0022-5347/02/1686-2359/0 Vol.

168, 2359 –2367, December 2002

THE JOURNAL OF UROLOGY® Printed in U.S.A.
Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.® DOI: 10.1097/01.ju.0000035599.35887.8f

Review Article

THE NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION

MARCEL D. WALDINGER
From the Department of Psychiatry and Neurosexology, Leyenburg Hospital, The Hague and Department of Psychopharmacology, Rudolf
Magnus Institute for Neurosciences, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

ABSTRACT

Purpose: Data showing the neurobiological background of rapid ejaculation was reviewed. In
addition, new hypotheses to integrate clinical symptomatology, psychopharmacotherapy and
psychotherapy of rapid ejaculation with brain function are provided.
Materials and Methods: A computerized MEDLINE search, and manual bibliographic review
of cross-references and neurobiological animal studies were performed. These reports were
analyzed, summarized and compared with the studies performed by the author.
Results: The literature on premature ejaculation published between 1887 and 2001 was
reviewed. It appeared that the various psychological hypotheses and psychotherapies have not
adequately been investigated. In contrast, psychopharmacological treatment studies, animal
research data and stopwatch assessments in men with rapid (premature) ejaculation indicate
that lifelong rapid ejaculation is a neurobiological phenomenon related to central serotonergic
neurotransmission and likely influenced by hereditary factors.
Conclusions: Basic and clinical psychopharmacological studies suggest that premature ejacu-
lation is a not a psychological disturbance but a neurobiological phenomenon.
KEY WORDS: penis, ejaculation, serotonin, serotonin uptake inhibitors, sex disorders

Since the 1990s various psychopharmacological studies have
shown that serotonergic antidepressants may effectively delay
ejaculation in men with lifelong premature ejaculation. These
results and animal data make it likely that premature ejacula-
tion is not a psychological disorder but a neurobiological phe-
nomenon. The consequences for understanding premature ejac-
ulation and its treatment are discussed.
HISTORY
We can distinguish 4 periods in the course of the last
century1 and 2 partly contrasting approaches, namely a so-
matic (urological or physiological) and a psychological (psy-
choanalytic or behavioristic) approach.2 The current era is
that of the neurobiological approach, characterized by evi-
denced based animal and human psychopharmacological re-
search, and antidepressant treatment as the first choice with
psychotherapy only in cases of serious coping problems.1
CHRONOLOGICAL CLASSIFICATION
The first period (1887 to 1917): rapid ejaculation. In
1887 Gross described what was presumably the first case
of rapid ejaculation in the medical literature.3 In 1901 a
report of von Krafft-Ebing followed that referred to abnor-
mally rapid ejaculation but did not yet use the word prae-
cox or premature.4
The second period (1917 to 1950): neurosis and psychoso-
matic disorder. In 1917 Abraham described the syndrome of
rapid ejaculation, which he called ejaculatio praecox.5 During
the early decades of the 20th century premature ejaculation
was viewed as a neurosis related to unconscious conflicts,
especially in psychoanalytic theory.5, 6 Treatment consisted
of classic psychoanalysis. The somatic approach was primar-
ily urological, which focused on local anatomical causes, such
2359
as hyperesthesia of the glans penis or a foreskin frenulum
that was too short, and on changes in the posterior section of
the urethra, particularly at the verumontanum. Advocated
treatment included prescription of an anesthetizing ointment
to incision of the frenulum or total destruction of the veru-
montanum by electrocautery.
In 1943 Schapiro argued that premature ejaculation is a
psychosomatic disturbance caused by the combination of a
psychologically overanxious constitution and “an inferior
ejaculatory apparatus as a point of least resistance for emo-
tional pressure.”7 Schapiro described 2 types of premature
ejaculation, namely type B, representing a continuously
present tendency to ejaculate rapidly from the first act of
intercourse, and type A, which led to erectile dysfunction.
Many years later the 2 types became distinguished as the
primary (lifelong) and secondary (acquired) forms of prema-
ture ejaculation, respectively.8
The third period (1950 to 1990): learned behavior. In the
third period premature ejaculation was considered to be
learned behavior. Rapid ejaculation associated with initial
rapid intercourse led to habituation and created performance
anxiety. Support for this behavioristic view was sought in
physiological experiments, in which the phenomenon of anx-
iety was emphasized. Although behavioral therapy was still
predominantly present in the literature, increasingly more
publications focused on psychoactive drugs as a treatment.
The third period (1990 to present): neurobiology and genet-
ics. The introduction of clomipramine and selective serotonin
re-uptake inhibitors (SSRIs) meant a dramatic change in
treatment for premature ejaculation. The efficacy of these
drugs in delaying ejaculation combined with the low side
effect profile made them first choice agents for premature
ejaculation on a daily as well as an on-demand basis.9 At the
same time animal and sexual psychopharmacological human
2360 NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION
studies10 attributed a serotonergic genesis11–13 and possible
genetic etiology14 to the neurobiological view of premature
ejaculation.
CLASSIFICATION ACCORDING TO THE PSYCHOLOGICAL OR
MEDICAL APPROACH
The psychological approach. According to the classic psy-
chological view premature ejaculation is considered a psycho-
sexual disorder with a psychogenic etiology and pathogenesis
that must be treated with psychotherapy.15 Initially uncon-
scious conflicts toward women were considered the core is-
sue. However, since the article of Semans about the stop-
start method,16 and particularly that of Masters and Johnson
about the squeeze technique17 the pathogenesis was believed
to be learned because initial intercourse was assumed to
have been achieved hurriedly. In the psychological approach
pathogenetic biological mechanisms remained unclear.
Although a rapid ejaculation reflex was mentioned there was
no information on the location of the neuronal circuitry of
that particular reflex.16 Also, increased sensitivity of the
glans penis was suggested. However, penile vibratory studies
provided conflicting data on primary pathogenetic penile hy-
persensitivity.18 –20
Not only the squeeze technique, but also all sorts of psy-
chotherapy, including thought stopping,21, 22 Gestalt thera-
py,23 transactional analysis,24 group therapy25, 26 and biblio-
therapy,27 have been suggested as treatment. Unfortunately
the effectiveness of these therapies was only suggested in
case reports but was never investigated in well designed
controlled studies. However, of all of these treatments the
squeeze method is said to give rise to short-term effective-
ness. In 2 studies that were not well designed its initial
effectiveness was confirmed but they also showed that the
ejaculatory control initially attained was virtually lost after a
3-year followup.28, 29
Definition of Premature Ejaculation: In the psychological
approach consensus on a definition of premature ejaculation
has never been reached due to conflicting ideas on the es-
sence of the syndrome. Masters and Johnson,17 and Kaplan30
suggested qualitative descriptions, for example female part-
ner satisfaction or male voluntary control. Masters and
Johnson defined premature ejaculation as male inability to
inhibit ejaculation long enough for the partner to reach or-
gasm in 50% of intercourse episodes.17 It is important to
realize that based on their definition they claimed that the
squeeze method was highly effective treatment. However, it
is obvious that their definition in terms of partner response is
inadequate because it implies that any male partner of fe-
males who has difficulty in reaching orgasm could be labeled
a premature ejaculator and also females should achieve or-
gasm on 50% of intercourse episodes.
Another way to define premature ejaculation is by quanti-
tative measures such as the duration of ejaculatory latency
or the number of thrusts before ejaculation. Definitions ac-
cording to the time before ejaculation varied from 1 to 7
minutes after vaginal intromission.31– 40 These cutoff points
(1 to 7 minutes) were not derived by objective measurements
but were subjectively chosen by the various investigators.
Premature ejaculation was a matter of many minutes and
cases of ejaculation within seconds were considered serious.
Equally subjective cutoff points were proposed for the num-
ber of thrusts as a criterion for premature ejaculation,
namely ejaculation within 8 to 15 thrusts.41– 43
Methodology of Psychological Studies: During the many
years in which the psychological approach prevailed, the
proposed psychological hypotheses and psychotherapeutic
treatments were not proved in any proper scientific
study.12, 44 For example, Masters and Johnson argued that
premature ejaculation was conditioned by experiencing first
sexual intercourse in a rapid way, such as by hurried con-
tacts in the back seats of a car or in places where detection
was possible and by consequent performance anxiety.45
However, evidenced based data for this assumption has
never been reported. Briefly, until today no evidenced
based psychological study has been available in the liter-
ature. Therefore, scientific knowledge about the funda-
mentals of the psychological approach remain to be eluci-
dated. It is rather peculiar that despite some available
studies of the poor response of psychological treatment and
insufficient study methodology37, 46 –50 the principles of the
psychological approach have never been altered and sub-
sequently tested. The methodological insufficiencies are
serious. For example, no objective and accurate measures
or clear definitions of ejaculation time, the number of
thrusts or satisfaction have been used. Men were only
asked about ejaculation latency without any quantifying
method. Furthermore, retrospective information was used
instead of prospective baseline measurements of each coi-
tus. Behavioral treatments were compared neither with
nonbehavioral treatment nor with random nonsense psy-
chological treatment. Moreover, assessments were only
made in men, whereas information from females about
partner ejaculation time was completely neglected.
The medical approach. Pharmacotherapy: Since the 1940s,
case reports have occasionally been published about various
drugs with efficacy for delaying ejaculation. Physicians at-
tempted to decrease penile sensation and delay ejaculation
by applying local anesthetics to the glans penis.7, 51–54 Others
tried to influence the peripheral sympathetic nervous system
by prescribing sympatholytic drugs, such as the ␣1 and ␣2-
adrenergic blocker phenoxybenzamine55–57 or the selective
␣1-adrenergic blockers alfuzosin and terazosin.58 In the
1960s case reports described the ejaculation delaying effects
of some neuroleptics. Thioridazine59 – 62 and chlorprothix-
ene63 delayed ejaculation by blocking central dopamine re-
ceptors. In the same period case reports of the delaying
effects of nonselective, irreversible monoamine oxidase inhib-
itors, for example isocarboxazid64 and phenelzine,65 were
published. However, the use of these various drugs was often
contraindicated by their disturbing and sometimes quite se-
rious side effects.
In 1973 Eaton reported the first study of clomipramine as
effective treatment for premature ejaculation.49 Later case
reports and double-blind studies43, 66⫺74 repeatedly demon-
strated the effectiveness of clomipramine at low daily doses
for delaying ejaculation. In 1993 Segraves et al reported the
first double-blind placebo controlled study showing that 25 to
50 mg. clomipramine can even be ingested on an on-demand
basis approximately 6 hours before coitus.43 On-demand
treatment was replicated in later studies.73 Unfortunately
similar to psychological studies, the majority of these initial
pharmacological studies were designed without a precise def-
inition of premature ejaculation and with a poor methodology
for quantifying the effects of treatment. The efficacy of clo-
mipramine was recognized by some sexologists but never
reached an international consensus.75
SSRIs: In 1994 Waldinger et al reported the first placebo
controlled study of 40 mg. paroxetine daily for successfully
treating premature ejaculation.76 The efficacy of paroxetine
at daily doses of 20 to 40 mg. was replicated in independent
studies at a regular daily dose77– 82 and in an on-demand
regimen.83 In addition, the efficacy of other SSR inhibitors,
such as 50 to 200 mg. sertraline daily74, 78, 79, 84 – 86 and 20
mg. fluoxetine daily,78, 87– 89 has been reported for delaying
ejaculation. There have only been 2 parallel group dose-
response studies. Clomipramine at 25 and 50 mg. daily,71
and paroxetine at 20 and 40 mg. daily77 showed a trend,
although it was not statistically significant, toward further
ejaculation delay when the dose was doubled.
In contrast to the insufficient methodology in psychological
studies and initial psychopharmacological studies, the well
 NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION
described methodology of psychopharmacological studies in
recent years is underlined. In last decade major methodolog-
ical improvements were developed. For example, in 1994
Waldinger et al operationally defined premature ejaculation
and introduced the intravaginal ejaculation latency time pa-
rameter, defined as the time between the start of intravagi-
nal intromission and the start of intravaginal ejaculation, as
an operational measure of ejaculation time.76 In the same
study we also used the medical interview of the female part-
ner as a comparative means for spouse estimation of ejacu-
lation time. The stopwatch, which was originally introduced
in 1973 as an accurate tool to measure ejaculation time,90
was prudently reintroduced in 1995 by Althof et al.72 In 1998
we introduced the baseline measurement of intravaginal
ejaculation latency time at each intercourse in a standard
period of 4 weeks with a stopwatch handled by the female
partner.78
Differential Efficacy of SSRIs for Delaying Ejaculation:
Using intravaginal ejaculation latency time, a stopwatch and
4-week baseline assessment at each intercourse comparative
placebo controlled studies showed a difference for delaying
ejaculation in various SSRIs at equivalent doses. It was
noted that 20 mg. paroxetine daily and 20 mg. fluoxetine
daily resulted in strong delays, 50 mg. sertraline daily re-
sulted in moderate delay but 100 mg. fluvoxamine daily and
20 mg. citalopram daily caused only mild to moderate delay.
The mild delay of fluvoxamine compared with paroxetine was
replicated in a placebo controlled male rat study using a
chronic administration treatment model,91 whereas after
acute treatment such a significant difference was not ob-
served.92 Because explanations in terms of transporter occu-
pancy, pharmacokinetics, metabolism or active metabolites
could be discarded, no adequate explanation can yet be of-
fered to explain these differential actions. However, it was
speculated that each SSRI enhances the amount of serotonin,
that is 5-hydroxytryptamine (5-HT), differentially and each
SSRI may also act differentially at different places in the
central nervous system, thereby, stimulating postsynaptic
5-HT receptors differentially.11, 12, 93 Moreover, the different
modes of action of SSRIs should further be explained by the
evaluation of other mechanisms that are potentially involved
in the mechanism of ejaculation. A likely candidate could be
the neuropeptide oxytocin, which has shown to be involved in
human orgasm.81
In a recent animal study the ejaculation delay induced by
fluoxetine was reversed by the administration of oxytocin.94
This finding suggests that fluoxetine induced delayed ejacu-
lation is related to inhibited oxytocin release. In another
study it was observed that oxytocinergic neurons contain
serotonergic receptors.95 In addition, in male and female
human orgasms oxytocin is released just before and during
orgasm.96, 97
Therefore, we suggest that the differential effects of SSR
inhibitors and other antidepressants on ejaculation may be
related to postsynaptic 5-HT receptors, which have differen-
tial influence on central oxytocinergic neurons intimately
involved in the ejaculation process.81 Further studies are
needed to investigate the presumed and intriguing role of
oxytocin in antidepressant induced delayed ejaculation.
ANIMAL STUDIES
In contrast to the prevailing psychological approach to
premature ejaculation, neuroscientists were already investi-
gating the role of central serotonin and dopamine neuro-
transmission in ejaculation in the 1970s. However, the in-
triguing findings of basic neurosciences were hardly
integrated with clinical practice in those years. What we
have learned to date in animal studies is that serotonin 5-HT
receptors are involved in the ejaculatory process. In addition,
using highly selective 5-HT receptor agonists and antago-
2361
nists it became evident that the role of 5-HT2C receptors in
ejaculation seems rather crucial. In addition to 5-HT2C re-
ceptors, a second subclass of 5-HT2 receptors, that is 5-HT2A
receptors, has also been investigated but until now its role in
ejaculation has not been identified.79 For example, in regard
to the 5-HT2C receptor male rat studies with d-lysergic acid
diethylamide and quipazine, which are nonselective 5-HT2C
agonists, suggest that stimulating 5-HT2C receptors delays
ejaculation.98 However, 2,5-dimethoxy-4-iodophenyl-2-
aminopropane, which equally stimulates 5-HT2A and
5-HT2C receptors, also increases ejaculation latency,99
whereas the selective 5-HT2A receptor agonist 2,5-di-
methoxy-4-methylamphetamine does not have this effect.98
Male rat studies have also shown the involvement of another
serotonin subtype receptor, namely the 5-HT1A receptor, in
the ejaculation process. Activation of postsynaptic 5-HT1A
receptors by the selective 5-HT1A receptor agonist
8-hydroxy-2-(di-n-propylaminotetralin) in male rats resulted
in shorter ejaculation latency.98
Based on 5-HT2C and 5-HT1A receptor interaction data in
animals Waldinger et al formulated the hypothesis that in
premature ejaculation in humans there is hyposensitivity of
the 5-HT2C and/or hypersensitivity of the 5-HT1A recep-
tor.100 The hypothesis that activation of postsynaptic 5-HT
receptors delays ejaculation was supported by 4 stopwatch
studies in humans with different SSRIs.78 – 81 However, in
these studies it was not obvious whether similar receptor
subtypes, that is 5-HT2C and 5-HT1A receptors, are also
involved in human ejaculation since SSRI treatment acti-
vates many different postsynaptic subtype receptors.11
To find an answer 2 human studies with the 5-HT2C
blocking antidepressants nefazodone and mirtazapine were
performed.79, 81 In a comparative double-blind placebo con-
trolled study with the 5HT2C/5-HT2A receptor antagonist
and 400 mg. daily of the 5-HT/noradrenaline re-uptake in-
hibitor nefazodone, nefazodone and placebo did not exert any
ejaculation delay in contrast to a significant delay after 20
mg. paroxetine daily and 50 mg. sertraline daily.79 In a
similar study the 5-HT2C/5-HT3 receptor antagonist, and
noradrenergic and specific serotonergic antidepressant mir-
tazapine did not induce ejaculation delay compared with the
significant delay resulting from 20 mg. paroxetine daily.81 It
should be emphasized that in these studies in men with
premature ejaculation neither antidepressant delayed ejacu-
lation, while for 5-HT2C antagonism shorter ejaculation la-
tency was expected. Therefore, further research is encour-
aged to elucidate still undiscovered pharmacological
mechanisms underlying the ejaculatory process.
Since to our knowledge the role of 5-HT2A and 5-HT3
receptors in ejaculation has not yet been identified in male
rats or humans, the lack of ejaculation delay associated with
these 5-HT2C receptor blocking drugs suggests that the
5-HT2C receptor is specifically involved in human ejacula-
tion and indirectly supports our hypothesis of 5-HT2C recep-
tor hypofunction in men with premature ejaculation.
However, the exact identification of the specific 5-HT recep-
tor subtypes involved in premature ejaculation is only possi-
ble by administering subtype selective 5-HT2C or 5-HT1A
receptor ligands. Unfortunately these agents are not yet
available for human use.
NEUROANATOMY
Most knowledge of the functional neuroanatomy of ejacu-
lation is derived from male rat studies. In regard to male rat
copulatory behavior one must distinguish among the brain,
brainstem and spinal cord regions that become activated
before and after ejaculation, when sensory information re-
turns from the genitals (fig. 1). The medial preoptic area in
the rostral hypothalamus and nucleus paragigantocellularis
in the ventral medulla101, 102 are suggested to have impor-
2362 NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION

FIG. 1. Central nervous system areas involved before, during and after ejaculation. Somatosensory fibers reach sensory cortex. Efferent
pathways run from hypothalamus down to sacral spinal cord and genitals. After ejaculation information is returned from genitals to various
areas in cerebrum. MEApd, posterodorsal medial amygdala. BNSTpm, posteromedial bed nucleus of stria terminalis. MPOA, medial preoptic
area. SPFp, medial parvicellular subparafascicular nucleus of thalamus. nPGi, nucleus paragigantocellularis.

tant roles in the process leading toward ejaculation.
Electrical stimulation of the medial preoptic area promotes
ejaculation.103 It is hypothesized that ejaculation is tonically
inhibited by serotonergic pathways descending from the nu-
cleus paragigantocellularis to the lumbosacral motor nuclei.
The current hypothesis is that the nucleus paragigantocellu-
laris is inhibited by inhibitory stimuli from the medial pre-
optic area. Disinhibition of the nucleus paragigantocellularis
is supposed to lead to ejaculation. The discovery of serotoner-
gic neurons in the nucleus paragigantocellularis and the
well-known ejaculation delay induced by serotonergic anti-
depressants suggests an action of the SSRIs inhibitors on the
nucleus paragigantocellularis. However, to our knowledge
the precise location in the central nervous system on which
SSRIs inhibitors act to inhibit ejaculation has yet not been
identified.
On the other hand, brain areas activated as a result of 1 or
more ejaculations have been observed in several mam-
mals.104 Using expression of the immediate early gene c-fos
as a marker for neural activity in male rats Coolen et al
detected distinct ejaculation related neural activation in sev-
eral brain regions after ejaculation, namely the posterome-
dial bed nucleus of the stria terminalis, a lateral subarea of
the posterodorsal medial amygdala, and the medial parvicel-
lular subparafascicular nucleus of the thalamus.105–107 All
available evidence suggests that ascending fibers from the
spinal cord, which signal ejaculation, activate the medial
parvicellular subparafascicular nucleus and the other brain
areas mentioned. Since it has been shown that this cluster of
activated neurons are extensively interconnected, mostly re-
ciprocally,107 a complete brain circuit related to ejaculation
seems to be involved. The functional significance of this ejac-
ulation subcircuit is still poorly understood but it may well be
that these areas have a role in satiety and, thus, in mediating
the post-ejaculatory interval.
These and many other animal studies have clearly shown
the existence of a neural circuitry for ejaculation in mam-
mals. This neural circuitry is partly elucidated but still
poorly understood. Interestingly a neurophysiological study
showed shorter latencies and greater amplitudes of somato-
sensory evoked potentials from the glans penis in men with
lifelong premature ejaculation compared with matched nor-
mal controls.108 This series and those of sacral evoked poten-
tial41, 42, 109 suggest that men with premature ejaculation
have greater cortical representation of sensory stimuli from
the glans penis than normal controls. However, such a larger
somatosensory cortical representation has not yet been iden-
tified. Brain imaging, for example positron emission tomog-
raphy, is required in humans to unravel the neural sub-
strate, particularly the cortical substrate, of the ejaculatory
process in men. Imaging may contribute to better under-
standing of which part of the circuitry is disturbed in prema-
ture ejaculation.
EMPIRICAL OPERATIONAL DEFINITION OF PREMATURE
EJACULATION
The American Psychiatric Association defines premature
ejaculation as “persistent or recurrent ejaculation with min-
imal sexual stimulation before, upon, or shortly after pene-
tration and before the person wishes it.”110 Until recently
any scientific basis for the DSM-IV definition was lacking.
For instance, the meaning of persistent, recurrent, minimal
and shortly after is vague and certainly needs further qual-
ification. Therefore, our group introduced a stopwatch
method to determine an empirically operational definition in
a study including 110 consecutively enrolled men with life-
long premature ejaculation.111 In this study the visibility of
stopwatch assessments by female partners as well as the
outcome was studied after instructing the couples to use a
stopwatch at home during each coitus for 4 weeks (fig. 2).
This method was accepted and well performed by all couples
included in this study. Of these men 90% ejaculated within 1
minute of intromission, including 80% who ejaculated within
30 seconds. The age of the men and duration of the relation-
ship were not correlated with ejaculation time. According to
 NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION
these data we have shown that ejaculation time can be mon-
itored with a stopwatch. In cases of premature ejaculation it
empirically appeared that ejaculation time was less than 1
minute in more than 90% of episodes of sexual intercourse
independent of age and the duration of relationship in those
men who complained of lifelong premature ejaculation. Thus,
assessment by stopwatch revealed that premature ejacula-
tion is a matter of seconds and not minutes.2, 111 To our
knowledge that study is the first stopwatch study in a white
Western European cohort. From a clinical point of view other
patient populations with complaints of rapid ejaculation
should be investigated in regard to cultural differences and
associated behavior. For example, do men in other countries
or cultures consider that they ejaculate prematurely when
they ejaculate within 4 minutes?
PREVALENCE
Premature ejaculation is said to be the most frequent male
sexual disorder.15 The prevalence in the general population
is estimated to be 4% to 39%.112–116 These prevalence studies
applied various frequently nonvalidated definitions and
methodologies of premature ejaculation. However, it should
be emphasized that normative data on ejaculation latency
time obtained by the stopwatch method in the general male
population are mandatory to really establish the prevalence
of lifelong premature ejaculation, defined as an ejaculation
time of less than 1 minute in men with complaints of rapid
ejaculation. Obviously an accurate definition of premature
ejaculation is necessary not only for clinical diagnosis and
treatment, but also for comparing data from different stud-
ies117 and performing epidemiological studies.
FAMILIAL OCCURRENCE OF PREMATURE EJACULATION
In 1943 Schapiro noted that men with premature ejacula-
tion seemed to have family members with similar com-
plaints.7 Remarkably to our knowledge this interesting ob-
servation has never been cited. To investigate the potential
familial occurrence of premature ejaculation we routinely
asked 237 consecutively enrolled men with premature ejac-
ulation about the family occurrence of similar complaints.14
Due to embarrassment only 14 men consented to ask male
FIG. 2. Intravaginal ejaculation latency time (IELT) measured with stopwatch in 110 men with lifelong premature ejaculation, of whom
90% ejaculated within 1 minute after vaginal penetration, including 80% within 30 seconds. Reprinted with permission.111
2363
relatives about ejaculation latency. These 14 men reported a
total of 11 first degree male relatives with information avail-
able for direct personal interview. In fact, 10 relatives ful-
filled our strict defined criterion of an ejaculation time of 1
minute or less. In this small select group of men the calcu-
lated risk of having a first relative with premature ejacula-
tion was 91% (CI 59 to 99). Therefore, the odds of family
occurrence is much higher than the suggested population
prevalence rate of 4% to 39%. Moreover, the high odds ratio
indicates a familiar occurrence of the syndrome far higher
than of chance alone. Based on this preliminary observation
the influence of genetics formerly noted by Schapiro7 gains
substantial credibility.
BIOLOGICAL VARIATION OF EJACULATION LATENCY TIME
According to the classic psychological view premature ejacu-
lation has always been considered a behavioral aberration, that
is a specific disorder caused by psychological factors with the
potential for cure. However, there is no scientific evidence to
support this view. On the other hand, the development of ob-
jective ejaculation time assessment methods (intravaginal ejac-
ulation latency time and stopwatch)76 – 81 and pharmacological
knowledge about the action of effective drugs are the corner-
stones of an upcoming neurobiological approach.12 Recently
Waldinger et al postulated the biological variability of intravag-
inal ejaculation latency time in men, ranging from extremely
rapid through normal or average to slow ejaculation.12, 93
However, due to a lack of epidemiological (stopwatch) re-
search the distribution of the mean and range values of
normal ejaculation latency time in the whole male human
population is not yet known.12
The assumption of population based variability of ejacula-
tion time implies that rapid ejaculation should be considered
a biological phenomenon rather than a behavioral aberra-
tion. This biological phenomenon is most probably differently
appreciated among individuals, populations and cultures.
There are men and women who cope well with rapid ejacu-
lation and do not consider it a major problem. However, in
other men and their sexual partners rapid ejaculation may
become a psychological or emotional problem. This problem
may become so severe that psychotherapeutic intervention
2364 NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION
may become beneficial to support the man or couple in coping
with premature ejaculation. Therefore, psychology is a sec-
ondary problem rather than the primary cause of premature
ejaculation.
EJACULATION THRESHOLD HYPOTHESIS
To understand the suggested biological variation of intra-
vaginal ejaculation latency time in relation to the serotoner-
gic system, delaying effects of SSRIs and suggested genetics
Waldinger and Olivier have proposed the existence of an
intravaginal ejaculation latency time threshold.12 When
there is a low threshold set point men can only sustain low
sexual arousal before ejaculation. Whatever these men do or
fantasize during intercourse any control of ejaculation re-
mains marginal and they ejaculate easily even when they are
not fully aroused. The assumption that men with premature
ejaculation ejaculate at lower levels of sexual arousal was
demonstrated by Spiess et al in a study comparing 10 men
with premature ejaculation (ejaculation at less than 2 min-
utes) and 14 controls (ejaculation at more than 3 minutes) by
physiological (penis circumference) and self-report measures
of sexual arousal.32 The low threshold is assumed to be
associated with low 5-HT neurotransmission and probably
hypofunction of the 5-HT2C receptor, as mentioned.
When there is a higher set point men experience more
control over ejaculation time. They can sustain more sexual
arousal before ejaculating. In these men 5-HT neurotrans-
mission varies around a normal or average level and 5-HT2C
receptor functions normally. To our knowledge the mean and
range values of the set points considered normal or average
are not known. When there is a high or very high set point,
men may experience difficulty in ejaculating or cannot
achieve ejaculation even when fully aroused sexually. At a
high set point 5-HT neurotransmission is supposed to be
increased and/or 5-HT2C receptor sensitivity is enhanced.
According to this threshold hypothesis it appears that the
level of 5-HT2C receptor activation determines the set point
and associated ejaculation latency time in an individual. In
men with premature ejaculation or any man on serotonergic
antidepressants SSRIs and clomipramine activate 5-HT2C
receptor and, therefore, change the set point to a higher level,
leading to a delay in ejaculation. The effects of SSRIs on the
set point appear to be individually determined since some
men respond with an intense delay, while others only expe-
rience slight delay at the same dose of the drug. Moreover,
cessation of treatment results in uniform resetting of the set
point within 3 to 5 days to the lower, individually determined
reference level, which is assumed to be genetically deter-
mined.
It is speculated that the threshold is mediated by serotonin
neurotransmission and 5-HT receptors in the brainstem93 or
spinal cord and may consist of serotonergic fibers that inhibit
neurons that convey somatosensory information from the
genitals. It is suggested that SSRIs enhance the inhibitory
effects of these serotonergic neurons. However, the cerebral
cortex may also mediate inhibitory impulses but currently
this finding has not been reported. In addition to the sug-
gested SSRI induced increased inhibition of sensory input,
SSRIs may also delay ejaculation by interfering with spinal
cord motoneurons of peripheral neurons that inhibit the in-
ternal genitals. Further studies are needed to unravel this
important and intriguing question.
COURSE OF RAPIDITY
It is generally believed that aging delays ejaculation. This
assumption may be true in men with a normal or average
ejaculation time but to our knowledge it has never been
investigated in men with premature ejaculation. In a stop-
watch study of 110 consecutively enrolled men 18 to 65 years
old with lifelong premature ejaculation 76% reported that
throughout their lifetime the speed of ejaculation had re-
mained as rapid as at the first sexual contacts in puberty and
adolescence, 23% reported that it had even become gradually
more rapid with aging and only 1% reported that it had
become slower.111 According to these data it is questionable
whether the fixed rapidity and even paradoxical shortening
of ejaculation latency time with aging should be considered
part of the pathogenetic process of premature ejaculation. We
think of the phenomenon of rapid ejaculation as a biological
variation and its paradoxical or fixed course through life as
pathological. Chronic premature ejaculation appears to be
the clinical syndrome of primary (lifelong) premature ejacu-
lation. To date there is no real cure for lifelong premature
ejaculation. Drugs may alleviate symptoms but only while
they are being administered.
PREMATURE EJACULATION AND ERECTILE DYSFUNCTION
Some men with premature ejaculation may express their
complaint as an erectile disorder since penile detumescence
after ejaculation occurs rapidly. On the other hand, erectile
dysfunction may be superimposed on lifelong existing prema-
ture ejaculation due to the efforts of these men to minimize
sexual excitement or to general causes of erectile dysfunc-
tion. One may wonder whether premature ejaculation is as-
sociated with an increased neurobiological risk for erectile
dysfunction. To our knowledge there is no evidence for such
an associated risk to date. To study such risk longitudinal
prospective studies in men with premature ejaculation and
matched controls are necessary but they have not yet been
performed.
It must be emphasized that the majority of men with
lifelong premature ejaculation do not suffer from concomi-
tant erectile difficulties. Most of these men do not seek help
due to rapid ejaculation. However, since some men start to
seek help after they have erectile difficulties, it may bias the
population with premature ejaculation that presents to a
urology clinic.
In our studies we recruited men with premature ejacula-
tion by advertisement. Of the respondents 75% had never
sought help for premature ejaculation, mostly due to embar-
rassment, and 95% did not have erectile difficulties.111 In
contrast, many of these men reported rapid achievement of
erection. In 1943 Schapiro called this phenomenon erectio
praecox7 but this term has never been quoted or referred to in
the literature. It may be speculated that aside from its rela-
tionship to the central serotonergic system premature ejacu-
lation is also related to increased oxytocin production. A
speculated increase in oxytocin release may be related to
ejaculatio praecox with erectio praecox. Animal studies show
that oxytocin stimulates ejaculation118, 119 and is a potent
inducer of penile erection.120
SSRIs are well known for delaying ejaculation and to a
lesser extent for inducing erectile difficulties and the loss of
sexual desire. The precise mechanism by which SSRIs inter-
fere with erectile function is not clear. The various SSRI
treatment studies of premature ejaculation are characterized
by a low incidence of erectile difficulties. However, in clinical
practice SSRI treatment may give rise to complaints of
slightly decreased rigidity of the erect penis.
The proved effectiveness of SSRIs for serotonergic related
disorders, such as depression, anxiety disorders, obsessive-
compulsive disorder and increased impulsivity, may raise the
question whether men with premature ejaculation are at risk
for these disorders. Our studies using a clinical interview and
the Symptom Check List with 90 items have repeatedly and
clearly indicated that men with lifelong premature ejacula-
tion are generally mentally and physically healthy, as
healthy as the average individual in the age matched general
nonpsychiatric male population.
 NEUROBIOLOGICAL APPROACH TO PREMATURE EJACULATION
BEHAVIORAL THERAPY AND THE NEUROBIOLOGICAL
APPROACH
Controversy over the most appropriate therapeutic ap-
proach is nourished by the confusing use of surrogate and
clinically relevant end points when interpreting treatment
results. For example, surrogate end points such as thrusting
with multiple stops must be distinguished from clinically
relevant ongoing successful thrusting. In contrast to the ben-
eficial clinical effects of pharmacotherapy, clinical effects as a
result of behavioral therapy still lack well designed investi-
gation. Further behavioral studies of the squeeze technique
with baseline and prospective stopwatch and intravaginal
ejaculation latency time assessment are imperative. The first
choice of treatment for premature ejaculation is psychophar-
macotherapy. It should be underlined that couples should be
briefly informed about current knowledge on the neurobio-
logical approach to premature ejaculation. On the other
hand, psychotherapy is only indicated in men or couples who
cannot cope with or cannot accept rapid ejaculation.1 In con-
trast to the classic psychological view, the purpose of psy-
chodynamic or cognitive psychotherapy is not to learn how to
delay ejaculation, but rather how to cope with rapid ejacula-
tion.1
CONCLUSIONS
Neurobiological research in the last decade has shown that
the classic psychological view of lifelong premature ejacula-
tion is no longer tenable. In contrast to the behavioristic
view, the neurobiological approach has gained support be-
cause of clinical and preclinical based evidence. According to
the latter view premature ejaculation should be considered
part of normally distributed ejaculation latency time in the
general male population independent of the natural course of
aging induced ejaculation delay. Paradoxically ejaculation
latency remains similar or even becomes more rapid with
aging. Rapid ejaculation seems to be related to disturbed or
maladaptive 5-HT2C receptor properties in specific brain
areas that can be restored by serotonergic agents. Cognitive
and emotional influences certainly interact with ejaculation
but psychological disturbances must be considered a second-
ary reaction. Based on various methodologically well de-
signed studies psychopharmacotherapy should be acknowl-
edged as primary treatment.121 A brief education on the new
neurobiological knowledge should accompany the prescrip-
tion of drugs. Although paroxetine and clomipramine are
highly efficacious for delaying ejaculation, further develop-
ment of more rapidly acting drugs would certainly benefit
modern patient care.
Drs. Dave H. Schweitzer and Berend Olivier reviewed the
manuscript.
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