Normal male sexual function:

emphasis on orgasm and ejaculation

Amjad Alwaal, M.D., M.Sc.,a,b Benjamin N. Breyer, M.D., M.A.S.,b and Tom F. Lue, M.D.b
a b
Department of Urology, King Abdulaziz University, Jeddah, Saudi Arabia; and Department of Urology, University of
California, San Francisco, California

Orgasm and ejaculation are two separate physiological processes that are sometimes difficult to distinguish. Orgasm is an intense tran-
sient peak sensation of intense pleasure creating an altered state of consciousness associated with reported physical changes. Antegrade
ejaculation is a complex physiological process that is composed of two phases (emission and expulsion), and is influenced by intricate
neurological and hormonal pathways. Despite the many published research projects dealing with the physiology of orgasm and ejac-
ulation, much about this topic is still unknown. Ejaculatory dysfunction is a common disorder, and currently has no definitive cure.
Understanding the complex physiology of orgasm and ejaculation allows the development of therapeutic targets for ejaculatory
dysfunction. In this article, we summarize the current literature on the physiology of orgasm and ejaculation, starting with a brief
description of the anatomy of sex organs and the physiology of erection. Then, we describe
the physiology of orgasm and ejaculation detailing the neuronal, neurochemical, and hormonal
control of the ejaculation process. (Fertil SterilÒ 2015;104:1051–60. Ó2015 by American Soci- Use your smartphone
ety for Reproductive Medicine.) to scan this QR code
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FUNCTIONAL ANATOMY OF
E
jaculatory dysfunction is one of of the penis. In this section, we summa-
the most common male sexual THE MALE GENITAL ORGANS rize some of those mechanisms.
dysfunctions that is often mis-
The male genital system consists of
diagnosed or disregarded. At present,
external and internal reproductive and Cerebral Control
there is no definitive cure for ejacula-
sexual organs such as the penis, pros-
tory dysfunctions (1). New research on Cerebrally controlled penile erections
tate, epididymis, and testes. Figure 1
the physiology of ejaculation keeps are induced through erotic visual stim-
shows the gross anatomy of the ejacu-
emerging to identify targets of treat- uli or thoughts. The main cerebral
latory structures. Table 1 provides a
ment. However, knowledge about this structures involved in erection are con-
summary of the functional anatomy
topic is still lacking. In the present tained within the medial preoptic area
of these organs (2–5).
article, we summarize the current liter- (MPOA) and paraventricular nucleus
ature on the physiology of ejaculation. (PVN) in the hypothalamus (6). Dopa-
We describe the anatomy of the organs PHYSIOLOGY OF ERECTION mine is the most important brain
involved and the erection physiology. The penile erection results from com- neurotransmitter for erection, likely
We discuss the physiology of orgasm plex neurovascular mechanisms. through its stimulation of oxytocin
and ejaculation as two separate physio- Several central and peripheral neuro- release (7). Another important neuro-
logical processes. In addition, we logical factors in addition to molecular, transmitter is norepinephrine, which is
describe the neurochemical and hor- vascular, psychological and endocrino- demonstrated through the erectogenic
monal regulation of the ejaculation logical factors are involved, and the effect of the a-2 agonist (Yohimbine)
process. balance between these factors is what (8). Several other brain neurotransmit-
eventually determines the functionality ters are involved in the erection process
to varying degrees such as nitric oxide
Received July 15, 2015; revised August 17, 2015; accepted August 26, 2015; published online
(NO), a-melanocyte stimulating hor-
September 16, 2015. mone (a-MSH), and opioid peptides (9).
A.A. has nothing to disclose. B.N.B. has nothing to disclose. T.F.L. has nothing to disclose.
Reprint requests: Amjad Alwaal, M.D., M.Sc., King Abdulaziz University, Department of Urology, P. O.
Box 80215, Jeddah, Saudi Arabia 21589 (E-mail: amjadwal@yahoo.com).
Autonomic Control
Fertility and Sterility® Vol. 104, No. 5, November 2015 0015-0282/$36.00
Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc.
Parasympathetic stimulation is the
http://dx.doi.org/10.1016/j.fertnstert.2015.08.033 main mediator for penile tumescence,

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(19). The eventual smooth muscle relaxation and

FIGURE 1
vasodilation results in blood flowing into the paired corpora
and filling of the sinusoids, with increased intracorporal
pressure (to >100 mm Hg during full erection) and
compression of the subtunical venules, markedly reducing
the venous outflow (13).

PHYSIOLOGY OF ORGASM
There is no standard definition of orgasm. Each specialty such
as endocrinology or psychology examines this activity from
each one's perspective, making it difficult to reach a
consensus on the definition. Orgasm is generally associated
with ejaculation, although the two processes are physiologi-
cally different (20). Certain physiological features are associ-
ated with orgasm, including hyperventilation up to 40
breaths/min, tachycardia, and high blood pressure (21). In
fact, faster heart rate was found to be an indicator of ‘‘real’’
male orgasm during intravaginal intercourse, differentiating
it from ‘‘fake’’ orgasm (22). Orgasm is also associated with
powerful and highly pleasurable pelvic muscle contractions
(especially ischiocavernosus and bulbocavernosus) (23),
along with rectal sphincter contractions and facial grimacing
(21). There is also an associated release and elevation in PRL
and oxytocin levels after orgasm; however, the significance
Gross anatomy of the ejaculation structures. (Reprinted with of this elevation is not entirely clear (24).
permission from Sheu G, Revenig LM, Hsiao W. Physiology of Studies using positron emission tomography, which mea-
ejaculation. In: Mulhall JP, Hsiao W, eds. Men's sexual health and
fertility: a clinician's guide. New York: Springer; 2014:15.) sures changes in regional cerebral blood flow, have identified
Alwaal. Normal male sexual function. Fertil Steril 2015. areas of activation in the brain during orgasm. Primary
intense activation areas are noted to be in the mesodience-
phalic transition zones, which includes the midline, the
zona incerta, ventroposterior and intralaminar thalamic
although central suppression of the sympathetic nervous sys-
nuclei, the lateral segmental central field, the suprafascicular
tem also plays a role. Parasympathetic supply to the penis is
nucleus, and the ventral tegmental area. Strong increases
derived from the sacral segments S2-S4 (10). However, pa-
were seen in the cerebellum. Decreases were noted at the en-
tients with sacral spinal cord injury still maintain erections
torhinal cortex and the amygdale (25).
through psychogenic stimulation, although of less rigidity
Quality and intensity of orgasms are variable. For
than normal. These psychogenic erections do not occur in pa-
instance, short fast buildup of sexual stimulation toward
tients with lesions above T9 (11), suggesting that the main
orgasm is associated with less intense orgasms than slow
mechanism for these erections is central suppression of sym-
buildup. Early orgasms are less satisfying than later orgasms
pathetic stimulation (12). Patients with lesions above T9 still
in life as the person learns to accept the pleasure associated
may maintain reflexogenic erections. This implies that the
with orgasms. Lower levels of androgen are associated with
main mechanism for reflexogenic tumescence is the preserva-
weaker orgasms, such as in hypogonadism or in older age
tion of the sacral reflex arc, which mediates erection through
(20). It has been suggested that pelvic muscle exercises,
tactile penile stimulation (13, 14).
particularly the bulbocavernosus and ischiocavernosus mus-
cles, through contracting those muscles 60 times, 3 times
Molecular Mechanisms daily for 6 weeks will enhance the pleasure associated with
The penis at baseline is in a flaccid state maintained by the orgasm (20). However, the effort and time associated with
contraction of corporal smooth muscles and constriction of such exercises prevent their utilization. The orgasm induced
cavernous and helicine arteries leading to moderate state of through deep prostatic massage is thought to be different
hypoxia with partial pressure of oxygen of 30–40 mm Hg from the orgasm associated direct penile stimulation.
(15). During sexual arousal, NO is released from cavernous Although penile stimulation orgasms are associated with
nerve terminals through the action of neuronal NO synthase 4–8 pelvic muscle contractions, prostatic massage orgasms
(16). The NO activates guanylate cyclase, which in turn con- are associated with 12 contractions. Prostatic massage or-
verts guanosine triphosphate to cyclic guanosine monophos- gasms are thought to be more intense and diffuse than penile
phate (15, 17), leading eventually to smooth muscle stimulation orgasms, but they require time and practice and
relaxation and vasodilation (18). Although the initiation of are not liked by many men (20, 26, 27).
tumescence is through neuronal NO synthase, the Following orgasm in men is a temporary period of inhibi-
maintenance of erection is through endothelial NO synthase tion of erection or ejaculation called the refractory period.

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TABLE 1

Summary of the functional anatomy of the male genital organs.

Organ Characteristics
Penis Composed of three chambers: paired corpora cavernosa (erectile bodies) and a midline ventral corpus spongiosum
(contains urethra)
Main blood supply: internal pudendal artery
Somatic sensation: pudendal nerve (S2-S4)
Autonomic nerve fibers: cavernous nerves (pelvic plexus) contain both sympathetic (hypogastric plexus) and
parasympathetic nerve fibers (S2-S4)
Urethra Four segments: prostatic urethra, membranous urethra (passes through the urogenital diaphragm), bulbar urethra,
and penile urethra (ends with a small dilatation at the fossa navicularis near the meatus)
Cowper's glands: located on both sides of the membranous urethra and open in the bulbar urethra
Veromontanum: small elevation of the posterior wall of the membranous urethra, related to ejaculatory ducts, prostatic
utricle, and prostatic ducts
Testis It is divided by fibrous septa into many lobules containing seminiferous tubules
Leydig cells: main source of T production
Seminiferous tubules: contain germ cells and sertoli cells. Forms the rete testis inside the testis mediastinum
Rete testis: gives rise to 15–20 efferent ductules
Epididymis Posterior and superior to the testicle
Composed of head, body, and tail
Efferent ductules unite to form the convoluted duct of the epididymis
Becomes the vas deferens at the end of the tail
Vas deferens Muscular tube; typically 45 cm long and has a 2.5 mm diameter
It is a continuation of the epididymis
Joins the seminal vesicle duct to form the ejaculatory duct, which then drains into the veromontanum
Supplied by the vasal artery, a branch of the inferior vesical artery
Prostate Surrounds the prostatic urethra
Composed of 70% glandular component and 30% fibromuscular component
Arterial supply: inferior vesical and middle rectal arteries
Seminal Paired structures; located lateral to the vas deferens
vesicles Typically 5 cm long and 1 cm wide
Joins the vas to form the ejaculatory duct
Arterial supply: inferior vesical and middle rectal arteries
Alwaal. Normal male sexual function. Fertil Steril 2015.

This is a poorly understood phenomenon, with some investi- inal fluid (1, 31). The organs involved in the ejaculation
gators suggesting a central rather than spinal mechanism process receive dense autonomic nerve supply, both
causing it (28). Elevated levels of PRL and serotonin after sympathetic and parasympathetic, from the pelvic plexus.
orgasm have been suggested as a potential cause; however, The pelvic plexus is located retroperitoneally on either side
there is much debate about their exact role (29). More research of the rectum, lateral and posterior to the seminal vesicle
is still needed in the area of male orgasm (20). (32). It receives neuronal input from the hypogastric and
pelvic nerves in addition to the caudal paravertebral
sympathetic chain (33). The sympathetic neurons play the
PHYSIOLOGY OF EJACULATION
predominant role in the ejaculation process. Their nerve
Ejaculation is a physiological process heavily controlled by terminals secrete primarily norepinephrine, although other
the autonomic nervous system. It consists of two main neurotransmitters such as acetylcholine and nonadrenergic/
phases: emission and expulsion. The main organs involved noncholinergic also play important roles (34). The role of the
in ejaculation are the distal epididymis, the vas deferens, hypogastric plexus in emission is best demonstrated
the seminal vesicle, the prostate, the prostatic urethra, and clinically by the loss of emission after non-nerve sparing
the bladder neck (30). para-aortic lymph node dissection for testicular cancer (35),
and induction of emission in paraplegic men through electri-
Emission cal stimulation of superior hypogastric plexus (35). Input from
genital stimulation is integrated at the neural sacral spinal
The first step in the emission phase is the closure of bladder level to produce emission (36). The emission phase of ejacula-
neck to prevent retrograde spillage of the seminal fluid into tion is also under a considerable cerebral control, and can be
the bladder. This is followed by the ejection of prostatic secre- induced through physical or visual erotic stimulation (37).
tions (10% of the final semen volume) containing acid phos-
phatase, citric acid, and zinc, mixed with spermatozoa from
the vas deferens (10% of the volume) into the prostatic urethra. Expulsion
Subsequently, the fructose-containing seminal vesicle fluid Expulsion follows emission as the process of ejaculation cli-
alkalinizes the final ejaculatory fluid. The seminal vesicle fluid maxes, and refers to the ejection of semen through the urethral
constitutes 75%–80% of the final seminal fluid. Cowper's meatus. The semen is propelled through the rhythmic contrac-
glands and periurethral glands produce a minority of the sem- tions of the pelvic striated muscles in addition to the

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bulbospongiosus and ischiocavernosus muscles (23). To Peripheral Nervous System

achieve antegrade semen expulsion, the bladder neck remains
Afferents. The main sensory input from the penis comes from
closed, whereas the external urethral sphincter is open. The
the dorsal nerve of the penis, which transmits sensation from
external sphincter and the pelvic musculature are under so-
the glans, prepuce, and penile shaft. It transmits signals to the
matic control; however, there is no evidence that voluntary
upper and lower segments of the sacral spinal cord (42). The
control plays a role in the expulsion process (30). The exact
glans contains encapsulated nerve endings, termed Krause-
trigger for expulsion is unknown. It has been suggested that
Finger corpuscles, whereas the remaining penile shaft con-
a spinal center is triggered during emission of seminal fluid
tains free nerve endings. Stimulation of these corpuscles
into the prostatic urethra (38). However, there is mounting ev-
potentiated by stimulation from other genital areas, such
idence through clinical and experimental studies to suggest
the perineum, testes, and penile shaft, play an important
that this is not the case. For instance, men can still have rhyth-
role in the ejaculation process (43). A secondary afferent route
mic contractions during orgasm despite ‘‘dry ejaculation,’’ for
is through the hypogastric nerve, which runs through the par-
example, due to prostatectomy (23, 39, 40). This, in addition
avertebral sympathetic chain to enter the spinal cord through
to the identification of spinal generator for ejaculation (SGE)
the thoracolumbar dorsal roots (44). The sensory afferents
in rats, led to the postulation that the process of expulsion is
terminate in the medial dorsal horn and the dorsal gray
a continuum of the process initiated through emission, after
commissure of the spinal cord (45).
reaching a certain spinal activation threshold (30, 41).
Efferents. The efferent peripheral nervous system constitutes
of sympathetic, parasympathetic, and motor nervous compo-
NEURONAL CONTROL OF EJACULATION
nents (46). The soma of the preganglionic sympathetic cell
Ejaculation is heavily controlled by the nervous system. bodies involved in ejaculation are located in the intermedio-
Figure 2 summarizes the reflex circuit necessary to elicit lateral cell column and in the central autonomic region of the
ejaculation. thoracolumbar segments (T12-L1) (47). The preganglionic
sympathetic fibers emerge from the ventral roots of the spinal
cord and travel through the paravertebral sympathetic chain
FIGURE 2 to relay either directly through the splanchnic nerve, or
through relaying first in the celiac superior mesenteric
ganglia and then through the intermesenteric nerve, to the
inferior mesenteric ganglia (48). The hypogastric nerve then
emanates from the inferior mesenteric ganglia to join the
parasympathetic pelvic nerve to form the pelvic plexus, which
then sends fibers to the ejaculation structures (49). The pre-
ganglionic parasympathetic cell bodies are located in the
sacral parasympathetic nucleus. The sacral parasympathetic
nucleus neurons travel then in the pelvic nerve to the post-
ganglionic parasympathetic cells located in the pelvic plexus.
The motor neurons involved in ejaculation are located in
Onuf's nucleus in the sacral spinal cord, which projects fibers
through the motor component of the pudendal nerve to reach
the pelvic musculature, including the bulbospongiosus, is-
chiocavernosus, and external urethral sphincter (50).

Central Nervous System

Spinal network. The thoracolumbar sympathetic, sacral
parasympathetic (mainly sacral parasympathetic nucleus),
and somatic sacral Onuf's nucleus ejaculatory spinal nuclei
play an important role in the integration of peripheral and ce-
rebral input and coordinating output to the pelviperineal
structures involved in ejaculation (46). An additional spinal
center is the SGE located in laminae X and VII of L3-L4 spinal
segments (51). The SGE contains spinal interneurons called
lumbar spinothalamic cells, which project fibers to the parvo-
Reflex circuit needed to establish ejaculation. (Reprinted with cellular subparafascicular nucleus of the thalamus in addition
permission from Sheu G, Revenig LM, Hsiao W. Physiology of to preganglionic sympathetic and parasympathetic neurons
ejaculation. In: Mulhall JP, Hsiao W, eds. Men's sexual health and innervating the pelvis (41). The SGE stimulation elicits a com-
fertility: a clinician's guide. New York: Springer; 2014:18.)
plete ejaculatory response resulting in collection of motile
Alwaal. Normal male sexual function. Fertil Steril 2015.
spermatozoa in anesthetized rats (52). Further research on

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the SGE spinal center is still needed, and it is unclear whether

FIGURE 3
it contains other cells than lumbar spinothalamic cells.
Brain network. Sensory and motor areas in the brain play an
important role in the ejaculation, which requires a highly coor-
dinated and integrated central process. The study by Holstege
et al. (25) using positron emission tomography showed that
certain areas in the brain are activated in the orgasm and ejac-
ulation process. Furthermore, specific areas in the brain have
been involved in the ejaculation process, as demonstrated in
animal immunohistochemical studies examining Fos protein
pattern of expression (53–56), and confirmed using a
serotonin 1A subtype receptor agonist proejaculatory
pharmacologic agent in rats (57). These are discrete areas
within the posteromedial bed nucleus of stria terminalis, the
parvicellular part of the subparafascicular thalamus, the
posterodorsal preoptic nucleus, and the posterodorsal medial
amygdaloid nucleus. There are reciprocal connections that
link those areas to the MPOA of the hypothalamus, a brain
area with a well-established role in controlling sexual behavior
as demonstrated by anatomical and functional studies (54, 55,
58). Electrical or chemical stimulation of the MPOA elicited
ejaculation (59–62), whereas an MPOA lesion was shown to
abolish both phases of ejaculation (63). No direct connections
of MPOA to the spinal centers for ejaculation were found on
Putative brain structures involved in ejaculation. BNSTpm ¼
neuroanatomical studies; however, there are projections of posteromedial bed nucleus of stria terminalis; MeApd ¼
MPOA to other regions in the brain involved in ejaculation, posterodorsal medial amygdaloid nucleus; MPOA ¼ medial preoptic
such as PVN, the periaqueductal gray, and the area; PAG ¼ periaqueductal gray; nPGi ¼ paragigantocellular
nucleus; PNpd ¼ posterodorsal preoptic nucleus; PVN ¼
paragigantocellular nucleus (nPGi) (64–66). paraventricular thalamic nucleus; SPFp ¼ parvicellular part of the
The PVN projects to pudendal motor neurons located in subparafascicular thalamus. (Reprinted with permission from
the L5-L6 spinal segment in addition to autonomic pregangli- Clement P, Giuliano F. Physiology of ejaculation. In: Mulhall JP,
onic neurons in the lumbosacral spinal cord in rats (45, 67, Incrocci L, Goldstein I, Rosen RC, eds. Cancer and sexual health.
New York: Springer; 2011:82.)
68). It also projects to nPGI in the brainstem (69). Bilateral
Alwaal. Normal male sexual function. Fertil Steril 2015.
lesions of the PVN with N-methyl-D-aspartate (NMDA)
results in a one-third reduction of the seminal ejaculate ma-
terial weight (70). The parvicellular part of the subparafascic-
ular thalamus was found to send projections to bed nucleus of
stria terminalis, medial amygdala (MeA), and MPOA (71, 72)
and receives input from lumbar spinothalamic cells (51). different sites of action within the spinal and the supraspinal
The precise role of these regions is still unclear but they are pathways, and the presence of multiple receptor types. Some
likely involved in relaying genital signals to MPOA (53, 55). of the molecules that received special attention for their role
The brainstem regions (nPGI and periaqueductal gray) have in ejaculation are mentioned later.
recently received increasing attention. The nPGI nucleus
likely plays an inhibitory role in ejaculation as evidenced
through the urethrogenital reflex experimental model, a rat Dopaminergic Control
model for the expulsion phase of ejaculation (73, 74). Using
the same model, the periaqueductal gray was found to be Dopamine is known to be important for normal male sexual
important for the ejaculation process, likely by acting as a response (76, 77). Two families of dopamine receptors exist,
relay between MPOA and nPGI (75). Midbrain structures D1-like (D1 and D5 receptors) and D2-like (D2, D3, and D4 re-
have a significant role in ejaculation; however, much is still ceptors) (46). In rats, D2-like receptors are known to stimulate
unknown about their exact role and further research is ejaculation (78, 79), and trigger ejaculation even in
needed. Figure 3 summarizes the putative brain structures anesthetized rats (80, 81). Systemic injection of the D3
involved in ejaculation. receptor agonist 7-OH-DPAT has been shown to trigger ejac-
ulation in rats without affecting arousal (82, 83). It also
triggers ejaculation in anesthetized rats when injected
NEUROCHEMICAL REGULATION OF directly into the cerebral ventricles or MPOA with the effect
EJACULATION being specifically reversed by the D3, not the D2 antagonist
Many neurotransmitters are involved in the ejaculation pro- (84, 85). The D3 receptor blockage has been shown to
cess. Defining the exact role of these neurotransmitters is inhibit the expulsion phase of ejaculation and lengthen
difficult given the variety of sexual parameters affected, the ejaculation latency in rats (86).

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Serotonergic Control and animals results in increased ejaculated spermatozoa

Evidence suggests that serotonin (5HT) inhibits ejaculation (103), confirming that oxytocin has a role in male genital tract
(87). Selective serotonin reuptake inhibitors increase 5HT motility. It was specifically found to augment powerful
tone resulting in impairment of ejaculation, which led to their epididymal contractions and sperm motility (104), an impor-
clinical use in premature ejaculation. This inhibitory effect is tant effect blunted by pretreatment with the oxytocin antag-
likely to occur in the brain (88), as 5HT effect on ejaculation in onist (des Gly–NH2d(CH2)5–[d-Tyr2,Thr4] ornithine
the spine is likely stimulatory (89). The amphetamine deriva- vasotocin) (105). Peripheral oxytocin receptors were found
tive p-chloroamphetamine leads to a sudden release of 5HT in to be highly expressed in the epididymis and tunica albuginea
synaptic clefts triggering ejaculation in anesthetized rats with (in smooth muscles more than epithelial cells), and to a lesser
complete spinal cord lesion (89). Intrathecal serotonin or se- extent in the vas deferens and seminal vesicle (104). Oxytocin
lective serotonin reuptake inhibitor injection leads to has a synergistic action on the epididymis with endothelin-1,
enhancement of the expulsion phase of ejaculation (88). There where they augment epididymal contraction and propel sper-
are 14 receptor subtypes for 5HT, with 1A, 1B, and 2C being matozoa forward (102, 106). Injection of oxytocin into the
the ones involved in ejaculation (90). It is difficult to desig- cerebral ventricles in male rats facilitated ejaculation by
nate one influence for each receptor subtype, as each receptor shortening the ejaculation latency and postejaculatory
could either activate or inhibit ejaculation depending on its refractory periods (107), whereas these effects were curbed
location within the central nervous system (46). using the oxytocin receptor antagonist (d(CH2)5–Tyr(Me)–
[Orn8]vasotocin) injected into the cerebral ventricles (108).
Despite these encouraging findings and some anecdotal
Nitric Oxide evidence suggesting that intranasal oxytocin can facilitate
The role of NO in ejaculation has received special attention af- orgasm in an anorgasmic male (109), a double-blind pla-
ter the introduction of type-5 phosphodiesterase (PDE5) in- cebo-controlled clinical study (110) failed to demonstrate
hibitors and using them for premature ejaculation. Nitric an effect of intranasal oxytocin on sexual behavior.
oxide has an inhibitory role on the ejaculation process (1).
Centrally, intrathecal sildenafil results in elevation of NO
and cyclic guanosine monophosphate levels in MPOA causing Prolactin
a decreased peripheral sympathetic tone and inhibition of Hyperprolactinemia has a marked inhibitory effect on male
ejaculation (91). N-Nitro-L-arginine methyl-ester injection, sexual desire (111). A modest increase in serum PRL levels
an NO synthase inhibitor, was shown to increase the number (15–20 ng/mL) has been detected in men after orgasm, and
of seminal emissions and reduce latency to first seminal emis- could be contributing to the after-orgasm refractory period
sion in rats (92). Peripherally, nitronergic innervation and NO (112). Some investigators have hypothesized that a low PRL
synthase were found in the seminal vesicle, vas deferens, level is a cause of premature ejaculation, where PRL levels
prostate, and urethra (93–97). Therefore, drugs such as were similarly low in those men with lifelong or acquired pre-
PDE5 inhibitors or NO donors are associated with reduced mature ejaculation (113). Further research is needed on this
seminal vesicle contraction and inhibit seminal emission issue.
(92). The administration of NO inhibitors, such as L-nitro-
arginine-methylester, diminishes human seminal vesicle
contraction (98), inhibits vasal contraction in guinea pigs Thyroid Hormones
(99), and decreases latency to ejaculation in rats (100). The relationship between thyroid hormonal abnormalities
Furthermore, reduced latency to emission was found in and ejaculatory dysfunction has been well documented
knockout mice for the gene encoding endothelial NO (114–116). In rats, L-thyroxin administration has been
synthase compared with their wild-type counterparts (101). shown to increase bulbospongiosus contractile activity and
seminal vesicle contraction frequency (117). Clinically, the
HORMONAL REGULATION OF EJACULATION prevalence of suppressed TSH, which is a marker of
Although male sexual function is heavily regulated by the hyperthyroidism, was found to be twofold higher in patients
hormonal system, there are few clinical studies performed with premature ejaculation than in patients who reported
to evaluate hormonal regulation of ejaculation, and the normal ejaculatory timing (118). In the first prospective
knowledge about hormonal effect on ejaculation is still lack- multicenter study (114) on the topic, half of
ing. We discuss some of the studies examining the effect of hyperthyroidism patients had premature ejaculation,
different hormones on ejaculation. whereas only 15% reported this symptom after cure of their
thyroid dysfunction. Another single-center prospective study
by Cihan et al. (116) demonstrated a prevalence of 72% of pre-
Oxytocin mature ejaculation in hyperthyroidism, which was reduced
Oxytocin is an oligopeptide synthesized in the supraoptic and after treatment. It also identified a positive correlation of
PVN of the hypothalamus and released from the posterior pi- € urk et al.
TSH with intravaginal ejaculation latency time. Ozt€
tuitary gland. Oxytocin serum level increases after male ejac- (119) found similar results. However, Waldinger et al. (120)
ulation to levels ranging from 20%–360% of normal levels found no correlation between TSH and intravaginal ejacula-
before reaching baseline at 10 minutes after ejaculation tion latency time in a cohort of Dutch men with lifelong pre-
(102). Pharmacologic oxytocin administration in humans mature ejaculation. A meta-analysis by Corona et al. (102)

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TABLE 2

Neurochemical and hormonal regulation of ejaculation.

Neurotransmitter/hormone Effect
Dopamine Stimulates ejaculation through D2-like receptors (D2, D3, and D4 receptors, mainly D3)
Serotonin Inhibits ejaculation in the brain and stimulates it in the spine through the receptors 5HT, with 1A, 1B, and 2C
Nitric oxide Inhibits ejaculation through reduction of seminal vesicle contraction and seminal emission
Oxytocin Synthesized in the supraoptic and PVN of the hypothalamus and released from the posterior pituitary gland
Augments powerful epididymal contractions and sperm motility
Acts in the CNS to stimulate ejaculation
Prolactin Secreted from the pituitary gland
Hyperprolactinemia has a marked inhibitory effect on male sexual desire, through inhibition of GnRH
(therefore T production) and dopamine production
Thyroid hormones Hypothyroidism and hyperthyroidism are associated with delayed and premature ejaculation, respectively
Glucocorticoids Cortisol levels are elevated after ejaculation in animal studies
No change in cortisol levels in humans
Replacement of cortisol in Addison disease improves sexual function including orgasm
Estrogens Regulates the emission phase of ejaculation through the regulation of epididymal contractility, luminal fluid
reabsorption, and sperm concentration
Androgens Low levels are associated with delayed ejaculation, whereas high levels are associated with premature ejaculation
Facilitates the control of the ejaculatory reflex through its androgen receptors in the MPOA and other
areas in the CNS
Pelvic floor muscles involved in ejaculation are androgen dependent
Note: CNS ¼ central nervous system; MPOA ¼ medial preoptic area; PVN ¼ paraventricular nucleus.
Alwaal. Normal male sexual function. Fertil Steril 2015.

demonstrated a threefold increase of hyperthyroidism in pa- is the reason for recommending Tamoxifen as a first-line
tients with premature ejaculation compared with controls, a treatment for idiopathic oligospermia by the World Health Or-
finding that was more pronounced in patients with acquired ganization (136). Finkelstein et al. (137) showed that E2
rather than lifelong premature ejaculation. They also showed deficiency, along with androgen deficiency, contributes to
an increase in intravaginal ejaculation latency time by 84.6  decreased libido and erectile function.
34.2 seconds (P¼ .001) upon treatment of hyperthyroidism.
These findings suggest that thyroid hormones do not only
Androgens
affect the ankle reflex, but also the ejaculatory reflex, and
screening patients with ejaculatory dysfunction for thyroid Testosterone, through its central and peripheral androgen re-
hormone abnormalities is warranted (102). ceptors, has a well-known role on male sexual function, partic-
ularly on libido (138). Low T levels are associated with delayed
ejaculation, whereas high levels were associated with prema-
Glucocorticoids ture ejaculation (102). This is likely because the emission phase
Cortisol (F) levels in several animal studies were found to be of the ejaculation relies on the NO-PDE5 system, which is influ-
elevated during arousal and ejaculation (121–123). In enced by T (138, 139). Testosterone facilitates the control of the
horses and donkeys, F was elevated 30 minutes after ejaculatory reflex through its androgen receptors in the MPOA
ejaculation, with unknown significance of this finding (124, and other areas in the central nervous system (140).
125). In addition, F levels were sharply elevated after Furthermore, pelvic floor muscles involved in ejaculation are
electroejaculation in several anesthetized animal studies androgen dependent (141). There are likely multiple
(126, 127). In humans, however, there was no change in F mechanisms involved in T action and further research is
levels whether during sexual stimulation or orgasm (128– needed to identify specific targets for treatment in the
131). Although hypercortisolism in men was associated with ejaculatory reflex. Table 2 summarizes the neurochemical and
reduced libido, no effect was identified on orgasm or hormonal regulation of ejaculation.
ejaculation (132). Replacement of F in Addison disease was In conclusion, ejaculation is a complex process involving
associated with improvement in overall sexual function several anatomical structures and under extensive neuro-
including orgasm (133). Data in humans are still too chemical and hormonal regulation. Orgasm, although associ-
preliminary to draw final conclusions, and further research ated with ejaculation, is a distinct physiological process,
is needed. different from ejaculation. Many aspects of these physiolog-
ical processes are still unknown and further research is needed
to identify treatments for ejaculatory dysfunction.
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