Evolving ideas about the male refractory
period
Kenneth R. Turley and David L. Rowland
Department of Psychology, Valparaiso University, Valparaiso, IN, USA
• The male refractory period (MRP) continues to be a topic
of discussion and debate within the field of sexual
medicine. To date explanations rely on central descending
(efferent) influences involving specific neurotransmitter
systems. Herein we explore the issue of the male refractory
period, identifying problems with current explanations,
specifying the parameters of an adequate model, and
suggesting possible mechanisms mediating this
phenomenon.
• We review the literature regarding existing explanations
for the MRP and look to other systems of physiological
regulation that might provide a model for the
conceptualization of the MRP.
• Our approach differs from traditional explanations in
that it emphasizes the possible roles of various
peripheral, rather than central, feedback (afferent)
Introduction
A significant challenge within the study of human
sexuality has been that of understanding the common vs
the differentiating elements of sexual response between
the sexes. Traditional models of human sexual response
have often emphasized similarities in sexual response
between men and women, although even early models
recognized differences [1]. As the study of sexual
response has evolved, greater attention has been given
to some of the uniquely characteristic response patterns
of each of the sexes [2]. In so doing, the understanding
and, of critical importance, the treatment of sexual
problems (which themselves are not equally distributed
across the sexes) have undergone substantial
re-conceptualization.
Sex differences occur at both the psychological and
biological levels. For example, ‘desire,’ a psychological
construct traditionally used to account for variation in the
intensity and frequency of sexual activity, appears to have
different origins and experiential elements across the sexes.
In men, significant variability in sexual desire appears to be
physiologically based, accounting for the long-held concept
442 © 2013 BJU International | 112, 442–452 | doi:10.1111/bju.12011
systems that affect peripheral autonomic functioning and
response.
• Yet our approach is consistent with other peripheral
regulatory feedback systems controlling autonomic
response related to such processes as heart rate,
respiration, and gut motility.
• Although direct empirical research supporting our
approach is lacking, sufficient evidence exists to support
the idea that such processes are not only possible but
likely with respect to the male refractory period. We
suggest several lines of research that might provide
empirical support for this approach.
Keywords
ejaculation, refractory period, autonomic, male,
baroreceptor, paracrine
of spontaneous ‘unprompted’ sexual desire; in women, a
greater proportion of the variability may originate from
contextual and partner stimuli and less from biological
predispositions.
At the neural level, differences in brain and spinal
organization and activation are known to occur in
non-humans during sexual response, and recent MRI
studies in humans have verified that different parts of the
brain may be maximally activated during sexual arousal in
men as compared with women [3–5]. At the peripheral
neurophysiological level, in addition to differences related
to analogous though different anatomical structures,
response patterns differ most obviously during the
orgasmic phase. Women often report multiple orgasmic
capacity; men, in contrast, rarely report multiple orgasms,
with the refractory period undoubtedly playing an adaptive
role in contributing to an adequate sperm count necessary
for impregnation.
While post hoc explanations have been offered for various
sex-related differences in sexual response, the underlying
substrates and associated mechanisms have seldom been
adequately described. In the present review, we explore one

of the more puzzling sex differences between males and
females, the male refractory period (MRP) after ejaculation.
Not only is the neural mechanism supporting the MRP
unclear, the neural site of this phenomenon, whether
cerebral, spinal or peripheral, has been the subject of
ongoing discussion.
The MRP refers to the period of inhibition of erectile
and ejaculatory response that follows ejaculation. In
non-humans, the analogous period between ejaculation and
the resumption of copulation is commonly referred to as
the post-ejaculatory interval (PEI). In humans, during this
sexually quiescent period, most men (and some women)
report genital hypersensitivity, even discomfort, upon
continuing stimulation. It is not clear whether sexual desire
and/or arousal are also actively inhibited during this
period, or whether anecdotal reports of diminished desire
and arousal are secondary to other factors, including genital
sensitivity and/or the inability to perform sexually. As with
most such parameters, the MRP shows both inter- and
intra-individual variation in men; in rats, such factors as
testosterone levels and sexual experience appear to play a
role in the PEI [6].
Current Hypotheses Regarding the MRP
Prevailing explanations of the MRP implicate CNS
fluctuations, probably cerebral rather than spinal, of key
messengers during or after orgasm [7], with much attention
focusing on the roles of central serotonin and prolactin
[8–11]; however, these two messengers provide only a
partial explanation for the MRP. Specifically, peri- and
post-orgasmic elevations in prolactin and serotonin are
observed in both men and women. How increased
concentrations of these substances at the cerebral level
render men but not women less capable of further sexual
response has not been adequately explained. In the case of
prolactin [12–17], one proposed mechanism relies on its
association with erectile dysfunction in chronic
hyperprolactinaemia through active suppression of penile
tumescence. While some degree of penile rigidity is
necessary for intercourse, it is not necessarily required for
orgasm and ejaculation. Thus, if prolactin were to account
for the MRP, it would need to affect more than tumescence;
that is, motivated men might seek continued stimulation,
and even in the absence of erection, would still be capable
of subsequent orgasms. Another mechanism is the observed
inverse relationship of prolactin and testosterone, but this
association is probably valid only in the case of chronic
hyperprolactinaemia. The role of prolactin in the alteration
of genital sensory perception also remains unexplained, as
prolactin’s known effect on libido makes it difficult to
distinguish whether alterations in the refractory period
after prolactin suppression result from unaltered, and thus
still elevated, sexual drive (i.e. reducing the relative
Male refractory period
refractory period through cognition or desire), or if it
actually prevents the inhibition of the physiological wiring
of orgasmic potential. Finally, clitoral erection is still
possible after female orgasm. Why prolactin causes
detumescence of the male phallus, but not the female, is
unclear.
Also unanswered is which psychophysiological
phenomenon in men, orgasm or ejaculation, is associated
with sufficient prolactin release to invoke a temporary,
though near complete, cessation of sexual response. If
orgasm causes prolactin elevations in both men and
women, it is unclear why men practising techniques to
delay ejaculation are capable of the perception of multiple
orgasms without the loss of drive and tumescence that
follows ejaculation. Conversely, if prolactin initiates the
MRP after orgasm, no explanation exists for the noticeable
loss of tumescence many men experience when incomplete
ejaculation occurs before orgasm (i.e. when modest
quantities of semen ‘leak’ into the urethra when men try to
delay ejaculation). Also, the issue of causality is unresolved:
whether chemical fluctuations during and after orgasm
cause the MRP, or whether the fluctuations result from the
mechanism accounting for the MRP itself, and thus serve
only as markers. Some men are capable of ejaculation even
though they do not experience orgasm (or the associated
tachycardia, diaphoresis, etc.). Finally, the fact that even
these men experience a refractory state suggests that
chemical changes associated with orgasm cannot
necessarily be equated with the various chemical changes
seen after ejaculation.
The role of serotonin is as problematic as that of prolactin:
for example, if increases in serotonin within the CNS
prevent (or delay) orgasm in the male, why do such
increases not prevent multiple orgasms in females? Also, it
is unclear why so-called ‘dry orgasms’ (assuming these also
affect serotonin) would not inhibit the desire for continued
stimulation. Furthermore, pre-synaptic and post-synaptic
serotonin of differing receptor subtypes appears to have
either inhibitory or excitatory arousal effects on male rats,
even to the extent of restoring full sexual function in
castrated males injected with a serotonin analogue; as such,
the role of central serotonin is not necessarily or always
inhibitory [18,19]. Finally, none of the proposed
mechanisms offered thus far provide any insight into the
increased duration of the MRP commonly seen in aging
men; nor do they explain differences which occur within
the same individual across different settings.
Expectations of an Adequate
Explanation of the MRP
Beyond the limitations of existing explanations for the
MRP, other aspects remain inadequately addressed. First,
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any mechanism that accounts for the MRP should closely
coincide with ejaculation and not necessarily orgasm, since
some men capable of orgasm without ejaculation report
repeated cycles of sexual excitation. Second, the explanation
for the MRP should offer, at least in part, a mechanism for
the restoration of sexual function after a period of time that
varies with the individual and with age. Specifically, current
models fail to explain why successive ejaculations in a short
timeframe typically lead to less intense orgasms, and why
periods of abstinence tend to intensify orgasms. They also
do not explain why these factors typically diminish with
age despite only modest declines in serum testosterone.
Third, since the MRP is generally common to sexually
mature males of most species, its mechanism should be
absent in prepubescent males and in females. Explanations
should therefore identify a mechanism by which puberty
transforms non-ejaculating males (presumably capable of
multiple orgasms according to Kinsey data) to ejaculating
males who exhibit a refractory period [20]. Finally, as part
of a comprehensive model, the mechanism should be able
to help explain how ‘sexual grounding’ occurs in both men
and women, that is, when the individual’s response to
stimulation is greatly enhanced and subjectively altered to
become ‘erotic’, rather than merely ‘sensory,’ as might be the
case for a medical urogenital examination [21].
An Approach to MRP Based on
Regulatory Models
Regulatory models of physiological systems may provide a
blueprint for understanding the MRP. Regulatory
autonomic activity modulates key homeostatic components
of cardiovascular (CV), pulmonary, gastrointestinal (GI),
and other systems [22]. Some of these regulatory activities
involve ascending autonomic pathways, while others rely
on neuroendocrine signalling. We propose that similar
processes are integral to the prolonged post-ejaculatory
refractory state, a distinguishing feature of the typical
human adult male sexual response compared with that of
the female. This approach is a departure from current
explanations for the post-ejaculatory refractory period (or
PEI) that cite the inhibitory influence of various
messengers in the brain and spinal system.
Autonomic Regulation in GI and CV
Systems as a Model
The descending or efferent (smooth muscle activation)
components of the autonomic nervous system are more
completely described and understood than components of
the ascending or afferent (sensory input/feedback) side;
however, CV physiology can illustrate how afferent
(ascending) autonomic information is used as a basis for
subsequent efferent autonomic control; baroreceptors
444 © 2013 BJU International
(pressure receptors) within the carotid sinus and other
vascular components relay stretch information (as a proxy
for pressure) to spinal and supraspinal autonomic centres
via the glossopharyngeal nerve. The precise nature of these
receptors is not completely understood, but afferent nerve
firing appears to be related to changes in ion channel
conductance at different states of cellular distortion or
stretching. This information is interpreted by the brain,
where homeostatic action is then relayed via efferent
autonomic fibres to cardiac and vascular tissues to increase
contractility or arteriolar tone. The resultant blood pressure
is sensed continuously by the same baroreceptors in a
closed-feedback loop, thus maintaining haemodynamic
stability.
Autonomic responses to signals from CV baroreceptors
demonstrate both acute and chronic adjustment. Efferent
vascular tone is not dependent on instantaneous changes of
the arterial waveform, but rather tracks the mean arterial
pressure, which is subject to change over time (as seen in
the progress of chronic hypertension) to create a new
regulatory ‘set’ point, that is, the homeostatic target. Thus
the set point to which autonomic tone responds varies over
time depending on prevailing stretch signals. In chronic
hypertension, the set point is much higher after the system
has adjusted to a chronic increase in pressure. Similarly, in
exercise, temporary set points have been demonstrated
[23]. These set points thus demonstrate chronic
adaptability, although at any given instant, acute changes
are still important regulators. CV physiological regulation
is, therefore, an example of a dynamic system where the
brain is not the sole originator of physiological response,
but rather an interpretive relay point for various signals,
including autonomic information in context, to then effect
physiological change through efferent nerve fibres.
Other examples of autonomic regulatory feedback include
the CV chemoreceptor system of the carotid bodies which
uses ascending autonomic regulatory functions to maintain
blood oxygenation, albeit accomplished via a different
mechanism from that of baroreceptors. As specialized
receptors detect minute alterations in blood pO2
concentrations and, in cases of CO2 deregulation, this
detection regulates minute ventilation in the lungs. As a
second example, the GI system depends on chemical
signalling for autonomic feedback as peristaltic regulation
relies heavily on neuroendocrine release of serotonin in a
paracrine fashion (a form of cell communication where
target and releaser are in close proximity) [24]. Specifically,
intraluminal serotonin agonism (i.e. targeting the mucosal
layer only) lowers the pressure thresholds for peristalsis;
however, bathing the serosa (outer serous membrane) in a
serotonin solution markedly raises pressure thresholds, just
as addition of serotonin antagonists to the luminal mucosa
does [25]. This demonstrates the importance of precision

paracrine signalling, since the physiological effect varies by
target location, even so closely within the same organ. In
addition, serotonin increases vagal afferent activity,
suspected to be involved in the development of nausea
[26]. Modification of these GI serotonin receptors has led
to treatment of irritable bowel syndrome, postoperative and
chemotherapy-induced nausea and vomiting, and similar
disorders [27,28]. As a final example, the Hering–Breuer
inflation reflex represents a similar feedback-type system
that maintains the respiratory rate [29,30]. Other
physiological events, including uterine contractions
responding to ruptured membranes of pregnancy and the
atrial natriuretic peptide system, can be added to the many
examples of short- and long-term regulation mediated
through peripheral autonomic feedback systems.
Application to Male Sexual Reflex
Physiology
Ejaculation is an event primarily under autonomic
control. As such, the same oversimplified paradigm that
had been applied to other physiological systems has
traditionally been applied to ejaculatory physiology,
specifically that of pre-programmed events within the brain
controlling peripheral responses via efferent autonomic
nerves, largely in response to simple tactile cues. We instead
propose that afferent autonomic regulators similar to those
found in GI and CV systems might provide an alternative
approach to the poorly understood events of ejaculation
and the MRP.
To reiterate, the MRP, a characteristic physiological
component of male sexual response compared with
females, is the transient period of time after ejaculation
associated with detumescence, reduced interest in sexual
activity, inability to ejaculate or experience orgasm, and
increased aversion to genital sensory stimulation [1].
Although women may experience some of these same
characteristics after orgasm, compared with men, the
duration of this phase is often shorter or altogether
absent.
Although a universally accepted definition of the MRP
has been lacking in the literature, whether it measures the
time from ejaculation until subsequent erection, or
ejaculation, or orgasm, here we define it as the time
elapsed after ejaculatory contractions in the sexually
abstinent adult male until another set of ejaculatory
contractions occurs. This definition does not examine
erectile function, nor does it require expulsion of seminal
fluid, although the capacity for either of these is typically
absent during the refractory state. Although orgasm and
ejaculation are, strictly speaking, distinct physiological
events, those factors that impact ejaculatory capacity
usually affect orgasm in men.
Male refractory period
Novel Approach to the MRP
Our approach differs from prevailing explanations as it
postulates that at the cerebral and spinal cord levels, the
functional importance of anatomical and physiological
male/female differences on sexual response is limited, with
the primary implication being that the salient differences
occur outside the CNS. Although anatomical sexual
dimorphisms have been noted in the adult human brain,
anatomical (and often functional) brain differences between
the sexes appear to be relatively limited compared with
individual variability within each sex. As such, our model
suggests that the observed differences between the sexes are
less dependent on CNS anatomical and physiological
differences than is implied in other explanations.
This approach also differs from current thinking in that it
assumes that central hormone or neurotransmitter
fluctuations over the sexual response cycle contribute to
desire and satiety, but are not primary constituents
influencing autonomic or reflexive sexual responses. We
focus instead on peripheral physiological changes that
potentially alter ascending signals involved in sexual reflex
activation. Although there are probably others, we suggest
two potential detection mechanisms, baroreception and
chemoreception, that may operate in a manner similar to
those found in other physiological systems to provide
localized regulatory feedback on sexual response. Specifically,
although prevailing sexual theory considers mainly
descending (efferent) autonomic functions, we postulate that
ascending (possibly autonomic) tracts relay information
from chemo- and baroreceptors in the genitourinary system
to modulate sexual reflex signals arising from peripheral
tactile stimulation and supraspinal origins.
A Broad Conceptualization of Sexual
Physiology
The essential features of our concept include initial somatic
and autonomic activation through sensory input,
descending activation of genital response, and ongoing
modulation of sexual/genital physiology and response
through continual ascending autonomic feedback which
changes over the course of the sexual response cycle and,
particularly, after ejaculation.
In brief, various sensory factors and receptors operate to
modulate sexual function, potentially at various neural
levels (supraspinal or spinal). In the sexually rested man
(not having ejaculated recently), sexual stimulation of the
penis and erotic thought (fantasy, visualization, etc.) lead to
vascular engorgement of the penis. This process is initiated
through psychogenic (supraspinal: e.g. erotic thoughts)
and/or reflexogenic (intraspinal: e.g. penile stimulation)
pathways leading to vascular engorgement from primarily
parasympathetic relaxation of smooth muscle. Vascular
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engorgement is only one component of erection, however,
as erection is strengthened considerably through the
bulbocavernosus reflex (BCR). In addition, local vascular
engorgement probably increases secretion into the seminal
vesicles, presumably increasing transmural pressure.
Although penile stimulation relays tactile information, the
‘sexual grounding’ that occurs (converting non-sexual
touch into sexual touch) may be less of a brain-activation
phenomenon as postulated in other models, but rather a
spinal and peripheral nervous system phenomenon where
somatic and testosterone-dependent autonomic sensory
signals are brought together to give the unique, pleasurable
sensation of sexual stimulation [21]. A process similar to
this is suggested in pain perception theory, in which
autonomic and somatic integration, under defined
circumstances, causes pain/arousal/emotion [31,32].
Thus, stimulation defined as ‘sexual’ may represent the
integration of somatic stimulation from the penis
combined with a continuous tone from autonomic sensory
organs in the peripheral nervous system, present in the
form of chemical sensory cells, or stretch receptors (i.e.
baroreceptors). This basal tone may increase as arousal
intensifies or is prolonged and may be augmented by tissue
stretch at the base of the penis within the pelvis (through
erection and BCR) and, more important to this discussion,
stretch within ejaculatory organs, specifically the seminal
vesicles. The combination of sexual sensory input from the
penis (somatic sensory ascending fibres) and (frequently)
erotic fantasy helps maintain the subjective appreciation of
arousal. These somatic sensory inputs may also play a
critical role in eliciting sexual reflex outflow, but only under
conditions of a baseline afferent autonomic tone. Increased
stimulation of the penis increases firing of the BCR, which
further increases penile rigidity, but also (i) increases
pressure within the pelvis and base of the penis and (ii)
increases nerve firing within the spinal cord as part of the
ejaculatory reflex, with ejaculation possibly representing a
massive triggering of stacked BCRs.
In the model, as ejaculation is completed, several events are
likely to occur. First, the tension of fluid within the seminal
vesicles is suddenly decreased, probably causing a decrease
in ascending nerve firing from this source. Second, the
ejaculate itself might interact with the penile urethra to
affect serotonin paracrine signalling, accounting for the
type of chemoreceptor signalling suggested below. This
process might diminish the BCR after ejaculation or
interact in other ways to affect signals ascending to the
spinal level. Third, along with the decreased BCR, the
intrapelvic pressure that helps to maintain erection and
increase spinal cord firing is diminished.
Detumescence is exacerbated by the norepinephrine release
that accompanies ejaculation, causing vasoconstriction and
446 © 2013 BJU International
decreasing blood flow to the penis. As the MRP is initiated,
precipitous loss of autonomic tone flowing from peripheral
sites causes a change in perception to stimulation.
Specifically, altered sensory input, where somatic input is
maintained but autonomic input decreases dramatically,
results in a loss of psychological sexual arousal and may
result in aversion to sensory stimulation. These events are
accompanied by a decrease in sexual response outflow
(including detumescence), ejaculatory reflex failure owing
to possible BCR attenuation, and stretch receptor changes
in the seminal vesicles. These changes persist until
metabolism degrades the chemical messengers responsible
for these effects, until new messengers are regenerated, or
until more fluid is regenerated in the seminal vesicles.
Thus, the MRP may represent a physiological uncoupling
of an autonomic–somatic integration platform peripherally,
resulting in unilateral sensory input insufficient to elicit
sexual responses centrally. In its entirety, this represents a
closed-loop negative feedback system in males that,
evolutionarily speaking, favours natural selection by
maintaining sperm counts by limiting too-frequent
ejaculation. Our model leaves most areas of existing sexual
response theory unchanged, where cerebral neuro-humoral
conditions govern fundamental drive, reward, and sensory
interpretation from sexual activity, and CNS outflow
mediates and regulates the smooth and skeletal muscular
contractions of orgasm. To these integrative and efferent
components, we add components of sensory and sacral
reflex integration involving afferent feedback mechanisms
that more completely explain observed phenomena while
parsimoniously reconciling male/female differences.
Baroreceptor Regulation and
Physiological Sexual Response
Intrapelvic pressure dynamics may affect arousal readiness
by mechanisms similar to those found in the CV system,
although carried via vagal visceral afferents rather than the
glossopharyngeal nerve. There are several anatomical sites
where stretch and pressure changes probably occur over the
sexual response cycle. Nerve plexuses and stretch-sensitive
nerve endings capable of relaying such information are
found in multiple organ systems of the body. Visceral
interoreception of the gut has received much attention
[28,33] and those of the male genital tract and their impact
on sexual regulation have been described [34,35]. Volume
in the seminal vesicles and other organs of the male genital
tract probably increases during arousal until the point of
emission and ejaculation, and then it decreases after
ejaculation. During the MRP, hormone-dependent secretion
then gradually restores vesicular fluid volume. These
volume changes may affect transmural pressure gradients,
or affect stretch-receptors in the vesicular walls, if present.
Similar to the CV system, chronic increases in pressure

may have little effect on sexual drive or capacity, but
sudden increases or decreases within a short timeframe
may have profound effects on autonomic outflow.
Stretch receptors may operate at a macro level as well. For
example, pubococcygeous muscle group strengthening in
those with weakened musculature heightens sexual
response (although subjects with normal muscle tone show
no significant improvement) [36,37]. Anecdotal evidence
suggests that in men, stronger pelvic musculature affords
greater control over ejaculation, presumably because
contractile tension physically prevents the release of semen.
How seminal ‘leak’ prevention prolongs sexual arousability
in men has not been previously explained. Additionally,
many men and women breath-hold (i.e. perform the
Valsalva manoeuvre) during arousal up to and through
orgasm, and whether voluntary or involuntary, this
behaviour tends to affect arousal (such as for ejaculatory
control [38]) or anecdotally to heighten arousal or orgasm.
Breath control and variations of breathing are often
employed in various sexual learning programmes. Although
the mechanisms are unknown, such sexual strategies
nevertheless suggest that pressure changes (and thus stretch
receptor variation) may play a role in sexual arousal and
response. Uterine stretch of pregnancy might increase
sexual response in some women through a similar
mechanism.
One possible mechanism of sexual baroreceptor–
autonomic integration is that of reciprocation where, for
example, one action serves a second action which then
reinforces the first. For example, the BCR helps maintain
erections, and erections strengthen the BCR leading to
ejaculation. The BCR augments erection by forcing blood
into the penile vasculature and, in turn, the erect penis
probably enhances the BCR by distention and
sensitization of free nerve endings (and possibly other
mechanisms). The intact BCR thus serves in a
positive-feedback cycle to help maintain erection and
support ejaculation. Despite similarities between orgasmic
contractions in men and women, documented research to
evaluate how the BCR and sexual reflexes are related over
the sexual response cycle is non-existent. For example,
BCR might gradually build during increasing arousal and
tumescence in men, peak at the time of ejaculation/
orgasm, and diminish rapidly after ejaculation. We might
expect a similar incremental pattern in women with
increasing genital and subjective arousal, minus the rapid
diminution following orgasm.
Baroreceptor regulation, then, might have specific
application to ejaculatory physiology in multiple ways. The
transmural pressure gradient within the seminal vesicles
very probably decreases after ejaculation with the decrease
in vesicular volume, and the time required for vesicular
Male refractory period
fluid re-accumulation may account for the duration of the
MRP. A correlation between vesicular secretion rate and
mean plasma testosterone concentration would help
explain why sexual interest and capacity are associated with
serum testosterone levels as men age, since increased
baroreceptor firing would result from increased vesicular
fluid volume and hence pressure. Men attempting a second,
repeated ejaculation in a short period of time often appear
to use behavioural strategies either voluntarily or
involuntarily that elevate pressure and activate stretch
receptors, including forceful pubococcygeous muscle
contraction and Valsalva manoeuvres. Finally, BCR may
vary greatly over the course of tumescence, ejaculation, and
detumescence in men, as stretch receptor activity in the
pelvic and peri-anal regions changes.
Similar baroreceptor mechanisms may be important in
female sexual physiology, contributing to the observed
patterns of arousal and sexual problems. The difficulty
many women experience in reaching orgasm may relate to
the lack of increased pressure transmitted to the pelvic
area, since clitoral vascular engorgement and BCR
contractions do not generate pressures similar to those
associated with male erection. Known manoeuvres such as
G-spot pressure during sexual activity and pubococcygeus
muscle strengthening might simply stimulate stretch or
pressure receptors in male-organ homologues, even if
vestigial, to speed onset and intensity of orgasm. In this
way, initial female arousal difficulty might be closely related
to the refractory period in males, since in both situations
a relative decrease (or initially low level) in pelvic
baroreceptor firing may prevent or retard the arousal
necessary to reach orgasm.
This concept might also explain other aspects of female
sexual response patterns. Some women require a longer
period of stimulation to reach orgasm, but once a single
orgasm has been reached, sequential orgasms are easier to
attain. Within the conceptual framework proposed, the
involuntary contractions of orgasm serve to reinforce the
pressure-dependent activity from within the pelvis,
enhancing the response of subsequent orgasms. This
process may also explain how pubococcygeous-muscle
strengthening improves sexual response in many
women.
The analogy to CV pressure autoregulation is important,
since similar mechanisms related to ‘set points’ may operate
in the sexual context. In the carotid sinus of the neck
artery, stretch receptors do not respond ‘beat to beat,’ but
rather take into account a mean arterial pressure, which is
subject to change over time (as seen in hypertension),
thereby creating a new set point. In men and women alike,
the actual nerve firing rate may not be as important as the
relative firing rate or change in the rate of firing rate within
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a given range. Regarding sexual response, men who have a
chronically low semen output or production may not
notice any change in their sexual response if this change
has occurred gradually, but a sudden decrease in volume
after ejaculation, or a rapid decline in testosterone, is likely
to have noticeable effects. The tension that results from
seminal volume may be important to sexual arousal and
drive, as higher testosterone levels are probably correlated
with increased seminal volumes, pressures, and sexual
arousal and drive.
Chemoreceptor Regulation via
Paracrine Signalling as an Additional
Feedback System
In addition to baroreceptor feedback, local neurochemical
signalling may influence sexual response [39]. Histological
characteristics of the urethra offer possible sites for
chemoreceptor signalling similar to that of the gut.
Neuroendocrine cells of paracrine function are found
throughout male and female urinary tracts of humans and
other mammalian species [40–43]. These cells are of two
types: open and closed. The open type is of interest since it
has a long extension from the cell body to the luminal
surface of the urethra where microvilli constantly sample
contents passing through the lumen. The closed type, like
the open type, has multiple dendritic projections that
enable communication with both neuroendocrine and
other cell types. Most of these cells secrete multiple
substances, including serotonin, somatostatin,
chromogranin A, and thyroid-stimulating hormone-like
peptide. In addition, the cells appear to have projections to
and from afferent and efferent autonomic neurons. Because
the cellular products and neural arrangements of the
neuroendocrine cells in the GI tract closely resemble those
of the genitourinary tract, we hypothesize that paracrine
signals that regulate autonomic GI motility may also
regulate autonomic sexual reflexes.
Among the possible sites of action of these chemical
signals, the seminal vesicles may be the most likely source
of the refractory-inducing agent for two major reasons:
first, they secrete the largest number of suspected
messengers; and second, seminal vesicle secretion typically
comprises the final component of the ejaculate.
Possible role for Peripheral Serotonin
One example of possible chemoreceptor regulation may be
through serotonin. Current evidence supports the notion
that peripheral serotonin’s effect on sensory fibres is
excitatory; specifically, sensory transmission is increased or
altered by serotonergic input [31]. For example, in people
who have received burns, mast cell release of serotonin
dramatically increases skin sensitivity, while serotonin
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blockade reduces this effect [32]. Alternatively, spinal
serotonin appears to blunt synaptic transmission such as
that from nociception, where descending inhibitory
pathways releasing serotonin on first-order decussation
decrease pain sensitivity [44].
Analogous to serotonin as a GI messenger or the mediator
of altered pain fibre transmission, serotonin fluctuations
emanating from neuroendocrine cells in the urogenital
apparatus can affect sexual response. Although the urethral
neuroendocrine cells, their relationship to afferent and
efferent neurons, and this homology to enteric autonomic
regulation have been known for several years, few
explanations have related paracrine function to neural or
sexual response in the urogenital tract. Yet some evidence is
suggestive: serotonin infused into the urethra of female rats
lowers the threshold of a stereotyped model of sexual
response, an effect that is abolished by specific 5-HT3
antagonists [45]. Although the precise mechanisms are
unknown, this finding suggests that serotonin’s
characteristic functions of enhancing sensory
responsiveness and enabling autonomic function in other
organ systems may also apply to sexual reflexes. Thus,
although centrally released serotonin may have dual
(inhibitory or excitatory) effects on sexual arousal,
peripheral serotonin appears to be exclusively excitatory.
Based on previous studies, we speculate that the peripheral
release of serotonin from paracrine cells within the urethra
is fundamental to maintaining the sexual arousal arc,
accomplished by serotonergic augmentation of urethral
afferent signals. In this scenario, as arousal increases, the
cells fire more actively as orgasm approaches, as well as
during orgasm itself. In the male (and only in the male),
however, accompanying or immediately after the onset of
cortical perception of orgasm, prostatic and vesicular fluid
enters the urethra lined by tissues containing these
paracrine cells. At this point, some component of semen
either inhibits the paracrine cells, turning off an excitatory
mechanism, or alternatively, causes such massive
stimulation that depletion and/or desensitization of the
system occurs, either in the interaction between the
paracrine cells and sensory fibres, or in the spinal cord. A
third possible scenario is that the paracrine cells contain
both serotonin and a variety of peptide messengers. In
most neurons having both classical and peptide
neurotransmitters, low frequency stimulation preferentially
releases the classical transmitter, whereas intense
stimulation releases the peptide neurotransmitter. Thus,
moderate chemical signalling in the urethra may release
(excitatory) serotonin, but ejaculation releases peptide
neurotransmitters, having a very different effect. All three
possibilities amount to excitation of sensory fibres before
ejaculation, and inhibition afterward. This inhibition
diminishes any further genitally derived arousal reflexes,
 Male refractory period

including erection, orgasm and ejaculation, and would manner similar to the alteration of peripheral sensory
continue until either the interrupting molecule is fibres, as is believed to occur in hyperalgesia [55].
metabolized, allowing the paracrine pathway to continue, or
Human semen also contains a wide variety of polyamines,
the receptors or signalling molecules are regenerated. In the
even after vasectomy, known to influence nerve
female where no ejaculation occurs, the paracrine signalling
conduction or receptor binding, including spermine,
within the urethra is allowed to continue freely after
spermidine and putresciney [56,57]. These basic amines
orgasm as it had done before it, allowing extended and/or
have been used in studies involving cellular electrical
multiple orgasms within a short period of time.
currents and acetylcholine receptors because of known
Although this discussion has focused on serotonin, we cite interactions at these sites [58]. Given their relatively high
it as one illustration of possible chemoreceptor feedback on concentrations in semen and the possibility of their
sexual response in general, and on ejaculatory response interaction on targets affecting nerve conduction, such
specifically. A number of neurotransmitters, compounds represent other seminal components of
neuroregulatory peptides, biologically active amine interest regarding the MRP.
compounds, and other substances of known regulatory
Magnesium is also found in normal human semen, with
function have been isolated in human semen [46,47]. Thus,
possible interactions on paracrine receptors or autonomic
one or more active components may interact with receptors
transmission. Many other minerals, neurotransmitters, and
in the urethra to impart profound inhibitory effects on
active compounds are found in semen, opening up the
further sexual arousal. Although many substances and
possibility of a multitude of candidate molecules, operating
mechanisms are possible, we briefly mention several
individually, in combination, or in succession.
additional candidates.

Other Possible Chemoreceptor Conclusion/Outlook

Regulators Peripheral sexual reflex regulation may provide an
alternative approach to the understanding of the MRP. We
One agent that might account for a decrease in
initially identified four expectations of a parsimonious
serotonergic afferent signal amplification is the peptide
explanation for the MRP. First, any mechanism that
somatostatin, acting on neuroendocrine cells in the urethra.
accounts for the MRP should closely coincide with
Significant concentrations of somatostatin-64 have been
ejaculation and not necessarily orgasm, as some men who
isolated in human semen; in vasectomized men, the
are capable of orgasm without ejaculation report repeated
concentrations were higher [45,46]. Fractioned sampling of
cycles of sexual excitation. Second, the explanation for the
semen during ejaculation has shown that concentrations
MRP should elaborate the mechanism for the restoration
appeared greatest in the middle division, although it was
of sexual function that varies with the individual and with
present throughout the ejaculate and no specific source was
age. Third, since the MRP is generally unique to and
identified. Whatever its origin, somatostatin release might
virtually universal in sexually mature males, its
alter the excitatory effects of paracrine signalling by
mechanism should be absent in women and, presumably,
serotonin through its activities in G-protein-mediated
prepubescent males. Finally, the mechanism should
inhibition of adenylate cyclase, activation of potassium
explain how genital sensory stimulation takes on an erotic
channels, and/or closing of calcium channels [48]. This
interpretation (rather than just tactile interpretation). Our
effect is probably similar to the inhibitory effects of
model of peripheral feedback regulator has the potential
somatostatin on serotonin secretion in the gut, believed to
to meet all these expectations, although not to the same
generally antagonize the biogenic amine release from
extent. We have, however, tied the MRP to ejaculation,
neuroendocrine cells [49,50]. Potential support of
identified a possible restorative mechanism, explained
somatostatin’s inhibition on sexual arousal is the finding
how the process would not occur in women, and linked
that octreotide, a somatostatin agonist, inhibits erection in
the process to an autonomically based erotic (vs simple
male rats [51].
sensory) response.
Prostaglandins, first isolated from semen in 1935, represent
Our approach, of course, is incomplete and lacks direct
yet another class of potential mediators of the MRP. Given
empirical support, but we hope to inspire investigational
the wide array of known physiological functions of
approaches that illuminate sexual reflex regulation more
prostaglandins [52–54], including use as a vasodilator to
completely. Although our approach offers numerous
treat erectile dysfunction, along with their relatively high
possibilities for investigation, we suggest several options.
concentrations in human semen (even after treatment
with NSAIDS), it is conceivable that one subtype of First, local anaesthetic infiltration of the seminal vesicles of
prostaglandin is responsible for the MRP, perhaps in a animal or human subjects prior to ejaculation might shed

© 2013 BJU International 449

Review
light on the role these organs play in the MRP. Given
adequate blocking of autonomic fibres within vesicular
walls, afferent autonomic signalling might be sufficiently
interrupted to affect arousability and/or the MRP. A marked
decrease in arousability would suggest that sexual readiness
is at least partially dependent on a continuous afferent tone
from the seminal vesicles. The opposite might be seen,
however, with no change in arousability from control and a
decreased refractory period owing to the absence of
tonacity change after ejaculation.
Second, spinal signal interruption through anaesthetic
intervention could be an option. Dense thoracic spinal
anaesthesia in healthy volunteers might sufficiently
interrupt brain interaction with peripheral sexual reflexes.
Under conditions of spinal anaesthesia, an ability to
ejaculate once, but an inability to ejaculate a second time
within a short timeframe (compared with baseline), would
support a peripheral regulatory mechanism. In addition,
retrospective analysis of ejaculatory patterns in spinal
cord-injured men might shed further light on this notion,
although such studies would be complicated by varied
types and levels of injury.
Third, animal studies could uncover the role of peripheral
tension receptors, for example, by implanting a
volume-maintaining device into the rodent genital tract.
With the device in place, we might expect mounts and
intromissions to increase, since vesicular stretch would be
maintained despite ejaculation, a process that has already
received preliminary, though perhaps anecdotal, support
[59,60]. Also, such studies might clarify the limited role of
such receptors, for example, as in vasectomized men who
still experience a refractory period.
Fourth, the impact of ejaculation on peripheral reflexes
might be investigated using transelectrical nerve
stimulation to elicit the BCR in conjunction with anal or
peritoneal muscle response over the sexual response cycle.
We hypothesize that in males the reflex will be weakened or
abolished after ejaculation, while in females this reflex will
be maintained even after a series of orgasmic contractions.
Finally, to explore possible systems involved in the integrity
of the MRP, one might employ pharmacological tools to
block ejaculatory contractions (to determine whether their
role is critical), or to pharmacologically mimic autonomic
ascending signals from the distended state of the seminal
vesicles. Another approach might involve injection of a
vesicular-distending compound that hardens, continuously
maintaining a distended state.
In conclusion, we believe that re-thinking the MRP as a
process that parallels other self-regulatory processes within
the body may prove a significant advance in the
understanding of this phenomenon.
450 © 2013 BJU International
Conflict of Interest
None declared.
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Correspondence: Kenneth R. Turley M.D., 3111 E. 18th St.
Sterling, IL 61081, USA.
e-mail: kennamy@hotmail.com
Abbreviations: MRP, male refractory period; PEI,
post-ejaculatory interval; 5-HT, 5-hydroxytryptamine
(serotonin); CV, cardiovascular; GI, gastrointestinal; BCR,
bulbocavernosus reflex.