Premature ejaculation - Keur der Wetenschap

Behavioural Brain Research 92 (1998) 111–118
Premature ejaculation and serotonergic antidepressants-induced delayed
ejaculation: the involvement of the serotonergic system
Marcel D. Waldinger a,d, *, Hemmie H.G. Berendsen b , Bertil F.M. Blok c , Berend Olivier d ,
Gert Holstege c
a Department of Psychiatry and Neurosexology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, Netherlands
b Department of Neuropharmacology, N.V. Organon, Oss, Netherlands
c Department of Anatomy and Embryology, Faculty of Medicine, Uniersity of Groningen, Groningen, Netherlands
d Department of Psychopharmacology, Rudolf Magnus Institute for Neurosciences, Faculty of Pharmacy, Utrecht Uniersity, Utrecht, Netherlands
Abstract
Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly
treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the
serotonergic antidepressants (SSRIs) in delaying ejaculation. We describe here the neurophysiology and the peripheral neuroanatomy
of ejaculation and provide a review of the involvement of serotonin in the central nervous system in relation to
serotonergic nuclei and their projections. A hypothesis of the role of 5-HT 1A and 5-HT 2C receptors in premature ejaculation is
postulated. © 1998 Elsevier Science B.V. All rights reserved.
Keywords: Premature ejaculation; Serotonergic antidepressants; Sexual dysfunction
1. Introduction
Premature ejaculation is defined as a persistent or
recurrent ejaculation with minimal sexual stimulation
before, on or shortly after penetration and before the
person wishes it [4]. Generally, premature ejaculation
was and still is considered a psychosexual disturbance
[1,41]. This led to the idea that the main option for
treating premature ejaculation were behavioural therapies
such as the stop-start technique [44], the squeeze
technique [33] and other psychotherapeutic interventions
[47]. However, in two longitudinal studies [17,27]
it was shown that the initial positive effects of behavioural
techniques disappear after 3 years.
Pharmacotherapy was also used to delay the ejaculation
time. Initially, local anesthetic ointments were recommended
[5,16,13], but later case reports and open
trials described the beneficial effects of monoamine-oxi-
* Corresponding author. Tel.: +31 70 3592086; fax: +31 70
3295046.
0166-4328/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.
PII S0166-4328(97)00183-6
dase inhibitors [6], clomipramine [24,23,43,3,26] and
benzodiazepines [42]. However, the use of pharmacotherapy
was considered as ‘only’ suppressive for the
disorder. The ‘real’ etiology was still thought to be
psychogenic, which is probably one of the reasons that
a neurobiological view regarding aetiology and pathogenesis
is still lacking.
The beneficial effects of the recently introduced selective
serotonergic re-uptake inhibitor antidepressants
(SSRIs), such as fluoxetine [15,55], paroxetine
[55,52,54], and sertraline [34,55] for treating premature
ejaculation, clearly indicates that the classical psychological
view of premature ejaculation is no longer tenable
as the only pathogenetic theory. Possibly,
serotonin plays a role in the ejaculation process. It
might as well be that genetic factors play a role in the
etiology of premature ejaculation [56].
This paper first describes the peripheral nervous
pathways associated with the ejaculation process, then
reviews the SSRI-induced ejaculatory retardation and
describes some essential features of the serotonergic

112
system. Finally, it will be postulated which serotonin
receptor subtypes might be involved in premature
ejaculation.
2. Neurophysiology and peripheral neuroanatomy of
ejaculation
Ejaculation occurs in two stages [7]. In the first stage,
the emission phase, sympathetic impulses produce peristaltic
smooth muscle contractions of the epididymis
and vas deferens, moving sperm to the posterior (prostatic)
urethra. At the same time, the seminal vesicles
and prostate contract rhythmically, expelling seminal
and prostatic fluid to mix with sperm. Finally, all these
fluids mix with mucus already secreted by the bulbourethral
glands. The combination of these fluids is
known as semen [46]. The emission is subjectively experienced
as ejaculatory inevitability, because at this point
ejaculation cannot be stopped. It is immediately followed
by the second phase, the expulsion or ejaculation
proper, in which semen is expelled out of the urethra by
rhythmic contractions of pelvic floor muscles.
The (preganglionic) sympathetic nerves, involved in
the emission phase, originate from the intermediolateral
columns of the spinal thoracolumbar cord from T10 to
L2 [32] and travel via the sympathetic chain and hypogastric
nerve (postganglionic) to the pelvic plexus (inferior
hypogastric plexus) or via the sympathetic chain
and pelvic nerve (nervi erigentes) to the pelvic plexus
[18]. From the pelvic plexus the sympathetic nerves are
mediated via the cavernous nerve to the vase deferentia
[18].
During emission the sphincter urethrae internus muscle
(bladder neck) contracts by sympathetic influence,
preventing the semen to enter the bladder (retrograde
ejaculation). The second phase is initiated by pressure
on the wall of the ampullae urethrae by the semen,
giving rise to afferent impulses which reach the S2–S4
sacral cord segments via the pudendal and pelvic nerves
[40]. The expulsion is mediated by motoneurons in the
nucleus of Onuf, which, by way of the pudendal nerve
[45] produce co-ordinated contractions of the bulboand
ischiocavernosus muscles of the pelvic floor. How
the afferent impulses of the urethral wall are relayed to
the motoneurons of Onuf’s nucleus is not known.
The ejaculatory response is triggered by genital and
cortical stimulation. In genital stimulation the afferent
sensory impulses are mediated via touch receptors on
the glans penis, which are connected with sensory fibers
that travel in the dorsal penile and pudendal nerves and
enter the sacral spinal cord. How cortical activation,
such as visual and auditory impulses, reach the ejaculation
related systems is not known.
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118
3. Peripheral serotonin and the central nervous system
The first indication of the presence of serotonin dates
from more than 100 years ago, when a vasoconstrictive
agent in blood was accidentally discovered, which later
appeared to be present in serum. In the 1930s, an agent
(enteramine) was discovered in the gut [20], but it was
not clear whether this agent was the same as that found
in serum. By the end of the 1940s this endogenous
factor was identified. After purification it was called
‘serotonin’ because of its ‘serum tonic’ properties. In
1952, it became clear that serotonin or 5-hydroxytryptamine
(5-HT; [39]) and enteramine were identical
[19].
4. Peripheral serotonin
The majority of 5-HT is found in the enterochromaffin
cells in the gastrointestinal tract, where it accounts
for approximately 80% of total body 5-HT
content [14,21]. In the periphery 5-HT acts as a vasoconstrictor
and pro-aggregator when released from aggregating
platelets, as a neurotransmitter in the enteric
plexuses of the gut and as an autocrine hormone when
released from enterochromaffin cells from the gut, pancreas
and elsewhere [25,21]. Circulating 5-HT does not
enter the brain because it cannot cross the blood–brain
barrier.
5. Serotonin in the central nervous system
After the discovery that 5-HT occurred in the central
nervous system also [51], Woolley and Shaw [57] postulated
in 1954, a central role for 5-HT in psychiatric
disorders, in particular because the 5-HT agonist D-
LSD exerted such a potent psychomimetic action. Reserpine,
a drug given in serious hypertension, was
found to induce a depressive mood. As reserpine induces
an initial release of 5-HT from presynaptic terminals
followed by the ceasing of 5-HT release, a relation
was suggested between low 5-HT levels and depression.
Further research has led to the hypothesis that a deficit
in monoamines (including 5-HT) could lead to depression.
This theory has led to the development of the
selective serotonin re-uptake inhibitors (SSRIs) which
proved to be effective antidepressants. The serotonin
system in the brain was visualized using histochemical
techniques (Falck–Hillarp techniques) in the 1960s.
This relatively primitive localization method was
strongly improved by the development of antibodies
against 5-HT [48] and later still, by autoradiographic
techniques, which made it possible to reveal detailed
5-HT receptor locations.

M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118 113
Fig. 1. A schematic representation of a serotonergic neuron and a post-synaptic neuron. All known 5-HT receptors and their putative localization
are depicted (hypothetical).
In 1979, using radioligand binding technology, two
classes of 5-HT receptors in the CNS were shown [38].
This was the start of an era in which a continuous
stream of new 5-HT receptors has been detected.
Presently, at least sixteen different 5-HT receptors have
been found, cloned and the structure described (5-
HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 1D, 5-HT 1E, 5-HT 1F,
5-HT 2A, 5-HT 2B, 5-HT 2C, 5-HT 3, 5-HT 4, 5-HT 5A, 5-
HT 5B, 5-HT 6, 5-HT 7). A schematic representation of
these different 5-HT receptors and their putative locations
are depicted on a cartoon of a 5-HT presynaptic
neuron and a post-synaptic neuron (Fig. 1).
5.1. Serotonergic neurons
Serotonergic cell bodies are present in the brainstem
in the raphe nuclei and adjacent reticular formation
(Fig. 2). There is a clear dichotomy in the 5-HT system
neuronal cell groups. Firstly, a rostral part with cell
bodies in the midbrain and rostral pons projecting to
the forebrain. Secondly, a caudal part with cell bodies
predominantly in the medulla oblongata with important
projections to the spinal cord. Both parts also
project to areas in the brainstem and the cerebellum
[31].
5.2. Rostral and caudal serotonergic cell groups
The rostral part of the 5-HT system consists of the
caudal linear nucleus and the dorsal and median raphe
nuclei. The number of 5-HT cells in the dorsal raphe is
the largest among all raphe nuclei and contains approx-
imately 24 000 in the cat and 165 000 in man [50].
Besides the raphe nuclei, a number of 5-HT neurons are
present in the adjoining reticular formation of pons and
midbrain. The caudal system contains the nuclei raphe
magnus, pallidus and obscurus and some in the adjoining
medullary reticular formation, solitary nucleus and
the area of the nucleus (sub)coeruleus.
5.3. Projections of the serotonergic cell groups
5.3.1. Ascending projections
The ascending 5-HT system consists of two more or
less parallel projection pathways, presumably with different
functions [50].
The first system is called ‘Basket-axon’ system and
originates in the median raphe nucleus. It has thick
fibers (M-fibers) that branch into short, thin fibers and
form large, round boutons (varicosities) with extensive
synaptic contacts. These beaded axons often intensively
embranch certain cortical cells (baskets) and form classical
synaptic contacts.
The second system originates in the dorsal raphe
nucleus. It has thin fibers (D-fibers) with many spindlesized
varicosities. These fibers branch extensively and
diffusely and contain small fusiform boutons. However,
these boutons do not seem to contain real synaptic
structures.
Both systems (M- and D-fibers) can be found together
in most brain areas, but to a different extent.
The cerebral cortex is the area where both systems
co-exist extensively, whereas the striatum almost exclusively
receives fine varicose D-fibers and the gyrus

114
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118
Fig. 2. A longitudinal view of rat brain with a schematic representation of the localization of the serotonergic cell bodies in the raphe nuclei and
in the brain stem reticular formation and the corresponding classification into the B-groups and their projections. CB, cerebellum; mfb, medial
forebrain bundle, CC, corpus callosum; OB, olfactory bulb; Cpu, caudate putamen; OC, optic chiasma; GP, globus pallidus; OT, olfactory
tubercle; H, hypothalamus; Pit, pituitary gland; Hip, hippocampal region; Sc, superior colliculus; lc, locus coeruleus; SN, substantia nigra; LS,
lateral septal nucleus; T, thalamus; MM, medial mammilary nucleus; V, ventrikel. For the 5-HT cell cluster, the 5-HT cells in structure
(classification into the rostral (r) and caudal (c) serotonergic system according to Tork (1991) are as follows: B1, raphe pallidus nucleus (c), caudal
ventrolateral medulla (c); B2, raphe obscurus nucleus (c); B3, raphe magnus nucleus (c), rostral ventrolateral medulla (c), lateral paragigantocellular
reticular nucleus (c); B4, raphe obscurus, dorsolateral part (c); B5, median raphe nucleus, caudal part (r); B6, dorsal raphe nucleus, caudal
part (r); B7, dorsal raphe nucleus, rostral part (r); B8, Median raphe nucleus, rostral part (r); caudal linear nucleus (r); B7, nucleus pontis oralis
(r); B9, Nucleus pontis oralis (r); Supralemniscal region (r).
dentatus primarily thick M-fibers. The functional role
of these two 5-HT systems is rather unclear, although
they display a differential sensitivity for certain substituted
amphetamines like MDMA [37]. Such drugs destroy
the fine varicose system but leave the thick,
beaded system intact.
5.3.2. Descending projections
The caudal raphe nuclei project to the caudal brain
stem and spinal cord. The raphe magnus nucleus predominantly
projects to the dorsal horn and the nuclei
raphe pallidus and obscurus to the ventral horn, intermediate
zone and the intermediolateral cell column
(IML) of the thoracolumbar and sacral spinal cord.
The latter areas contain preganglionic sympathetic and
parasympathetic motoneurons, respectively.
5.3.3. Afferents of the caudal serotonergic raphe nuclei
The afferents of the caudal raphe nuclei originate
largely from medial structures in the so called limbic
system. The most important are the mesencephalic periaqueductal
grey and medial cell groups in hypothalamus
and pre-optic area [28].
5.3.4. Regulation
Serotonergic neurons have various mechanisms to
regulate their own activity, viz. somatodendritic autoreceptors
(5-HT 1A receptors), presynaptic autoreceptors
(5-HT 1B/1D receptors) and the 5-HT re-uptake process
(5-HT transporter).
5.3.4.1. Somatodendritic (5-HT 1A) autoreceptors. The
5-HT 1A autoreceptors are present in high densities on
the cell bodies and dendrites of serotonergic neurons in
the raphe nuclei (Fig. 3). Upon activation of these
receptors, the firing rate of the 5-HT neuron decreases.
Under normal physiological conditions endogenous 5-
HT activates this 5-HT 1A autoreceptor. It is as yet not
clear from where this endogenous 5-HT originates, but
it is assumed that it derives from somatodendritic release,
which differs from synaptic release. Application
of the selective 5-HT 1A receptor agonists (i.e. 8-OH-
DPAT or flesinoxan) either systemically or locally in
the raphe nuclei, inhibits the release of 5-HT in the
synaptic cleft.
5.3.4.2. 5-HT 1B/1D autoreceptors. This pre-synaptic receptor
inhibits, after activation, the 5-HT release into
the synaptic cleft. The 5-HT 1B/1D receptor is coupled to
an inhibitory (GI-protein) transaction mechanism that
apparently blocks the release of 5-HT from the synaptic
vesicles in an as yet not understood manner. This
feedback mechanism of the cell, where the released
5-HT inhibits its own release, is a frequently occurring
principle in neurotransmitter regulation and provides
the system with the possibility to prevent overstimulation
of (post)synaptic receptors.
5.3.4.3. 5-HT re-uptake. If 5-HT is released into the
synaptic cleft it should be removed again as fast as
possible to prevent overstimulation of the
(post)synaptic receptors (desensitization). The 5-HT
neuron, therefore, possesses large quantities of 5-HT
transporters (5-HTT), not only on the synaptic endings
but also on the cell bodies and dendrites of serotonergic
neurons. Apart from this 5-HT cell system, glial cells
have also a transport system which presumably contributes
to the remove of released 5-HT. After blockade
of the 5-HT transporters via selective serotonin re-uptake
inhibitors (SSRIs), the synaptic 5-HT increases,

M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118 115
Fig. 3. Schematic representation of acute and chronic activation SSRI administration and the effect on the 5-HT 1A autoreceptor.
although this process is counteracted by activation of
5-HT 1A autoreceptors, which are stimulated by enhanced
5-HT and inhibit the 5-HT release.
5.3.4.4. Acute and chronic administration of SSRIs. After
acute administration of an SSRI all 5-HT transporters
are blocked. This leads to high 5-HT levels in
the extracellular space around the 5-HT cell bodies in
the raphe nuclei, leading to activation of 5-HT 1A autoreceptors
and thus to a decrease in the firing frequency
of the cell and a decreased release of 5-HT in
the synaptic cleft. This decreased release is (completely
or partially) compensated by blockade of the
5-HT re-uptake in the synaptic cleft. The net effect in
the synaptic cleft is difficult to predict, both an increase
in or lack of effect have been observed. If a
post-synaptic increase occurs, activation of the presynaptic
5-HT 1B/1D autoreceptor will further dampen
the release process. In general, acute administration of
SSRIs will presumably lead to a mild increase of 5-
HT neurotransmission leading to some stimulation of
all post-synaptic 5-HT receptors.
After chronic administration a number of adaptive
processes may play a role, although much is still quite
speculative. Because the 5-HTTs are chronically
blocked, a chronically enhanced level of 5-HT is
present at somatodendritic level. This leads to desensitization
of the 5-HT 1A receptors and consequently to
lesser (or no) inhibition of the cell firing of the 5-HT
neuron, leading to higher 5-HT release. Simultaneously,
also the synaptic 5-HTTs are chronically
blocked which means, together with the enhanced re-
lease of 5-HT, to strongly enhanced synaptic levels of
5-HT. It is possible, although not fully elucidated yet,
that the 5-HT 1B/1D autoreceptors also desensitize,
which might contribute to the process of enhanced
5-HT neurotransmission. The net effect of chronic
SSRI administration is thus a strongly enhanced 5-HT
neurotransmission. Apparently, activation of one (or
more) of the post-synaptic 5-HT receptors, contributes
to the antidepressant and anxiolytic effects of the SS-
RIs.
6. Premature ejaculation and 5-HT
Some of the SSRIs appear effective in inhibiting the
premature ejaculation both after acute and chronic
administration [55,52,54,53] whereas their antidepressant
and anxiolytic effects only gradually emerge over
time. This remarkably rapid onset is not well understood.
It is suggested that acute blockade of 5-HT
re-uptake enhances 5-HT transmission into the
synapse. These acute synaptic effects occur within
hours of administering antidepressant SSRIs. Since
the rapid onset of postponement of ejaculation by
SSRIs has a similar time course as the synaptic effects
it is suggested that the postponement of ejaculation is
mediated by the acutely enhanced 5-HT neurotransmission.
Apart from their rapid onset of action, the question
remains why SSRIs, such as paroxetine [55,52,54],
fluoxetine [55], sertraline [34,55] and to a lesser extent
also fluvoxamine [55] delay ejaculation time. Human
ejaculation is peripherally activated by 1-noradrener-

116
gic nerve stimulation. Since paroxetine has no sympatholytic
effects, it is suggested that the effect of paroxetine
on the delay of ejaculation is on the central
nervous system.
The involvement of the central serotonergic neurotransmission
in human ejaculation has been investigated
in animal studies. Induction of penile erections
in rats and rhesus monkeys showed that responses
due to SSRI treatment are identical to those seen
after selective activation of 5-HT 2C receptors [49,8,12]
and are different from the responses seen after 5-
HT 1A and 5-HT 2A receptor stimulation [58,11,36,30].
Moreover, a cross familiarization study showed that
the drug stimuli of the SSRI’s fluoxetine and paroxetine
most resemble those of a 5-HT 2C-receptor agonist
[10]. Apparently, it seems that the responses from
SSRI treatment in these animals are due to 5-HT 2C
receptor activation [12,49]. Since paroxetine treatment
results in ejaculation retardation, it is suggested that
in humans premature ejaculation is caused by hyposensitivity
of 5-HT 2C receptors. Such a concept
would correspond with the results of rat studies in
which the 5-HT receptor agonists D-LSD (D-lysergic
acid diethylamide) and quipazine increase the ejaculation
latency [2]. Furthermore, DOI (2,5-dimethoxy-4iodophenyl-2-aminopropane)
which equally stimulates
5-HT 2A and 5-HT 2C receptors, also increases the ejaculation
latency [22], while the selective 5-HT 2A receptor
agonist DOM (2,5-dimethoxy-4-methylamphetamine)
does not have this effect [2].
In male rats also another 5-HT subtype receptor
seems to be involved in the ejaculation process. Activation
of 5-HT 1A receptors by the selective 5-HT 1A
receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-npropylaminotetralin)
shortens the ejaculation latency
time and reduces the number of intermissions preceding
ejaculation in animals [2]. The behavioral response
to activation of 5-HT 1A receptors is attenuated or
completely blocked by co-activation of 5-HT 2C receptors
indicating that functional interactions between
these receptors exists [9]. Extrapolating these findings
from animal research to human premature ejaculation
one might speculate that premature ejaculation may
be caused by the hypersensitive 5-HT 1A receptor.
Treatment of premature ejaculation by an SSRI will
then induce activation of the 5-HT 2C receptor and
consequently decrease the function of the 5-HT 1A receptor
or restore the balance between 5-HT 1A and
5-HT 2C receptor function, resulting in an overall delay
of ejaculation.
However, the identification of which specific 5-HT
receptor subtypes are involved in the human ejaculation
process is only possible by administration of subtype
selective 5-HT ligands in patients with premature
ejaculation. Unfortunately, these agents are not yet
available for human use.
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118
7. SSRIs and their neurophysiological substrates of
sexual side effects
Although it is well known that SSRIs have sexual
side effects in humans, such as retardation of ejaculation
and anorgasmia [35], the neural substrates involved
in these effects are unknown. The bulk of
psychopharmacological studies using SSRIs for depression,
anxiety disorders or the obsessive-compulsive
disorder have investigated their effects on serotonergic
neurons and their projections to cortical and subcortical
structures. However, studying sexual effects of SS-
RIs, such as their effect on ejaculation, necessitates
studies not only on cortical and subcortical functions,
but also on brainstem functions, spinal cord mechanisms
and the peripheral nervous system.
The recent description of the emotional motor system
(EMS) by Holstege [28,29] might represent a neuroanatomical
substrate for the emotional influences on
basic neurogenital pathways. Further research into the
relationship between the central serotonergic system
and the EMS might illuminate the speculative idea
that a threshold for ejaculation is set and modulated
somewhere in the central nervous system and can be
changed by SSRI treatment.
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