Gur Et Al-2015-Andrology

ANDROLOGY
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
The characterization, current

medications, and promising
therapeutics targets for premature
ejaculation
1,2
1
Received: 6-Sep-2014
Revised: 3-Feb-2015
Accepted: 21-Feb-2015
S. Gur and 2S. C. Sikka
Department of Pharmacology, School of Pharmacy, Ankara University, Ankara, Turkey, and

Department of Urology, Tulane University Health Sciences Center, New Orleans, LA, USA
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
Premature ejaculation (PE) is the most prevalent male sexual

problem affecting 2030% of men of all age groups. This sexual
condition is poorly defined and associated with substantial negative personal and interpersonal psychologic consequences. Historically, the etiology of PE includes a wide range of biologic and
psychological factors and should be considered as a psychoneuro-uro-endocrine disorder affecting the couple (Jannini &
Lenzi, 2005).
Thus, PE becomes psychogenic and capable of provoking a psycho-relational imbalance. While it is known that all behavioral
dysfunctions may negatively influence organic processes (psychosomatic evidence), it is also evident that a disease or a body symptom may affect behavior. To explain the pathogenesis of primary
PE the ejaculation distribution theory was advanced postulating
that the intravaginal ejaculation latency time (IELT) in heterosexual men is represented by a biologic continuum with men with
lifelong PE belonging to the extreme left side of the IELT curve.
In this review, we focus on the physiology and pharmacology
of ejaculation, pathophysiology of PE, promising therapeutics
targets, and current medications for PE.
The prevalence rates of PE is 2030% (Waldinger, 2007b) and

is largely dependent on the definition of different pathologic
conditions (Hatzimouratidis et al., 2010). In clinical study by
Porst et al. (2007), the prevalence of PE overall was 22.7% (24.0%
in the United States, 20.3% in Germany, and 20.0% in Italy) and
did not vary significantly with age among men over 24 year.
The four PE subtypes [lifelong, acquired, natural variable PE,
and subjective ejaculatory dysfunction (EjD)] are characterized
by different etiologies and pathogenesis and, therefore, should
be separately defined (Waldinger, 2007a, 2008a; Waldinger &
Schweitzer, 2008). The prevalence of lifelong PE (as <1 min
IELT) is about 2% (Patrick et al., 2005). The prevalence of lifelong and acquired PE is probably high in the general male population. In addition, the prevalence of natural variable PE and
subjective PE is high in the male population (Waldinger, 2007b,
2008a; Waldinger & Schweitzer, 2008). Recently, Althof et al.
(2014) insisted that there are relevant dissimilarities between PE
prevalence rates in the general population and clinic settings
because the majority of men with PE do not receive appropriate
treatment.
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Andrology, 2015, 3, 424442
2015 American Society of Andrology and European Academy of Andrology
PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES
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
sympathetic, parasympathetic, and motor outflow for the two

phases of ejaculation, emission, and expulsion. The onset of
ejaculation is triggered i.e. by sensory inputs to the spinal control center during the sexual activity prior to ejaculation. These
sensory inputs may involve somatosensory, visceral sensory, or
proprioceptive inputs (Coolen et al., 2004; Carro-Juarez & Rodriguez-Manzo, 2005). In addition, the SEG integrates this outflow
with inputs conveying biochemical or mechanical information
from the accessory sex organs (Carro-Juarez et al., 2003). In
addition, the SEG is under inhibitory and excitatory influence of
supraspinal sites (Carro-Juarez & Rodriguez-Manzo, 2008). The
efferent limb of the reflex responsible for emission consists of
sympathetic efferent fibers (thoracic 10Lumbar 2, termed a
secretory center) that cause sequential contractions of the epididymis, vas deferens, seminal vesicles, and prostate with closure of the bladder neck (Vignozzi et al., 2008). Ejaculation is
initiated somatically from the sacral spinal cord (S2S4, termed
a mechanical center) via the pudendal nerve (Fig. 1), causing
rhythmic contractions of the bulbospongiosus and bulbocavernous muscles and other associated perineal muscles, which force
the ejaculate through the distal urethra (Giuliano & Clement,
2005).
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.
Andrology, 2015, 3, 424442
425
S. Gur and S. C. Sikka
neurotransmission, decreased function of 5-HT1A receptors,

and/or a hypofunction of 5-HT2C receptors (Waldinger et al.,
1998a).
Serotonergic fibers in brain and spinal areas
Serotonergic fibers have been found in all spinal cord areas
containing sensory axons and motor neurons involved in ejaculation. These are distributed to the dorsal and ventral horns, dorsal commissural gray and thoracolumbar intermediolateral cell
column, and sacral parasympathetic nucleus of the lumbosacral
spinal cord (Maxwell et al., 1996). In addition, serotonergic postsynaptic receptors have been found in the area where LSt cells
are located (Marson & McKenna, 1992).
In the nucleus paragigantocellularis, an area in the ventrolateral medulla of the brainstem, serotonergic neurons are
found to innervate the bulbospongiosus muscles involved in
the inhibition of ejaculation (Marson & McKenna, 1992). Medial preoptic area (MPOA) might lower the ejaculatory threshold by removing the tonic serotonergic inhibition exerted by
the paragigantocellularis (Murphy & Hoffman, 2001). Lesions
of the anterior lateral hypothalamic area in male rats strongly
affect the occurrence of ejaculations, showing the excitatory
role of this brain region in the regulation of ejaculation (Kippin et al., 2004). The injections of SSRIs into the lateral hypothalamic area have been demonstrated to increase ejaculation
latency (Coolen et al., 2004; Giuliano & Clement, 2006; Giuliano, 2007; Waldinger, 2007b).
Serotonin receptors
Multiple serotonin receptors have been characterized, for
example, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, etc. (Peroutka &
Snyder, 1979). At least three-serotonin receptor subtypes have
been identified as having a role in ejaculation, these include 5HT1A, 5-HT1B, and 5-HT2C (Fig. 3). Of these, 5-HT1A and 5HT1B/D receptors are located pre-synaptically and mediated
negative feedback of 5-HT on its synaptic release (Barnes &
Sharp, 1999). Activation of the 5-HT1A receptor has a proejaculatory effect, however, activation of the 5-HT1B and 5-HT2C
receptors delays ejaculation (Hellstrom, 2009). Stimulation of
the 5-HT2C receptor with 5-HT2C agonists results in a delay of
ejaculation in male rats, whereas stimulation of post-synaptic 5HT1A receptors results in shortening of ejaculation latency (Ahlenius et al., 1981). Thus, it has been hypothesized that men with
PE may have decreased sensitivity of 5-HT2C receptors and/or
hypersensitivity of the 5-HT1A receptor (Fig. 3; Waldinger, 2002;
Waldinger & Olivier, 2005). Theoretically, strategies to enhance
serotonergic neurotransmission include blocking 5-HT reuptake, stimulation of 5-HT release, enhancement of 5-HT synthesis, use of 5-HT agonists to stimulate inhibitory receptors
(e.g., 5-HT2C), or use of antagonists of stimulatory receptors
(e.g., 5-HT1A).
Activation of 5-HT2C receptors adjusts the ejaculatory set
point and delays ejaculation. However, the extent of delay
depends on several factors including the type, dose, and frequency of the SSRI administration as well as the genetically
determined ejaculatory threshold set point (Sadeghi-Nejad &
Watson, 2008). To prevent overstimulation of post-synaptic 5HT receptors, 5-HT transporters (5-HTT) rapidly remove 5-HT
from the synapse back into the pre-synaptic neuron (Giuliano &
Clement, 2006).
428
Andrology, 2015, 3, 424442
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
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
lacking, subjective PE has also been defined as premature-like

EjD (Waldinger, 2007b, 2008a; Waldinger & Schweitzer, 2008).
NEUROTRANSMITTER SYSTEMS IN EJACULATION

The ejaculatory reflex is neurochemically regulated. Several
neurotransmitter systems have been implicated in this process.
The central serotonin and dopamine-containing neurons play a
primary role through their neurotransmitters. Dopamine
enhances seminal emission/ejaculation via D2 receptors,
whereas serotonin acts as an inhibitor via 5HT1B and 2C receptors (Fig. 3). Other neuromediators including acetylcholine,
adrenaline, neuropeptides, oxytocin, gamma-aminobutyric acid
(GABA), and nitric oxide (NO) have a secondary role (Giuliano &
Clement, 2005; Peeters & Giuliano, 2008). All these transmitters
act together to form a balance between excitatory and inhibitory
neurotransmission. The imbalance caused by disrupting any of
these systems can promote either PE or retarded ejaculation.
Serotonin (5-HT)
Serotonin appears to be a key mediator that control ejaculation (Waldinger, 2002, 2007b; Janssen et al., 2009). Both human
and animal studies showed that serotonin plays an important
role in sexual and particularly ejaculatory activity (Pattij et al.,
2005; Waldinger, 2005; de Jong et al., 2006; Olivier et al., 2006;
Chan et al., 2011). In some cases, a biologic variation in the IELT
in men may be because of different regulation of the serotonergic receptor subtypes and/or to other genetic factors.
The central serotonergic system modulates ejaculation in animal and human. Serotonin modulation of ejaculation is an
important area for genetic research. The ejaculatory reflex is not
under the direct control of the serotonergic system, whereas
other neurotransmitter systems in the spinal cord can influence
this response. The serotonergic modulation of the IELT is variable among men and may even be absent. This means that serotonergic genetic polymorphisms may only be found in men with
PE who respond with a delay in ejaculation upon treatment with
an SSRI. In addition, the persistently short IELTs in men with
lifelong PE are associated with diminished serotonin
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.
Andrology, 2015, 3, 424442
427
neurotransmission, decreased function of 5-HT1A receptors,

and/or a hypofunction of 5-HT2C receptors (Waldinger et al.,
1998a).
Serotonergic fibers in brain and spinal areas
Serotonergic fibers have been found in all spinal cord areas
containing sensory axons and motor neurons involved in ejaculation. These are distributed to the dorsal and ventral horns, dorsal commissural gray and thoracolumbar intermediolateral cell
column, and sacral parasympathetic nucleus of the lumbosacral
spinal cord (Maxwell et al., 1996). In addition, serotonergic postsynaptic receptors have been found in the area where LSt cells
are located (Marson & McKenna, 1992).
In the nucleus paragigantocellularis, an area in the ventrolateral medulla of the brainstem, serotonergic neurons are
found to innervate the bulbospongiosus muscles involved in
the inhibition of ejaculation (Marson & McKenna, 1992). Medial preoptic area (MPOA) might lower the ejaculatory threshold by removing the tonic serotonergic inhibition exerted by
the paragigantocellularis (Murphy & Hoffman, 2001). Lesions
of the anterior lateral hypothalamic area in male rats strongly
affect the occurrence of ejaculations, showing the excitatory
role of this brain region in the regulation of ejaculation (Kippin et al., 2004). The injections of SSRIs into the lateral hypothalamic area have been demonstrated to increase ejaculation
latency (Coolen et al., 2004; Giuliano & Clement, 2006; Giuliano, 2007; Waldinger, 2007b).
Serotonin receptors
Multiple serotonin receptors have been characterized, for
example, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, etc. (Peroutka &
Snyder, 1979). At least three-serotonin receptor subtypes have
been identified as having a role in ejaculation, these include 5HT1A, 5-HT1B, and 5-HT2C (Fig. 3). Of these, 5-HT1A and 5HT1B/D receptors are located pre-synaptically and mediated
negative feedback of 5-HT on its synaptic release (Barnes &
Sharp, 1999). Activation of the 5-HT1A receptor has a proejaculatory effect, however, activation of the 5-HT1B and 5-HT2C
receptors delays ejaculation (Hellstrom, 2009). Stimulation of
the 5-HT2C receptor with 5-HT2C agonists results in a delay of
ejaculation in male rats, whereas stimulation of post-synaptic 5HT1A receptors results in shortening of ejaculation latency (Ahlenius et al., 1981). Thus, it has been hypothesized that men with
PE may have decreased sensitivity of 5-HT2C receptors and/or
hypersensitivity of the 5-HT1A receptor (Fig. 3; Waldinger, 2002;
Waldinger & Olivier, 2005). Theoretically, strategies to enhance
serotonergic neurotransmission include blocking 5-HT reuptake, stimulation of 5-HT release, enhancement of 5-HT synthesis, use of 5-HT agonists to stimulate inhibitory receptors
(e.g., 5-HT2C), or use of antagonists of stimulatory receptors
(e.g., 5-HT1A).
Activation of 5-HT2C receptors adjusts the ejaculatory set
point and delays ejaculation. However, the extent of delay
depends on several factors including the type, dose, and frequency of the SSRI administration as well as the genetically
determined ejaculatory threshold set point (Sadeghi-Nejad &
Watson, 2008). To prevent overstimulation of post-synaptic 5HT receptors, 5-HT transporters (5-HTT) rapidly remove 5-HT
from the synapse back into the pre-synaptic neuron (Giuliano &
Clement, 2006).
428
Andrology, 2015, 3, 424442
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
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
ANDROLOGY
plays a role as one of the main mechanisms controlling the

effects of oxytocin (Veening et al., 2014). In a recent study, oxytocin had moderate role in the pro-ejaculatory effect of the 5HT1A receptor agonist 8-OH-DPAT (de Jong & Neumann, 2014).
Thus, if oxytocin receptors in the brain and at the spinal site are
to be reasonable targets for PE drugs then several obstacles have
to be overcome. The oxytocin receptor antagonists require further investigations for PE treatment.
THE ENDOCRINE SYSTEM IN EJACULATION

The endocrine system is involved in the control of ejaculatory
function in the brain as well as in peripheral organs. However,
all aspects of male reproduction are hormonally regulated,
whereas the endocrine control of the ejaculatory reflex is still not
fully understood. Sex steroids, thyroid, and pituitary hormones
control ejaculation at different levels. Some of these hormones
such as testosterone, prolactin, and thyroid-stimulating hormone play some independent role (Corona et al., 2011).
Androgens
Androgens profoundly affect ejaculatory reflex by acting on
several areas within the central and peripheral nervous system
as well as on the end organs of male reproductive system. Testosterone can also positively affect the emission phase of the
ejaculatory reflex. Androgen receptors are expressed in the
MPOA, the bed nucleus of the stria terminalis, the median amygdalae and the posterior thalamus, all regions deeply involved in
the supraspinal control of ejaculation (Swaab, 2007). Previous
findings (Corona et al., 2008) showed that low testosterone levels
and the presence of hypogonadal symptoms are associated with
an overall lower propensity to ejaculate (Cohen, 1997). However,
testosterone or dihydrotestosterone injections completely
restored the ejaculatory response, and ejaculate volume in orchidectomized (or hypogonadal) cynomolgus monkeys (Weinbauer
et al., 1990).
Crucial nuclei controlling ejaculation at the spinal cord level,
such as the spinal nucleus of the bulbocavernosus, are androgendependent. Interestingly, bulbocavernous muscle, like other muscles (ischiocavernosus and levator ani) of the pelvic floor involved
in the ejaculation, is specifically androgen-dependent. In fact,
hypertrophic action on the levator ani is a strong predictor of
effective anabolic androgen responses (Kicman, 2008).
Thyroid and prolactin hormone
A majority of the patients with thyroid hormone disorders
experience sexual dysfunction. Hyperthyroidism affects both the
emission and expulsion phases of ejaculation. Effects of hyperthyroidism on ejaculation pathways probably take place mainly
in the supraspinal centers above T8 level. Elevated thyroid hormone level triggers shortened ejaculation latency time in male
rats (Cahangirov et al., 2011). Spinal transection of the rats
resolves the effects of thyroid hormone on ejaculation parameters (Cahangirov et al., 2011). The relationship between hyperthyroidism and shortened ejaculatory latency time in a recent
preliminary experimental study was observed in a para-chloroamphetamine (PCA) induced ejaculation in the rat model (Cihan
et al., 2009). In multicenter, prospective study by Carani et al.
(2005) evaluated the prevalence of PE in male patients with
hyperthyroidism. The 50% prevalence of PE in men with hyperthyroidism fell to 15% after thyroid hormone normalization
Andrology, 2015, 3, 424442
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).
CURRENT TREATMENT PROTOCOLS OF PE

Currently, available treatment options for PE include oral
pharmacotherapy and topical anesthetics. Oral pharmacotherapy includes SSRIs, phosphodiesterase (PDE)-5 inhibitors, antipsychotics, tricyclic antidepressants, and a1-adrenoreceptor
antagonists (Table 1). In addition, local anesthetic treatment is
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Andrology, 2015, 3, 424442
used to relieve the symptoms of this disease. Obviously, when a

cause of acquired PE is identified (e.g., hyperthyroidism; Carani
et al., 2005), the associated anxiety/depression and sexual symptom might be cured by therapy (Carani et al., 2005; Table 1).
Oral pharmacology
Selective serotonin reuptake inhibitors
Multiple well-controlled evidence-based meta analysis of
studies have demonstrated the efficacy and safety of SSRIs in
delaying ejaculation, thus confirming their role as first-line
agents for the treatment of lifelong and acquired PE (Waldinger
et al., 2004a; McMahon et al., 2011). All SSRIs do not delay ejaculation to the same extent, and the ejaculation-delaying effects
seem associated with differential adaptive changes of 5-HT
receptors.
Currently five SSRIs are commonly used in the treatment of
PE, dapoxetine (Priligy Johnson & Johnson, New Brunswick, NJ,
USA), fluoxetine (Prozac; Eli Lilly, Indianapolis, IN, USA), paroxetine (Paxil; GlaxoSmithKline PLC, Philadelphia, PA, USA),
sertraline (Zoloft; Pfizer, New York City, NY, USA), citalopram
(Celexa; Forest Laboratories, New York City, NY, USA) and escitalopram (LexaproForest Laboratories, New York City, NY, USA;
Table 1). One of the disadvantages of the traditional SSRIs is that
they require multiple dosing before becoming effective (Waldinger, 2007a). This has led to the search for other compounds
with on demand treatment of PE.
Since the half-life of currently used SSRIs is long, there has
been keen interest in developing a short acting, efficacious SSRI
that can be used on-demand for PE (McMahon et al., 2011;
McMahon, 2012). Chronic administration of SSRIs prolong IELT,
but acute administration is associated with a mild increase in
the 5-HT release at the nerve terminal. SSRI use should not be
stopped suddenly but reduced gradually over several weeks
(Sadeghi-Nejad & Watson, 2008). This is more common with the
SSRIs that have shorter half-lives (Hellstrom, 2009). Clinically it
is well-known that a subgroup of men with lifelong PE do not
respond to SSRI treatment with ejaculation delay. In these men,
the serotonergic system is unable to modulate the ejaculation
reflex. In fact 5-HT1A receptor antagonists in the pre-clinical
trial have been shown to delay ejaculation when used concomitantly and acutely with an SSRI, but were not effective in delaying ejaculation when used alone (Ahlenius & Larsson, 1999; de
Jong et al., 2005). This combination therapy is very promising
and further studies are required before conclusions can be
drawn regarding their use.
Selective serotonin reuptake inhibitor-related adverse events
include fatigue, yawning, nausea, diarrhea, perspiration, ED,
reduced libido, and absent ejaculation (Hellstrom, 2009; McMahon et al., 2011). The other non-sexual side effects of SSRIs
include insomnia, constipation, and loss of appetite. The incidence rate of suicide/suicidal ideation in the overall SSRI population, and the percentage of PE patients experiencing suicidal
ideation with SSRI use are still unknown. In the previous study
by Hammad et al. (2006) the relationship between antidepressant drugs and suicidality in pediatric patients participating in
randomized, placebo-controlled trials has been demonstrated.
In the meta-analysis overall suicidality risk was conducted individually for SSRIs in depression trials as a group and for all
evaluable trials combined. There was no completed suicidal
ANDROLOGY

Table 1 Currently available treatment options for PE.
Oral pharmacotherapy
Opioid analgesic
Drugs
Mechanism of action
Efficacy on PE
Dosage
Citation
Tramadol
Stimulating the l-opioid

receptor and inhibiting
NA and 5-HT re-uptake
Inhibits the reuptake of
NA and 5-HT
A highly significant increase

in the mean IELT
(vs. baseline data)
Increase the IELT fourfold
(comparison of baseline
patient characteristics)
Significant increase in IELT
(vs. placebo)
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
Highest selectivity for the

human 5-HT transporter
Sertraline
Sildenafil
Vardenafil
Tadalafil
A modest increase in the

median IELT (compared
with baseline data)
Increase in geometric mean
IELT (vs. placebo)
Modest efficacy, on-demand
administration (vs. placebo)
Improved ejaculatory control
occurring within 1 2 weeks
and increased frequency of
intercourse (vs. placebo)
A significant increase in PE
parameters (IELT, PE grade,
ISS of patients and their sexual
partners, and the frequency of
intercourse) and augmenting
the total duration of erection;
and lessening the central
sympathetic output
Improvement in IELT (vs. placebo);
post-ejaculatory refractory time
and variations of scores at the
Index of PE questionnaire.
An increase in IELT (vs. placebo)
Moderate effect, missing data
Escitalopram
PDE5-inhibitors
a1-Adrenoreceptor antagonists Alfuzosin

and terazosin
Silodosin
Topical treatments
Short acting, highly potent

inhibitor of the 5-HT
reuptake transporter
Sodium
sulfacetamide
(SS) cream
Lignocaine spray
25, 50, 100 or

200 mg
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)
Significant lengthening of the

medium IELT (vs. pre-treatment
condition)
Local anesthetic-a mixture
The mean ejaculatory latency
of nine traditional medicines was prolonged (vs. placebo)
48 mg
Tian
et al. (2004)
9.6%
Linton &
Wylie (2010)
Dinsmore
et al. (2007)
LidocainePrilocaine Most used agent

cream and spray
Dyclonine and
alprostadil
combination
520 mg/day
Increase in IELT (baseline IELTs

were not stated)
2.4-fold increase in baseline IELT,
improvement in ejaculatory
control (vs. placebo)
Mean IELTs after dosing were
increased (baseline IELTs were
not stated)
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
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
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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.
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
ANDROLOGY
vibratory stimulation (ELT), but the difference from placebo was

significant with vardenafil (P < 0.001).
Tadalafil: A controlled study involving effect of tadalafil
(20 mg) alone and in combination with fluoxetine (90 mg) in life
long-PE patients showed that the increase in IELT was greater in
patients who received combined treatment with fluoxetine taken
once a week and tadalafil taken before sexual relations when
compared with placebo, fluoxetine, or tadalafil alone (Mattos
et al., 2008).
Tramadol
The oral opioid analgesic tramadol (Ultram; Johnson & Johnson) has been successfully used as a treatment for PE. This centrally acting analgesic has two mechanisms of action (i) by
stimulating the l-opioid receptor and (ii) inhibiting noradrenaline and serotonin reuptake thus delaying ejaculation (Salem
et al., 2008). On-demand use of low-dose tramadol is effective
for lifelong PE with minimal short-term adverse effects. However, the maximum study duration was 18 weeks with limited
follow up, and there are no data regarding long-term safety,
potential for abuse, and drug dependence with the long-term
use. Tramadol hydrochloride therapy promises a high success
rate in the treatment of PE especially at low dosages (25 and
50 mg). However, more follow-up studies and long-term placebo-controlled studies is needed to define successful therapy
and potential side effects (Kaynar et al., 2012; Eassa & El-Shazly,
2013).
Clomipramine
The tricyclic antidepressant, clomipramine (Anafranil) inhibits
the reuptake of noradrenaline, and serotonin. It is commonly
used in the treatment of obsessive-compulsive disorders. Several
studies showed that continuous and on-demand dosing have
success in increasing IELT (Waldinger et al., 2004a; Abdollahian
et al., 2006; Mirone et al., 2014). The use of clomipramine is limited by its associated side effects, mainly fatigue, dizziness, dry
mouth, and hypotension. During continuous dosing, the adverse
event profile of clomipramine in men with PE was reported to be
worse than with SSRI treatment (Mohee & Eardley, 2011). On
demand clomipramine with 25 mg dose has been shown to
increase the IELT fourfold with a low side effects and led to a
clinical relevant ejaculation delay (Waldinger et al., 2004a).
Alpha1-adrenoreceptor antagonists
Ejaculation is a sympathetic spinal cord reflex and could theoretically be delayed by a1-adrenergic blockers. Therefore, these
agents have been considered for the treatment of PE (Cavallini,
1995; Basar et al., 2005). Two studies investigated the usefulness
of the a-1 adrenoreceptor antagonists terazosin and alfuzosin in
PE patients (Cavallini, 1995; Basar et al., 2005). Although success
rates up to 50% in delay of the ejaculation and partner satisfaction were reported, well-established efficacy parameters such as
IELT or validated PE questionnaires were not used in these studies, thus reducing the broader interpretation of these data (Cavallini, 1995; Basar et al., 2005). Both these studies were limited
by the use of non-validated endpoints of patient impression of
change in ejaculation interval and sexual satisfaction (McMahon
& Porst, 2011).
Silodosin, a highly selective a1A-adrenoceptor antagonist has
been shown to be effective for lower urinary tract symptoms
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ANDROLOGY
(LUTS) when evaluated as a new treatment option for PE (Sato

et al., 2012). Silodosin has been suggested as a novel therapy for
PE but needs validation in controlled clinical trials (Sato et al.,
2012).
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
Andrology, 2015, 3, 424442
of lignocaine and prilocaine in a metered-dose aerosol delivery

system (Mohee & Eardley, 2011). Each spray delivers 7.5 mg of
lidocaine and 2.5 mg of prilocaine. It is fast acting and appears
to be efficacious in small studies. It does not penetrate keratinized epithelium, and only anesthetizes the glans; however,
there still appears to be some hypoesthesia associated with its
use (Dinsmore et al., 2007). TEMPE produced a 2.4-fold increase
in baseline IELT and significant (P < 0.01) improvement in ejaculatory control resulting in both patient and partner sexual satisfaction (Dinsmore et al., 2007). However, some female partners
reported a burning sensation during intercourse (Dinsmore
et al., 2007; Dinsmore & Wyllie, 2009).
Dyclonine and alprostadil combination
Dyclonine is a local anesthetic usually used in dentistry. It has
been combined with the vasodilator alprostadil for treating PE.
The product is applied to the tip of the penis in the region of the
meatus and has shown positive results (Padma-Nathan & Yeager, 2006). However, the data are limited and further studies are
warranted before any useful conclusions regarding this potential
combination can be made.
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
high prevalence of prostatic inflammation/infections in PE, as

well as for a higher than normal prevalence of PE in patients
with CP (Screponi et al., 2001). Recently, the association
between intravaginal ejaculatory latency time (IELT) and
National Institutes of Health-CP Symptom Index (NIH-CPSI) in
men with different PE syndromes were assessed (Gao et al.,
2014). Men with PE displayed worse NIH-CPSI scores than men
without complaints of PE. Relationships between IELT and NIHCPSI scores were high in men with acquired PE (Gao et al.,
2014). Finally, considering the role of prostatic diseases in the
pathogenesis of PE, the prevention procedure should be based
on both sexual and andrological education of young and adult
males. The mechanism linking CP and PE remains unknown,
and there are some methodological limitations of the existing
data.
Chronic prostatitis and PE
Twenty-six to 77% of men with CP or CPPS report early ejaculation (Liang et al., 2004; Trinchieri et al., 2007). Prostatic
inflammation and chronic bacterial prostatitis have been
reported as common findings in men with PE (Screponi et al.,
2001; Shamloul & el-Nashaar, 2006). Considering the role of the
prostate in the ejaculatory mechanism, a direct influence of the
local inflammation in the pathogenesis of a few cases of
acquired PE seems possible (Lotti et al., 2009). While physical
and microbiological examination of the expressed prostatic
secretion in men with painful ejaculation or CP/CPPS is recommended, there is insufficient evidence to support routine screening of men with PE for this condition.
THE ROLE OF COUPLE AND THAT OF PARTNERS CONSEQUENCES
PE leads to personal and interpersonal distress to the man, his
partner, and the couple. The couple usually starts with simple
vaginal containment, without pelvic thrusting. As the feeling of
control increases, thrusting can begin, enabling the man to recognize the clues preceding his point of ejaculatory inevitability.
Because the squeeze technique carries some risk of discomfort,
many sex therapists prefer the stopstart method.
Sexological therapy of PE starts from the approach that it is
the couple, not the individual, which is dysfunctional. Therapeutic success in PE therapy is often unpredictable (Hawton & Catalan, 1986), being more frequent in highly motivated couples with
a good relationship (Kilmann et al., 1987). There are many reasons for therapy failure.
Female sexual dysfunction was diagnosed in 78% of women
who has a male partner with PE compared to only 40% of female
partner of healthy men (Kaya et al., 2014). Recent survey showed
the detrimental effects of PE on relationship and sexual dissatisfaction in the female partner, the factors impacting on intimacy,
and how it can lead to the termination of the relationship (Burri
et al., 2014). The medical sexologists aim is to identify the specific role of each factor and to start etiological and symptomatic
counseling and therapies in a holistic and eclectic way, taking
into account the potency of the drugs and the couples
dynamics.
Most notably, an important source of female distress are not
only parameters related to performance such as control or duration but rather inappropriate attention focus and the negligence
of other forms of sexual activities (Burri et al., 2014). Lack of sexual privacy was associated with EjDs and with the inability to
ANDROLOGY
maintain an erection during intercourse (Boddi et al., 2014). In

the interests of the couple, this complex therapeutic process
should be performed by a sex therapist in harmony with behavioral approaches.
In recent data, Limoncin et al. (2013) measured PE related
female sexual distress using a new diagnostic tool, the Female
Sexual Distress ScaleRevisedPE (FSDSRPE) questionnaire.
This was mostly filled with psychometric needs for sexual distress in the partners sexual dysfunction. When all subjects completed the FSDSRPE, it was observed that the female partners
practiced considerably higher sexual distress than controls. After
adjusting for confounders such as age, relationship duration,
and educational level, there was a significant association
between female sexual distress and a male partner with PE.
Interestingly, women with a partner who had PE were more
likely than controls to experience significant sexual distress
(P = 7.129.83 times greater according to the regression model).
Further interesting evidence is that the perception of sexual distress did not differ across age groups and was not influenced by
relationship duration or educational level. In addition, Rosen &
Althof (2008) proposed that factors other than PE may increase
susceptible to sexual distress in women who have a partner with
PE (Rosen & Althof, 2008).
In very recent clinical study, the cross-cultural differences in
womens perception of PE in a total of 1463 sexually active
women from three different countries-Mexico, South Korea, and
Italy was reported (Burri & Graziottin, 2015). A significant differences in the degree of distress caused by PE were detected
between the three countries. Lack of control was most common
reason for distress for women in Mexico and South Korea,
whereas short latency was reported for women in Italy. Mexico
reported the highest rates of previous relationship breakups
owing to PE (28.9%), whereas Italian women reported the lowest
relationship satisfaction and South Korean women the highest.
This data suggest that better understanding of sexual issues and
distressing mainly owing to PE which are important in different
cultures. Therefore, the likelihood of success for any such treatment requires couples sexual perspective and should be carefully considered.
NOVEL CONCEPTS
Role of dopamine
Recent study identified the problem of PE as the most frequent
complaint (51.4%) in Parkinsons disease especially young
patients (Jitkritsadakul et al., 2015). The known pharmacologies
of the implicated dopamine agonists suggest a possible substrate
for the pathological hypersexuality leading to PE. Perhaps, excessive stimulation of the D2 and D3 mediates this disorder. In such
patients the treatment of PE should perhaps start with reduction
or tapering of the dopamine agonist. Also targeting brain D3
receptors may provide a therapeutic approach for treating ejaculatory disorders in humans. A selective dopamine D3 receptor
antagonist (SB-277011) delayed ejaculation in such men by specifically inhibiting the expulsion phase without impairing either
emission or erection (Clement et al., 2009). Thus, targeting
dopamine D3 receptors would be an interesting therapeutic
approach in PE treatment.
Dopamine seems to have a role in facilitating sexual arousal
and in lowering the ejaculatory threshold suggesting that
Andrology, 2015, 3, 424442
435
ANDROLOGY
dopamine antagonists may have an inhibitory function (Greco

et al., 2002). However, the selective role of these receptors in the
control of ejaculatory functions needs further study, and it will
be interesting to develop newer more potent and selective agonist and antagonists that will target PE (Clement et al., 2009).
Role of Rho-kinase
Amobi et al. (2006) showed that Ca2+-sensitization mediated
by Rho kinase is involved in agonist- or depolarization of rat epididymal and vas deferens. Also Rho kinase inhibitors (Y-27632
and HA 1077) attenuate their contractility (Amobi et al., 2006).
Such drugs would have a future in the treatment of this disorder.
Role of purinergic receptors
Purinergic receptors are among potential novel targets for PE,
as they control vas deferens and prostate smooth muscle excitability. In afferent nerve functions, contraction of the vas deferens to sympathetic nerve stimulation is reduced by up to 60%
and responses to P2X receptor agonists are abolished (Mulryan
et al., 2000). P2X1-purinoceptor provides a safe and effective
therapeutic target (White et al., 2013). In our previous study, we
suggested that purinergic P2Y agonists and their pharmacologic
response in PE patients may serve useful purpose (Gur et al.,
2007). ATP is a critical determinant of mechanosensation and 5HT release via autocrine activation of slow P2Y1-phospholipase
C/inositol-1,4,5-triphosphate-Ca or inhibitory P2Y12-purinergic
pathways, and fast ATP-gated P2X3-channels. Ulcertive colitisinduced downregulation of P2X3-channels (or A2B) may be
mediated by impaired 5-HT signaling (Linan-Rico et al., 2013).
Role of relaxin
Relaxin is a 6 kDa peptide with a structure similar to insulin
and has a wide spectrum of actions (Sherwood et al., 1986;
Dschietzig et al., 2006). Increasing evidence shows that relaxin
immunoreactivity is also present in the seminal vesicles and in
the ampular region of the vas deferens (Yki-Jarvinen et al., 1983).
Locally produced relaxin acts as an autocrine or paracrine agent
in the testis and vas deferens. Thus, relaxin may be playing an
important role in ejaculating function and male reproduction
and should be the target of newer drugs for PE issues.
Role of mirabegron, a novel b3-AR agonist
Mirabegron is a novel b3-AR agonist for the treatment of
overactive bladder with symptoms of urge urinary incontinence
(Takasu et al., 2007). There is no study concerning b3-AR mechanisms and treatment of PE with mirabegron.
Role of protein tyrosine kinase inhibitors
We recently demonstrated that imatinib caused human corpus
cavernosum smooth muscle relaxation in vitro that is mediated
by NO/guanosine monophosphate signaling. In addition, it
involves the large-conductance Ca(2+)-activated K(+)-channels
[BK(Ca)] and inhibit the upregulated protein tyrosine kinase
pathway (Gur et al., 2013). Also imatinib has significant erectile
and systemic vasodilator activity in the rat that is not dependent
on NO release (Pankey et al., 2013). Imatinib induces prostatic
smooth muscle relaxation in vitro (Ozgur-Akdemir et al., 2011).
Considering all this imatinib may benefit PE patients. Future
studies are needed for better understanding of its role in PE
treatment.
436
Andrology, 2015, 3, 424442
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
anesthetic agents. Recently there has been movement away from

IELT to just ELT in the interest of eliminating the heterosexual
bias. Ongoing research will help in better understanding of the
pathophysiology as well as in new efficacious and safe treatments of this most common sexual problem in men affecting
their partners as well.
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.
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ANDROLOGY

The characterization, current

S. Gur and 2S. C. Sikka

Department of Pharmacology, School of Pharmacy, Ankara University, Ankara, Turkey, and

Premature ejaculation (PE) is the most prevalent male sexual

The prevalence rates of PE is 2030% (Waldinger, 2007b) and

Andrology, 2015, 3, 424442

2015 American Society of Andrology and European Academy of Andrology

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

sympathetic, parasympathetic, and motor outflow for the two

2015 American Society of Andrology and European Academy of Andrology

Andrology, 2015, 3, 424442

S. Gur and S. C. Sikka

neurotransmission, decreased function of 5-HT1A receptors,

Andrology, 2015, 3, 424442

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

lacking, subjective PE has also been defined as premature-like

NEUROTRANSMITTER SYSTEMS IN EJACULATION

2015 American Society of Andrology and European Academy of Andrology

Andrology, 2015, 3, 424442

S. Gur and S. C. Sikka

neurotransmission, decreased function of 5-HT1A receptors,

Andrology, 2015, 3, 424442

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

plays a role as one of the main mechanisms controlling the

THE ENDOCRINE SYSTEM IN EJACULATION

S. Gur and S. C. Sikka

CURRENT TREATMENT PROTOCOLS OF PE

Andrology, 2015, 3, 424442

used to relieve the symptoms of this disease. Obviously, when a

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

Stimulating the l-opioid

A highly significant increase

Highest selectivity for the

A modest increase in the

Moderate effect, missing data

a1-Adrenoreceptor antagonists Alfuzosin

Short acting, highly potent

25, 50, 100 or

Significant lengthening of the

LidocainePrilocaine Most used agent

Increase in IELT (baseline IELTs

S. Gur and S. C. Sikka

Andrology, 2015, 3, 424442

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

vibratory stimulation (ELT), but the difference from placebo was

S. Gur and S. C. Sikka

(LUTS) when evaluated as a new treatment option for PE (Sato

Andrology, 2015, 3, 424442

of lignocaine and prilocaine in a metered-dose aerosol delivery

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

high prevalence of prostatic inflammation/infections in PE, as

maintain an erection during intercourse (Boddi et al., 2014). In

S. Gur and S. C. Sikka

dopamine antagonists may have an inhibitory function (Greco

Andrology, 2015, 3, 424442

2015 American Society of Andrology and European Academy of Andrology

PREMATURE EJACULATION PATHOPHYSIOLOGY AND POTENTIAL TREATMENT MODALITIES

anesthetic agents. Recently there has been movement away from

Barnes NM & Sharp T. (1999) A review of central 5-HT receptors and

Andrology, 2015, 3, 424442

S. Gur and S. C. Sikka