compared to 30 mg
dapoxetine (P < 0.05) and paroxetine (P < 0.01) and can be directly administrated in cases of severe PE (e.g., IELT <30 s; Simsek
et al., 2014). However, caution to patients should be advised for
60 mg dose of dapoxetine (McMahon et al., 2013b).
Interestingly, a low dose of dapoxetine combined with mirodenafil showed better results in terms of IELT, overall sexual act
time, and PE profile index score, and similar treatment-emergent
adverse events, compared with that of dapoxetine alone (Lee
et al., 2013). Thus, men with comorbid ED and PE may be treated
with both a PDE5 inhibitor and dapoxetine which is stable and
well-tolerated. Currently, SSRIs such as dapoxetine, a more popular treatment option for PE (Mirone et al., 2014) has been
approved in Europe but has not been approved in US, yet.
Paroxetine: Paroxetine is effective with daily dosing, increasing
IELT up to eightfold. This is compared to the 1.4-fold increase
achieved with placebo (P < 0.001) and the pause-squeeze
method (P < 0.05; Abdel-Hamid et al., 2001) followed by sertraline (4.1) and fluoxetine (3.9; Waldinger et al., 2004a). However,
median IELT only increased by 4 min from baseline (1 min) with
paroxetine compared with 3 min with the squeeze technique.
A recent study comparing daily paroxetine (20 mg) in combination with acupuncture concluded that this treatment was
superior (P = 0.001) to placebo in terms of IELT and PE diagnostic tool scores and more effective than acupuncture in delaying
ejaculation (Sunay et al., 2011).
Citalopram and escitalopram: Citalopram and its S-enantiomer,
escitalopram have provided inconsistent results in the treatment
of PE (Waldinger et al., 2001; Safarinejad & Hosseini, 2006). Of the
currently available SSRIs, escitalopram has the highest selectivity for the human serotonin transporter relative to noradrenaline
and dopamine transporters. Daily escitalopram treatment affects
semen parameters of patients with lifelong PE (Koyuncu et al.,
2011). In a recent randomized, placebo-controlled, double-blind
study, treatment with escitalopram demonstrated a 4.9-fold
increase in geometric mean IELT (Safarinejad, 2007). Both these
drugs increased sexual intercourse satisfaction as well as frequency. On a daily treatment basis, the onset of effect is gradual
and usually takes 23 weeks, although in some patient it takes
57 days. However, some patients will not respond to such treatment and even when they respond some men lose efficacy over
time (Posternak & Zimmerman, 2005). Neither this phenomenon,
called tachyphylaxis, nor the lack of efficacy has a satisfying
432
ANDROLOGY
scientific explanation to date. Citalopram is effective and safe in
the treatment of PE in men after failed treatment with fluoxetine
(Dadfar & Baghinia, 2010).
Fluoxetine and sertraline: The use of fluoxetine to treat PE was
first described by Forster & King (1994). Waldinger et al. (1998a,
b) demonstrated varying efficacy with a number of SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) in the treatment
of PE, although with different side-effect profiles. On-demand
administration of sertraline and fluoxetine 46 h prior to sexual
intercourse yielded modest efficacy that was lower than daily
dosing therapy (Waldinger et al., 2004a). Once the medication
discontinued, PE relapse was reported by the majority of
patients; that is, the medication must be continued for as long as
the couple are sexually active and in the control of PE.
DA-8031: DA-8031 is a newer agent for the treatment of PE
with high specificity and selectivity for the serotonin transporter
compared with other monoamine transporters and receptors
involved in neurotransmission (Kang et al., 2013). The efficacy
of DA-8031was determined in in-vivo pharmacologic studies
using two pre-clinical animal models by (i) electrical stimulation
of the sensory branch of the pudendal nerve (SBPdn); and (ii) in
a PCA-induced ejaculation model. DA-8031 effectively suppressed the ejaculatory responses both in the peripheral SBPdn
induced and the PCA-induced ejaculation models with a possible site of action on the central nervous system comprising the
brain and spinal cord. It is anticipated that the proven efficacies
in these pre-clinical models will accelerate the development of
DA-8031 in human clinical studies (Kang et al., 2013).
PDE5 inhibitors (PDE5i)
The NO-cyclic guanosine monophosphate (cGMP)-PDE5 system is one of the most important pathways involved in the regulation of contractility of the male genital tract, which is under
testosterone control. Because of their central roles in smooth
muscle relaxation and tone regulation and success of PDE5i or
the treatment of ED, the PDEs have also become an attractive
target for PE drug development. The rationale for targeting PDEi
for PE is based on the presence of PDE5 mRNA in human vas
deferens and prostate (Mancina et al., 2005; Uckert et al., 2006),
and the fact that PDE5 inhibitors can reverse adrenergic tone in
human vas deferens and seminal vesicle (Medina et al., 2000;
Uckert et al., 2007).
The concept that PDE5i may exert a beneficial effect in men
with PE is still unresolved and open to speculation. Many men
with PE also have concomitant ED. Whether the men with PE
develop secondary ED owing to performance anxiety because of
PE, or whether the men with ED ejaculates early during intercourse before the erection fails is unknown. There was, however,
a rationale to use PDE5i in these men. Marked good quality
penile rigidities were obtained with PDE5 inhibitors in the
post-ejaculatory period, but the difference was significant
(P < 0.01) only with sildenafil and vardenafil treatment (Gokce
et al., 2011). In fact, PDE5i may play a role in treating PE complicated by ED, but it may not be ideal treatment for simple PE as
suggested earlier (Abdel-Hamid, 2004). Regarding the first construct of latency, introducing PDE5i to the treatment mix does
not meaningfully increase latency, as adequately demonstrated
by McMahon et al. (2006). Further large multicenter studies
using PDE5i are warranted to support the use of PDE5i in men
with PE and ED.
2015 American Society of Andrology and European Academy of Andrology
Selective serotonin reuptake inhibitor and PDE5i combination before intercourse significantly induced longer IELT as
compared with chronic SSRI alone in patients with PE (Polat
et al., 2014). In patients with comorbid ED and PE (n = 429)
who were prescribed a PDE5i and dapoxetine, mean IELT significantly increased with dapoxetine which was well-tolerated
(McMahon et al., 2013a). Recently Jannini et al. (2013) suggested that PDE5i should be used before dapoxetine in PE
patients with comorbid ED, and counseling should be offered
to all subjects with sexual dysfunction. Controversial issues still
exist in almost all sexual dysfunction cases and intuition, experience, and evidence should guide in deciding using of first line
of treatment.
In the latest review article, Jannini et al. (2013) debated, the
relationship between PE and ED, the role of NO and the NOS
enzymes, the simple way to recognize ED in PE patients use of
PDE5is in PE patients irrespective of the ED comorbidity. McMahon et al. (2006) suggested that treatment with sildenafil failed
to significantly increase baseline IELT in men with lifelong PE
but normal erectile function. In addition, sildenafil improved
patients ejaculatory control. As PE and ED share a vicious cycle,
where a man trying to control his ejaculation instinctively
reduces his level of excitation (which can lead to ED) and a man
trying to achieve an erection basically attempts to increase his
excitation (which can lead to PE; McMahon et al., 2006). PE and
its treatment(s) are mostly based on mental and psychological
background and a PDE5i may be less useful as a primary therapy
for the treatment of PE (McMahon et al., 2006). Recently, Jannini
et al. (2011) suggested a need of well-designed studies on the
possible use of PDE5is in PE patients without ED and in addition
verification for the role of NO and PDE5 in the mechanism of
ejaculation.
Sildenafil: A clinical trial simultaneously compared sildenafil,
paroxetine, and the squeeze technique in patients with PE and
showed increased IELT in the sildenafil group compared with
the other two treatment groups (Wang et al., 2007). Other clinical studies compared the effectiveness of clomipramine, sertraline, paroxetine, sildenafil, and pause-squeeze technique in men
and showed three- to four-fold increase in IELT in the sildenafil
group compared with other treatments. Sildenafil treatment was
also superior in terms of patient satisfaction (Abdel-Hamid
et al., 2001). Unfortunately, higher incidence of side effects with
the combined treatment was observed. Sildenafil retards the
ejaculatory response by modulating contraction of the seminal
vesicle smooth muscle. In addition, PDE5i can reduce the tension of isolated human seminal vesicle tissue and enhance the
production of cyclic adenosine monophosphate (cAMP) and
cGMP. In isolated human seminal vesicle experiments, the contractile activity in response to electrical field stimulation was
reduced by the PDEi in a dose-dependent manner. Also, the frequency of spontaneous contractions was decreased by 50% in
the presence of sildenafil or vardenafil (Uckert et al., 2009).
Thus, sildenafil and other PDE5i may have potential role in
improving IELT in PE patients.
Vardenafil: Recent small studies in men with lifelong PE compared vardenafil (Aversa et al., 2009) or sertraline in a randomized, prospective, crossover design (Mathers et al., 2009) and
showed an increase in IELT as well as improvement in outcome
measures with vardenafil as requested by the patient. In a laboratory setting, PDE5i seem to prolong the median duration of
2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
433
ANDROLOGY
TOPICAL TREATMENTS
Topical application of such agents like lidocaineprilocaine
cream is a simple, efficacious, and attractive local treatment
option for PE (Table 1). However, differences do exist among the
various products and there can be local side effects (Atikeler
et al., 2002; Henry & Morales, 2003). Topical agents can be used
on as needed basis and systemic side effects are usually minimal. So far, there has been no consensus on the dosage of medication or the timeframe for application of topical anesthetic
agents. Several topical agents have been used including severance-secret (SS) cream, lignocaine spray, lidocaineprilocaine
cream, and dycloninealprostadil combination (Choi et al.,
1999; Henry & Morales, 2003; Wyllie & Powell, 2012). The theory
that men with PE have penile hypersensitivity provides a rationale for using locally effective topical desensitizing agents. Compared with other medications for PE, topical anesthetic agents
were reported to cause unique side effects, including hypoesthesia of the penile shaft, local irritant symptoms, loss of erection,
and numbing of the vagina of the partner. Despite good efficacy,
minimal systemic side effects, and on demand use, topical
anesthetic agents may have several potential limitations that
include inconvenience of use, messiness, and interference with
spontaneity, etc.
SS cream
The SS cream (Cheil Jedan Corporation, Seoul, Korea) is available for use only in Korea and all studies evaluating its efficacy
have been performed by the same research group. The SS cream
is a mixture of nine traditional medicines, including Korean ginseng, bufonoid venom, and cinnamon. Subsequently, a renewed
SS cream has been formulated that has two main components of
the SS cream, namely Korean ginseng and bufonoid venom in a
hydrobase with an enhancer and without the smell and color of
the original SS cream (Tian et al., 2004). Some of these components have local anesthetic as well as vasoactive properties. This
SS cream should be used an hour before intercourse and washed
off immediately before intercourse, and some patients complain
that it has an unpleasant smell and color. SS cream is not
approved for use in Europe or the USA (Linton & Wylie, 2010).
Lignocaine spray
This spray, which has been available for many years, can be
bought over the counter without a prescription. The local anesthetic lignocaine (9.6%) is the active ingredient in this spray and
it works in the same way as other topical anesthetic agents.
However, there is a limited clinical data for its use.
LidocainePrilocaine cream and spray
The eutectic mixture (EMLA; AstraZeneca, London, UK) is a
local anesthetic cream that contains 2.5% of both lidocaine and
prilocaine in a metered-dose aerosol delivery system for topical
application. However, genital hypoesthesia has been reported in
both sexes (Busato & Galindo, 2004).
Topical eutectic mixture for PE (TEMPE) also known as
PSD502 (Plethora Solutions PLC, London, UK) is a formulation
434
HYALURONIC ACID
Hyaluronic acid is a natural and safe compound that has been
widely used in the esthetic medicine for the treatment of osteoarthritis. Complications are very rare and easily manageable by
expert surgeons (Littara et al., 2013). Filler materials have shown
an important role in the field of glans penis augmentation and
was found to prevent PE (Kwak et al., 2008; Abdallah et al.,
2012). Hyaluronic acid injection can be effectively used for treatment of PE allowing an increase in IELT. A hundred and ten
male patients were treated with hyaluronic acid injections in the
deep dermis of their glans penis to increase the volume and the
circumference of their penis to prevent premature ejaculation
and improve sexual satisfaction. The IELT time increased
remarkably from a baseline value after 6 months of the
procedure.
PROSTATE AND PROSTATIC DISEASES IN THE PE
A careful examination of the prostate should be performed
before starting any pharmacological or psychosexual treatment
for PE. Benign prostatic hyperplasia (BPH) is a common condition and a frequent cause of LUTS in adult men (Boyle et al.,
2003). Recently, changes in sexual function before and after the
treatment of BPH have attracted attention. Both a-blockers and
5-a reductase inhibitors (ARIs) were associated with significantly
higher risk of EjD than placebo. Combination therapy with
a-blockers and 5ARIs (e.g., finasteride and dutasteride increased three-fold the risk of EjD (Gacci et al., 2014). Tamsulosin
(a-blocker) is a typical therapeutic agent for BPH, and had inhibitory effects in the emission phase of ejaculation, including
decreased ejaculatory volume Giuliano & Clement, 2012. Besides
the improvement of LUTS, tamsulosin can help the subjective
symptoms of PE in patients with LUTS + PE (Choi et al., 2014).
In recent clinical trial, LUTS and ED were significantly and independently correlated with PE (Lee, 2014). Retrograde or abnormal ejaculation was the most commonly reported side effect in
the patients treated with silodosin (Cho & Yoo, 2014).
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)
is a common etiology of PE. There is evidence for an intriguingly
2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
435
ANDROLOGY
FUTURE PERSPECTIVES
The population of men with PE is not homogenous and many
men with PE do not seek medical attention. Consequently, there
is an intense search for efficient and safe pharmacologic treatment of PE but no such agent with acute onset of action is yet
available.
Only SSRIs, desensitizing creams and to a lesser extent PDE5
inhibitor have shown some effectiveness for the treatment of PE.
Although PE can be treated in many patients with currently
available procedures as discussed in this review, long-term success rates have been disappointing. It has been postulated that
on-demand treatment for PE with the conventional SSRIs may
only be successful when combined with a 5-HT1A receptor
antagonist or some other treatment that would acutely enhance
serotonin release. One of the disadvantages of the traditional
SSRIs is that they require multiple dosing before becoming effective (Waldinger, 2007a). Although for SSRIs to have a role in the
treatment of PE, these must be used with caution and patients
must be warned that such use is off-label and with some risk of
suicidal ideation. However, the increased risk among adults
under age 25 and diminished risk in aged 65 for suicidal behavior should be re-examined in PE patients using dapoxetine.
All these medications are used off-label for the treatment of
PE except for dapoxetine which has been recently licensed in
several European countries and provides an effective, ondemand treatment regimen with relatively minimal side effects.
While it is evident that PDE5 inhibitors are the first choice in
patients with comorbid ED and PE (where one may be secondary
to the other), well-designed multicenter studies on the possible
use of PDE5 inhibitors in PE patients without ED are still limited.
The issue will be less controversial when further information on
the role of NO and PDE5 in the mechanism of ejaculation is
available.
Previous studies have revealed that tamsulosin is effective in
improving LUTS and erectile function. However, it has some
inhibitory effects on ejaculation, including decreased ejaculatory
volume. However, these inhibitory effects on ejaculation can be
beneficial to patients with PE. Further studies are needed to confirm the effects of tamsulosin on PE.
The treatment of PE is complex, and guidelines for such treatment are limited because of the unclear definition of the disease,
causing a barrier to carrying out standardized evidence-based
studies. In fact reconceptualizing the definition and diagnostic
criterion of the definition of lifelong and acquired PE disorder
will enable researchers to design methodologically rigorous
studies to improve our understanding of acquired PE. Currently,
it is important for the physician to consider all aspects of etiology, pathobiology, and possible treatment approaches when
treating PE as each patient may respond differently and side
effects are variable. Treatment should be discussed with the
patient and his partner, according to the diagnosis and their
individual needs. Marked improvement has been made in this
field; however, clarification of definition and further studies on
treatment are required. Before starting therapy for PE, correct
diagnosis has to be made considering the patients reported IELT
and the duration and type of PE. Concomitant ED should be
either ruled out or confirmed by appropriate studies. Large multicenter, prospective randomized clinical trials should be carried
out in the future to confirm the safety and efficacy of topical
ACKNOWLEDGEMENTS
The authors declare that the manuscript has not been received
any support, including sponsorship and any sources of material.
Drs S. Gur and S. C. Sikka have no conflicts of interest to declare.
Both authors contributed equally to the design and to the drafting of the manuscript.
REFERENCES
Abdallah H, Abdelnasser T, Hosny H, Selim O, Al-Ahwany A & Shamloul
R. (2012) Treatment of premature ejaculation by glans penis
augmentation using hyaluronic acid gel: a pilot study. Andrologia 44
(Suppl. 1), 650653. doi: 10.1111/j.1439-0272.2011.01244.x.
Abdel-Hamid IA. (2004) Phosphodiesterase 5 inhibitors in rapid
ejaculation: potential use and possible mechanisms of action. Drugs
64, 1326.
Abdel-Hamid IA, El Naggar EA & El Gilany AH. (2001) Assessment of as
needed use of pharmacotherapy and the pause-squeeze technique in
premature ejaculation. Int J Impot Res 13, 4145. doi: 10.1038/
sj.ijir.3900630.
Abdollahian E, Javanbakht A, Javidi K, Samari AA, Shakiba M &
Sargolzaee MR. (2006) Study of the efficacy of fluoxetine and
clomipramine in the treatment of premature ejaculation after opioid
detoxification. Am J Addict 15, 100104. doi: 10.1080/
10550490500419151.
Ahlenius S & Larsson K. (1999) Synergistic actions of the 5-HT1A receptor
antagonist WAY-100635 and citalopram on male rat ejaculatory
behavior. Eur J Pharmacol 379, 16.
Ahlenius S, Larsson K, Svensson L, Hjorth S, Carlsson A, Lindberg P,
Wikstrom H, Sanchez D, Arvidsson LE, Hacksell U & Nilsson JL. (1981)
Effects of a new type of 5-HT receptor agonist on male rat sexual
behavior. Pharmacol Biochem Behav 15, 785792.
Ali MY, Ping CY, Mok YY, Ling L, Whiteman M, Bhatia M & Moore PK.
(2006) Regulation of vascular nitric oxide in vitro and in vivo; a new
role for endogenous hydrogen sulphide? Br J Pharmacol 149, 625634.
doi: 10.1038/sj.bjp.0706906.
Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW,
Adaikan PG, Wikstrom H, Sanchez D, Arvidsson LE, Hacksell U &
Torres LO. (2014) An update of the international society of sexual
medicines guidelines for the diagnosis and treatment of premature
ejaculation (PE). Sex Med 2, 6090. doi: 10.1002/sm2.28.
Amobi NI, Chung IP & Smith IC. (2006) Attenuation of contractility in rat
epididymal vas deferens by Rho kinase inhibitors. Auton Autacoid
Pharmacol 26, 169181. doi: 10.1111/j.1474-8673.2006.00367.x.
Argiolas A, Collu M, Gessa GL, Melis MR & Serra G. (1988) The oxytocin
antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin inhibits male copulatory
behaviour in rats. Eur J Pharmacol 149, 389392.
Arletti R, Bazzani C, Castelli M & Bertolini A. (1985) Oxytocin improves
male copulatory performance in rats. Horm Behav 19, 1420.
Assalian P. (1998) Clomipramine in the treatment of premature
ejaculation. J Sex Res 24, 213215. doi: 10.1080/00224498809551414.
Atikeler MK, Gecit I & Senol FA. (2002) Optimum usage of
prilocaine-lidocaine cream in premature ejaculation. Andrologia 34,
356359.
Aversa A, Pili M, Francomano D, Bruzziches R, Spera E, La Pera G &
Spera G. (2009) Effects of vardenafil administration on intravaginal
ejaculatory latency time in men with lifelong premature ejaculation.
Int J Impot Res 21, 221227. doi: 10.1038/ijir.2009.21.
2015 American Society of Andrology and European Academy of Andrology
ANDROLOGY
437
438
ANDROLOGY
Dinsmore WW, Hackett G, Goldmeier D, Waldinger M, Dean J, Wright P,
Callander M, Wylie K, Novak C, Keywood C, Heath P & Wyllie M.
(2007) Topical eutectic mixture for premature ejaculation (TEMPE): a
novel aerosol-delivery form of lidocaine-prilocaine for treating
premature ejaculation. BJU Int 99, 369375. doi: 10.1111/j.1464410X.2006.06583.x.
Dschietzig T, Bartsch C, Baumann G & Stangl K. (2006) Relaxin-a
pleiotropic hormone and its emerging role for experimental and
clinical therapeutics. Pharmacol Ther 112, 3856. doi: 10.1016/
j.pharmthera.2006.03.004.
Eassa BI & El-Shazly MA. (2013) Safety and efficacy of tramadol
hydrochloride on treatment of premature ejaculation. Asian J Androl
15, 138142. doi: 10.1038/aja.2012.96.
Forster P & King J. (1994) Fluoxetine for premature ejaculation. Am J
Psychiatry 151, 1523.
Gacci M, Ficarra V, Sebastianelli A, Corona G, Serni S, Shariat SF, Maggi
M, Zattoni F, Carini M & Novara G. (2014) Impact of medical
treatments for male lower urinary tract symptoms due to benign
prostatic hyperplasia on ejaculatory function: a systematic review and
meta-analysis. J Sex Med 11, 15541566. doi: 10.1111/jsm.12525.
Gao J, Xu C, Liang C, Su P, Peng Z, Shi K, . . . Zhang X. (2014)
Relationships between intravaginal ejaculatory latency time and
national institutes of health-chronic prostatitis symptom index in the
four types of premature ejaculation syndromes: a large observational
study in china. J Sex Med 11, 30933101. doi: 10.1111/jsm.12696.
Giuliano F. (2007) 5-Hydroxytryptamine in premature ejaculation:
opportunities for therapeutic intervention. Trends Neurosci 30, 7984.
doi: 10.1016/j.tins.2006.12.002.
Giuliano F & Clement P. (2005) Neuroanatomy and physiology of
ejaculation. Annu Rev Sex Res 16, 190216.
Giuliano F & Clement P. (2006) Serotonin and premature ejaculation:
from physiology to patient management. Eur Urol 50, 454466. doi:
10.1016/j.eururo.2006.05.055.
Giuliano F & Clement P. (2012) Pharmacology for the treatment of
premature ejaculation. Pharmacol Rev 64, 621644. doi: 10.1124/
pr.111.004952.
Godpodinoff ML. (1989) Premature ejaculation: clinical subgroups and
etiology. J Sex Marital Ther 15, 130134. doi: 10.1080/
00926238908403817.
Gokce A, Halis F, Demirtas A & Ekmekcioglu O. (2011) The effects of
three phosphodiesterase type 5 inhibitors on ejaculation latency time
in lifelong premature ejaculators: a double-blind laboratory setting
study. BJU Int 107, 12741277. doi: 10.1111/j.1464-410X.2010.09646.x.
Goodman RE. (1980) An assessment of clomipramine (Anafranil) in the
treatment of premature ejaculation. J Int Med Res 8(Suppl. 3), 5359.
Greco E, Polonio-Balbi P & Speranza JC. (2002) Levosulpiride: a new
solution for premature ejaculation? Int J Impot Res 14, 308309. doi:
10.1038/sj.ijir.3900901.
Gur S, Kadowitz PJ & Hellstrom WJ. (2007) Purinergic (P2) receptor
control of lower genitourinary tract function and new avenues for drug
action: an overview. Curr Pharm Des 13, 32363244.
Gur S, Sikka SC, Abdel-Mageed AB, Abd EZ, Rezk B, Pankey E, Kadowitz
PJ & Hellstrom WJ. (2013) Imatinib mesylate (Gleevec) induces human
corpus cavernosum relaxation by inhibiting receptor tyrosine kinases
(RTKs): identification of new RTK targets. Urology 82, 745, e711746.
doi: 10.1016/j.urology.2013.04.030.
Haensel SM, Mos J, Olivier B & Slob AK. (1991) Sex behavior of male and
female Wistar rats affected by the serotonin agonist 8-OH-DPAT.
Pharmacol Biochem Behav 40, 221228.
Haensel SM, Klem TM, Hop WC & Slob AK. (1998) Fluoxetine and
premature ejaculation: a double-blind, crossover, placebo-controlled
study. J Clin Psychopharmacol 18, 7277.
Hammad TA, Laughren T & Racoosin J. (2006) Suicidality in pediatric
patients treated with antidepressant drugs. Arch Gen Psychiatry 63,
332339. doi: 10.1001/archpsyc.63.3.332.
ANDROLOGY
Kilmann PR, Milan RJ Jr, Boland JP, Mills KH, Caid C, Davidson E, Bella
B, Wanlass R, Sullivan J & Montgomery B. (1987) The treatment of
secondary orgasmic dysfunction II. J Sex Marital Ther 13, 93105. doi:
10.1080/00926238708403882.
Kim SC & Seo KK. (1998) Efficacy and safety of fluoxetine, sertraline and
clomipramine in patients with premature ejaculation: a double-blind,
placebo controlled study. J Urol 159, 425427.
Kippin TE, Sotiropoulos V, Badih J & Pfaus JG. (2004) Opposing roles of
the nucleus accumbens and anterior lateral hypothalamic area in the
control of sexual behaviour in the male rat. Eur J Neurosci 19, 698704.
Kitrey ND, Clement P, Bernabe J, Alexandre L & Giuliano F. (2007)
Microinjection of the preferential dopamine receptor D3 agonist 7hydroxy-N, N-di-n-propylaminotetralin hydrobromide into the
hypothalamic medial preoptic area induced ejaculation in
anesthetized rats. Neuroscience 149, 636641. doi: 10.1016/
j.neuroscience.2007.06.051.
Koyuncu H, Serefoglu EC, Yencilek E, Atalay H, Akbas NB & Sarica K.
(2011) Escitalopram treatment for premature ejaculation has a
negative effect on semen parameters. Int J Impot Res 23, 257261. doi:
10.1038/ijir.2011.35.
Kwak TI, Jin MH, Kim JJ & Moon DG. (2008) Long-term effects of glans
penis augmentation using injectable hyaluronic acid gel for premature
ejaculation. Int J Impot Res 20, 425428. doi: 10.1038/ijir.2008.26.
Lee JH. (2014) Associations between premature ejaculation, lower
urinary tract symptoms, and erectile dysfunction in middle-aged
Korean policemen. J Sex Med 11, 15121518. doi: 10.1111/jsm.12461.
Liang CZ, Zhang XJ, Hao ZY, Shi HQ & Wang KX. (2004) Prevalence of
sexual dysfunction in Chinese men with chronic prostatitis. BJU Int
93, 568570.
Limoncin E, Tomassetti M, Gravina GL, Ciocca G, Carosa E, Di Sante S,
Gentile V, Mirone V, Montorsi F, Lenzi A, Jannini EA. (2013) Premature
ejaculation results in female sexual distress: standardization and
validation of a new diagnostic tool for sexual distress. J Urol 189, 1830
1835. doi: 10.1016/j.juro.2012.11.007.
Linan-Rico A, Wunderlich JE, Grants IS, Frankel WL, Xue J, Williams KC,
Harzman AE, Enneking JT, Cooke HJ, Christofi FL. (2013) Purinergic
autocrine regulation of mechanosensitivity and serotonin release in a
human EC model: ATP-gated P2X3 channels in EC are downregulated
in ulcerative colitis. Inflamm Bowel Dis 19, 23662379. doi: 10.1097/
MIB.0b013e31829ecf4d.
Linton KD & Wylie KR. (2010) Recent advances in the treatment of
premature ejaculation. Drug Des Devel Ther 4, 16.
Littara A, Palmieri B, Rottigni V & Iannitti T. (2013) A clinical study to
assess the effectiveness of a hyaluronic acid-based procedure for
treatment of premature ejaculation. Int J Impot Res 25, 117120. doi:
10.1038/ijir.2013.13.
Lotti F, Corona G, Mancini M, Biagini C, Colpi GM, Innocenti SD,
Innocenti SD, Filimberti E, Gacci M, Krausz C, Sforza A, Forti G,
Mannucci E & Maggi M. (2009) The association between varicocele,
premature ejaculation and prostatitis symptoms: possible
mechanisms. J Sex Med 6, 28782887. doi: 10.1111/j.17436109.2009.01417.x.
Lotti F, Corona G, Maseroli E, Rossi M, Silverii A, Deglinnocenti S,
Rastrelli G, Forti G & Maggi M. (2013) Clinical implications of
measuring prolactin levels in males of infertile couples. Andrology 1,
764771. doi: 10.1111/j.2047-2927.2013.00114.x.
Mancina R, Filippi S, Marini M, Morelli A, Vignozzi L, Salonia A, Montorsi
F, Mondaini N, Vannelli GB, Donati S, Lotti F & Maggi M. (2005)
Expression and functional activity of phosphodiesterase type 5 in
human and rabbit vas deferens. Mol Hum Reprod 11, 107115. doi:
10.1093/molehr/gah143.
Marson L & McKenna KE. (1992) A role for 5-hydroxytryptamine in
descending inhibition of spinal sexual reflexes. Exp Brain Res 88, 313
320.
439
440
ANDROLOGY
deferens by sildenafil. Br J Pharmacol 131, 871874. doi: 10.1038/
sj.bjp.0703657.
Melnik T, Althof S, Atallah AN, Puga ME, Glina S & Riera R. (2011).
Psychosocial interventions for premature ejaculation. Cochrane
Database Syst Rev 10, 8: CD008195. doi: 10.1002/
14651858.CD008195.pub2.
Mirone V, Arcaniolo D, Rivas D, Bull S, Aquilina JW, Verze P & PAUSE
Study Team. (2014) Results from a prospective observational study of
men with premature ejaculation treated with dapoxetine or alternative
care: the PAUSE study. Eur Urol 65, 733739. doi:10.1016/
j.eururo.2013.08.018.
Modi NB, Dresser MJ, Simon M, Lin D, Desai D & Gupta S. (2006) Singleand multiple-dose pharmacokinetics of dapoxetine hydrochloride, a
novel agent for the treatment of premature ejaculation. J Clin
Pharmacol 46, 301309. doi: 10.1177/0091270005284850.
Modi NB, Nath R, Staehr P, Gupta SK, Aquilina JW & Rivas D. (2009)
Pharmacokinetic, pharmacodynamic, and electrocardiographic effects
of dapoxetine and moxifloxacin compared with placebo in healthy
adult male subjects. J Clin Pharmacol 49, 634642. doi: 10.1177/
0091270009333486.
Mohee A & Eardley I. (2011) Medical therapy for premature ejaculation.
Ther Adv Urol 3, 211222. doi: 10.1177/1756287211424172.
Morales A, Barada J & Wyllie MG. (2007) A review of the current status
of topical treatments for premature ejaculation. BJU Int 100, 493
501.
Mulryan K, Gitterman DP, Lewis CJ, Vial C, Leckie BJ, Cobb AL, Brown JE,
Conley EC, Buell G, Pritchard CA & Evans RJ. (2000) Reduced vas
deferens contraction and male infertility in mice lacking P2X1
receptors. Nature 403, 8689. doi: 10.1038/47495.
Murphy AZ & Hoffman GE. (2001) Distribution of gonadal steroid
receptor-containing neurons in the preoptic-periaqueductal graybrainstem pathway: a potential circuit for the initiation of male sexual
behavior. J Comp Neurol 438, 191212.
Olivier B, Chan JS, Pattij T, de Jong TR, Oosting RS, Veening JG &
Waldinger MD. (2006) Psychopharmacology of male rat sexual
behavior: modeling human sexual dysfunctions? Int J Impot Res 18
(Suppl. 1), S14S23. doi: 10.1038/sj.ijir.3901330.
Ozgur-Akdemir A, Demirturk K, Karabakan M, Volkan-Oztekin C,
Abdulkadir NA, Cetinkaya M, Gur S & Hellstrom WJ. (2011) Imatinib
mesylate (Gleevec) as protein-tyrosine kinase inhibitor elicits smooth
muscle relaxation in isolated human prostatic tissue. Urology 78, 968.
e961966. doi: 10.1016/j.urology.2011.06.033.
Padma-Nathan H & Yeager JL. (2006) An integrated analysis of
alprostadil topical cream for the treatment of erectile dysfunction in
1732 patients. Urology 68, 386391. doi: 10.1016/
j.urology.2006.02.027.
Pankey EA, Lasker GF, Gur S, Hellstrom WJ & Kadowitz PJ. (2013)
Analysis of erectile responses to imatinib in the rat. Urology 82, 253.
e217224. doi: 10.1016/j.urology.2013.04.009.
Patrick DL, Althof SE, Pryor JL, Rosen R, Rowland DL, Ho KF, McNulty P,
Rothman M & Jamieson C. (2005) Premature ejaculation: an
observational study of men and their partners. J Sex Med 2, 358367.
doi: 10.1111/j.1743-6109.2005.20353.x.
Patrick DL, Rowland D & Rothman M. (2007) Interrelationships
among measures of premature ejaculation: the central role of
perceived control. J Sex Med 4, 780788. doi: 10.1111/j.17436109.2007.00464.x.
Pattij T, de Jong TR, Uitterdijk A, Waldinger MD, Veening JG, Cools AR,
van der Graaf PH, Olivier B. (2005) Individual differences in male rat
ejaculatory behaviour: searching for models to study ejaculation
disorders. Eur J Neurosci 22, 724734. doi: 10.1111/j.14609568.2005.04252.x.
Peeters M & Giuliano F. (2008) Central neurophysiology and
dopaminergic control of ejaculation. Neurosci Biobehav Rev 32, 438
453. doi: 10.1016/j.neubiorev.2007.07.013.
ANDROLOGY
441
442
ANDROLOGY
Waldinger MD, Hengeveld MW, Zwinderman AH & Olivier B. (1998b)
Effect of SSRI antidepressants on ejaculation: a double-blind,
randomized, placebo-controlled study with fluoxetine,
fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol 18,
274281.
Waldinger MD, Zwinderman AH & Olivier B. (2001) SSRIs and
ejaculation: a double-blind, randomized, fixed-dose study with
paroxetine and citalopram. J Clin Psychopharmacol 21, 556560.
Waldinger MD, Zwinderman AH & Olivier B. (2004a) On-demand
treatment of premature ejaculation with clomipramine and
paroxetine: a randomized, double-blind fixed-dose study with
stopwatch assessment. Eur Urol 46, 510515; discussion 516. doi:
10.1016/j.eururo.2004.05.005.
Waldinger MD, Zwinderman AH, Schweitzer DH & Olivier B. (2004b)
Relevance of methodological design for the interpretation of
efficacy of drug treatment of premature ejaculation: a systematic
review and meta-analysis. Int J Impot Res 16, 369381. doi:
10.1038/sj.ijir.3901172.
Waldinger MD, Zwinderman AH, Olivier B & Schweitzer DH. (2005)
Proposal for a definition of lifelong premature ejaculation based on
epidemiological stopwatch data. J Sex Med 2, 498507. doi: 10.1111/
j.1743-6109.2005.00069.x.
Wang WF, Wang Y, Minhas S & Ralph DJ. (2007) Can sildenafil treat
primary premature ejaculation? A prospective clinical study. Int J Urol
14, 331335. doi: 10.1111/j.1442-2042.2007.01606.x.
Weinbauer GF, Jackwerth B, Yoon YD, Behre HM, Yeung CH & Nieschlag
E. (1990) Pharmacokinetics and pharmacodynamics of testosterone
enanthate and dihydrotestosterone enanthate in non-human
primates. Acta Endocrinol (Copenh) 122, 432442.
White CW, Choong YT, Short JL, Exintaris B, Malone DT, Allen AM, . . .
Ventura S. (2013) Male contraception via simultaneous knockout of
alpha1A-adrenoceptors and P2X1-purinoceptors in mice. Proc Natl
Acad Sci U S A 110, 2082520830. doi: 10.1073/pnas.1318624110.
Wylie KR & Ralph D. (2005) Premature ejaculation: the current literature.
Curr Opin Urol 15, 393398.
Wyllie MG & Powell JA. (2012) The role of local anaesthetics in premature
ejaculation. BJU Int 110(11 Pt C), E943E948. doi: 10.1111/j.1464410X.2012.11323.x
Yki-Jarvinen H, Wahlstrom T & Seppala M. (1983) Immunohistochemical
demonstration of relaxin in the genital tract of men. J Reprod Fertil 69,
693695.
Zorba OU, Cicek Y, Uzun H, Cetinkaya M, Onem K & Rifaioglu MM.
(2012) Autonomic nervous system dysfunction in lifelong premature
ejaculation: analysis of heart rate variability. Urology 80, 12831286.
doi: 10.1016/j.urology.2012.08.029.