REVIEWS

The hormonal control of ejaculation

Giovanni Corona, Emmanuele A. Jannini, Linda Vignozzi, Giulia Rastrelli and Mario Maggi
Abstract | Hormones regulate all aspects of male reproduction, from sperm production to sexual drive.
Although emerging evidence from animal models and small clinical studies in humans clearly point to a role
for several hormones in controlling the ejaculatory process, the exact endocrine mechanisms are unclear.
Evidence shows that oxytocin is actively involved in regulating orgasm and ejaculation via peripheral, central
and spinal mechanisms. Associations between delayed and premature ejaculation with hypothyroidism
and hyperthyroidism, respectively, have also been extensively documented. Some models suggest that
glucocorticoids are involved in the regulation of the ejaculatory reflex, but corresponding data from human
studies are scant. Oestrogens regulate epididymal motility, whereas testosterone can affect the central
and peripheral aspects of the ejaculatory process. Overall, the data of the endocrine system in regulating
the ejaculatory reflex suggest that widely available endocrine therapies might be effective in treating sexual
disorders in these men. Indeed, substantial evidence has documented that treatments of thyroid diseases are
able to improve some ejaculatory difficulties.
Corona, G. etal. Nat. Rev. Urol. 9, 508519 (2012); published online 7 August 2012; doi:10.1038/nrurol.2012.147

Introduction
Ejaculationthe ejection of seminal fluidis essen- sensation of an ejaculatory inevitability. The true ejacu-
tially a spinal reflex triggered by genital and/or brain lation is then somatically activated from the sacral spinal
stimulation. 1,2 The process has three distinct phases: cord (the mechanical centres at S2S4) by the pudendal
emission, ejection (expulsion, or true ejaculation itself) nerve. Activation of the pudendal nerve provokes rhyth-
and orgasm. The ejaculation reflex is coordinated by the mic contractions of the pelvic floor (bulbospongiosus,
spinal ejaculatory generator (SEG), which is located at bulbocavernosus and levator ani muscles), which force
the T12L1L2 level of the spinal cord (Figure1).1,2 The the ejaculate through the distal urethra. Sensory inputs
SEG regulates the sympathetic, parasympathetic and somatosensory, visceral sensory or proprioceptiveto
motor outflow that prompts ejaculation. This nervous the spinal control centre during sexual activity trigger
outflow is combined by the SEG with inputs of bio- the onset of ejaculation. Finally, orgasm (with its emo-
chemical or mechanical information from the accessory tional, cognitive, perceptive and autonomic aspects) is
sex organs.1,2 the final phase of the reflex that usually coincides with
Supraspinal sites regulate the inhibition and excita- ejaculation.3 However, orgasm can also occur without
Endocrinology Unit, tion of the SEG via an intricate interaction of central ejaculation, for example, in prepubertal boys.4
Medical Department, serotonergic and dopaminergic neurons, as well as the Owing to the expansive nervous components par-
Azienda Usl Bologna
Maggiore-Bellaria auxiliary involvement of other neurotransmitters.1,2 Both ticipating in the ejaculation reflex, that multiple neuro
Hospital, Largo parasympathetic and sympathetic nerves are activated transmitters are involved is unsurprising.510 In this
Nigrisoli2, 40133
Bologna, Italy
in an integrated and time-coordinated fashion, prompt- Review, we discuss the endocrine control of the ejacu-
(G.Corona). School of ing the efferent limb of the reflex (the emission phase). latory reflex. The understanding of the involvement of
Sexology, Department Specifically, the parasympathetic nerves regulate the the endocrine system in the ejaculatory process and
of Experimental
Medicine, University of secretion of seminal fluid from the epithelial cells of the intravaginal ejaculatory latency time (IELT) is still in its
LAquila, Coppito, accessory sex glands, whereas the sympathetic nerves infancy, despite the knowledge that male reproduction is
Building 2 Room
A2/54, Via Vetoio,
(T10L2, the secretory centre) actuate contractility of the largely hormonally regulated.11 Pituitary (oxytocin and
67100 LAquila, Italy epididymis and vas deferens as well as the distal trans- prolactin), thyroidal, adrenal and gonadal hormones
(E.A. Jannini). Sexual port of spermatozoa. Next, the activity of adrenergic might control ejaculation at various levels as well as
Medicine and Andrology
Unit and Department of neurons, which originate in the pelvic plexus, causes con- overall latency time, although few clinical studies are
Clinical tractions of the seminal vesicles and prostate. These con- currently available.1215
Physiopathology,
University of Florence,
tractions work to expel sperm and seminal fluid into the
Viale Pieraccini 6, posterior urethra, which is adjacent to the bladder neck. Pituitary hormones
50139 Florence, Italy The filling of the posterior urethra in turn prompts the Neurohypophyseal hormones: oxytocin
(L. Vignozzi,
G.Rastrelli, M. Maggi). urethralmuscular reflex, which is accompanied by the The epididymis can store approximately 200 million
immotile sperm, which must be propelled through
Correspondence to:
M. Maggi Competing interests the epididymis and vas deferens during ejaculation. 16
m.maggi@dfc.unifi.it The authors declare no competing interests. Peristaltic-like contractions17 of the head (caput) and

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 FOCUS ON SEXUAL MEDICINE

body (corpus) of the epididymis result in a continual Key points

basal outflow of sperm towards the distal region of the
Oxytocin is actively involved in regulating orgasm and ejaculation via peripheral,
epididymis (cauda).18 Muscle contractions coordinated
central and spinal mechanisms
by adrenergic nerve stimulation are essential for the Peripheral prolactin levels might mirror central serotonergic tone
emission phase of the ejaculatory process. Experimental Associations between delayed ejaculation and premature ejaculation with
sympathetic denervation results in a decrease innot hypothyroidism and hyperthyroidism, respectively, have been extensively
elimination ofepididymal contractile activity,19 which documented
suggests that other non-neuronal factors take part in Animal models suggest that glucocorticoids might be involved in the regulation
regulating contractility in the epididymis. of the ejaculatory reflex, but data in human are scant
The epididymis is a male target for oestrogens that regulate epididymal motility
Oxytocin is an oligopeptide (composed of nine amino
by conditioning the responsiveness of the contractile hormones and local
acids) synthesized in the supraoptic and paraventricular peptides
nuclei of the hypothalamus that is emitted by the poste- Hypogonadal symptoms and low testosterone levels might reduce the ability to
rior pituitary.20 Although oxytocin-producing neurons ejaculate, which suggests that androgens have a central and peripheral role in
are equally present in the supraoptic and paraventricular the ejaculation reflex
nuclei of both females and males without sexual dimor-
phism,20 oxytocin is best known for its noteworthy role
in lactation and parturition.21 Oxytocin levels are main-
Cortex
tained at high levels in women to ensure rapid milk
ejection reflex and uterine contractility.22,23
By contrast, the physiological effects of oxytocin
in males have been a matter of intense debate for a Paraventricular
nucleus Medial preoptic
number of years. Debackere and colleagues first postu- nucleus
lated in the 1960s that oxytocin could be released into Locus coeruleus
the circulatory system during sexual activity.24 Using
a cross-circulation technique, they found that manual Paragigantocellular
nucleus
stimulation (per rectum) of seminal vesicles prompted
a milk-ejection response in the female partner,24 con-
firming that the male genital tract is involved in the
regulation of oxytocin response. Further studies have
demonstrated that an oxytocin surge occurs during male
sexual activity, peaking during 2528 or soon after orgasm
and detumescence.29,30 A study in men around the time
of sexual stimulation and orgasm found an increase in
plasma oxytocin levels immediately after orgasm and
a subsequent rapid decline to baseline levels within
10minutes. 31 Indeed, oxytocin levels in men during
orgasm vary considerably (increases between 20% and Sympathetic centres
360% of the basal level), which matches data from many T12L1
other species including bulls,32 rats and rabbits33 and Emission

stallions.34 Interestingly, experiments of the pharmaco- Spinothalamic cells

logical administration of oxytocinwhich was found to L3L4
Spinal generator
increase the number of ejaculated spermatozoa in dif- of ejaculation
ferent animal species,21,35 including humans36might
have uncovered the hormones specific role in regu-
lating male genital tract motility. Oxytocin treatment
also stimulates invivo37,38 and invitro3537,39 epididymal Somatic (expulsion)
motility. Hence, the oxytocin pathway should be consid- and pasymphatetic
(secretion) centres Bladder
ered for pharmacological interventions in patients with S1S3
ejaculatory disturbances. Pudendal nerve
In the 1980s, a specific oxytocin receptor was identi- Testis Afferent stimuli
Efferent stimuli
fied and characterized in the male pig genital tract.40,41 Motor supply BSM
The receptor was found to be highly expressed in the
epididymis and tunica albuginea, with a lower abundance
in vas deferens41 and seminal vesicles.40 The expression of
a specific oxytocin receptor in the epididymis was further
Figure 1 | Neurological control of ejaculation. Ejaculation is the result of the
demonstrated in several other animal species, including
coordinated contractile activity involving different ejaculatory organs organized by
monkeys,42,43 rabbits,36,44 bulls,45 sheep46 and humans36,43 the spinal ejaculatory generator, located at the T12L1L2 level of the spinal cord.
Although the receptor is localized in both the epithelial Afferent information is received by the spinal ejaculatory generator, which
and muscular cells36,4651 of the epididymis, expression coordinates sympathetic, parasympathetic and motor outflow to induce the
is highest in the smooth muscle cells of the epididymal different phases of ejaculation. Abbreviation: BSM, bulbospongiosus muscle.

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2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
cauda, which is structured in three thick layers 36,43
that mediate forceful contractile activity. By contrast,
expression of oxytocin and its receptor in the epididy-
mal caput is primarily localized in the epithelial com-
partment,36,4749 where they synergistically interact with
endothelin1.42 Endothelin1 was discovered as a potent
vasoconstrictor that acts through two distinct receptor
subtypes: endothelin1 receptor (ETA) and endothelin B
receptor (ETB).47,48 Endothelin1 is also produced by the
basal epididymal epithelial cells, which are positioned
opposite the smooth muscle layers that express the recep-
tors and mediate contractility.41,47,48 ETA and ETB are
also expressed in the epithelial cells where they mediate
endothelin1-induced oxytocin release.49
The expression of oxytocin-neurophysin1 (known
as neurophysin1), which is an oxytocin-synthesis-
associated protein, and heightened concentrations of
OXT mRNA indicates that the human epididymis syn-
thesizes oxytocin alongside endothelin1.49 The cross-
talk and feed-forward interaction between oxytocin
and endothelin1 presumably supports the autonomous
peristaltic contractions of the epididymis that enables
sperm progression. Computer analysis and time-lapse
videomicrography experiments of the rat epididymis
have shown that contractions in the caput are indeed
peristaltic and progress is unidirectional towards the
cauda.50 Oxytocin dose-dependently increases both the
fluid volume and sperm number in the luminal fluid of
the cauda within 10minutes of administration (10g
and 100g).51 These effects were selectively blunted by
pretreatment with a selective oxytocin antagonist (des
GlyNH2d(CH2)5[d-Tyr 2,Thr 4] ornithine vasotocin),51
which indicates that oxytocin promotes powerful
epididymal contractions that directly lead to a consid-
erable increase in the transport of spermatozoa towards
the vas deferens and the ejaculate.51 Collectively, these
data support the notion that oxytocin generated in the
central nervous system (CNS) upon orgasm could acti-
vate the secretion endothelin1 and oxytocin locally in
the epididymis, creating a reciprocal and synergic cross-
activation of contractile factors. The distinct upsurge
of plasma oxytocin levels during orgasm might also
promote semen emission during ejaculation and favour
penile detumescence.52
A central, extrahypothalamic release of oxytocin
by the paraventricular nuclei at ejaculation facilitates
sexual behaviour in several experimental animal studies.
Oxytocin-producing neurons project to several extra
hypothalamic areas of the CNS and the spinal cord. 53
In rats, oxytocin concentration increases threefold in
the cerebrospinal fluid 5minutes after ejaculation and
returns to the basal level within 20minutes.54 In a study of
male rats free to mate with an amenable female, oxytocin
(injected directly into the cerebral ventricle) shortened
the ejaculation latency and postejaculatory refractory
periods and, therefore, facilitated ejaculatory behav-
iour.55 When administered via an intracerebroventricular
route, oxytocin also increased the latencies of mount and
intromission.33 A selective oxytocin receptor antagonist
(d(CH2)5Tyr(Me)[Orn8]vasotocin) delivered into the
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2012 Macmillan Publishers Limited. All rights reserved
ventricular system of the brain of sexually energetic male
rats curbed their sexual behaviour (including ejacula-
tion) and reversed the prosexual effects of apomorphine,
which is a nonselective dopamine-receptor agonist.56 In
an experimental rat model of premature ejaculation,
rapid ejaculation was characterized by activation of
an increased number of oxytocin-containing neurons
(revealed by Fos immunoreactivity) in the supraoptic
nuclei.57 Injury of the paraventricular nucleus (specifi-
cally, the parvocellular neurons) in male rats reduced
the number of oxytocin-immunoreactive fibres in the
lumbosacral spinal cord, abolished the postejaculation
increase of oxytocin levels in the cerebrospinal fluid, pro-
longed mount and intromission latencies and reduced
the postejaculatory interval.54 These observations further
demonstrate the central role of oxytocin in mammalian
sexual behaviour.
Central release of oxytocin also mediates functions
with a sensory component, such as those activated
during intercourse and orgasm. For example, oxytocin
has repeatedly been implicated in sensory-related pair
bonding (in animal models as well as in humans):
expression of positive affect, affectionate touch and pro-
prioceptive contact.58,59 Furthermore, intraventricular
injection of oxytocin increased pain thresholds, whereas
central administration (within the supraoptic nuclei) of
antioxytocin serum decreased the nociceptive thresh-
old, which suggests that the antinociceptive role of
the supraoptic nuclei is directly related to the release
of oxytocin.6062
The spinal nucleus of the bulbocavernosus (SNB) is a
sexually dimorphic motor nucleus in the lower lumbar
spinal cord that innervates the striated bulbocaverno-
sus muscle. The striated bulbocavernosus muscle and
its associated levator ani participate in the ejaculatory
reflex in an androgen-dependent manner, receiving
spinal oxytocinergic projection from the paraventricu-
lar nuclei.63 Introduction of lesions to the paraventricular
nuclei with Nmethyld-aspartic acid reduced the
number of oxytocin-immunoreactive fibres at the level of
L5L6, which was associated with a significant decrease
in seminal emission at ejaculation (P<0.01).64 However,
the mount, intromission and ejaculatory latencies were
unaffected by these lesions, confirming the role of
oxytocin in the first part of the ejaculatory reflex.64
The effect of the oxytocin antagonist (d(CH 2) 51,
Tyr(Me)2,Orn8)oxytocin on ejaculation induced by
intracerebroventricular injection of the D(3) dopamine
receptor agonist 7hydroxy2-(diN-propylamino)
tetralin (7-OH-DPAT) was studied in anaesthetized
male rats. 65 Using seminal vesicle pressure (SVP),
electromyograms of the bulbospongiosus muscle and
intracavernosal pressure as physiological markers
of the ejaculatory emission phase, expulsion phase
and of erection, respectively, intravenous injection of
(d(CH2)51,Tyr(Me)2,Orn8)oxytocin did not impair the
seminal vesicle and intracavernosal pressure increases
induced by 7OH-DPAT, but did diminish the bulbo
spongiosus muscle burst frequency (P<0.05).65 When
delivered intracerebroventricularly, the antagonist

dose-dependently inhibited the sexual responses pro-
voked by 7OH-DPAT, including the number of ejacu-
lations, latency time, SVP and bulbospongiosus muscle
responses and latencies. When delivered intrathecally
at the level of the L6 segment, the antagonist reduced
the duration of bulbospongiosus muscle responses and
the occurrence of ejaculation without affecting intra
cavernosal pressure; the same result was not observed
when the agent was delivered at the level of the T13
segment. 65 These results suggest that brain oxytocin
receptors mediate the sexual responses evoked by intrac-
erebroventricularly delivered 7OH-DPAT, whereas
L6 spinal oxytocin receptors solely affect ejaculation.
Furthermore, peripheral oxytocin receptors are mini-
mally involved sexual responses induced by the agonist.65
Clearly, oxytocin is actively involved in regulat-
ing orgasm and ejaculation via peripheral, 52 central
and spinal mechanisms.66 However, in a double-blind,
placebo-controlled clinical study, intranasal oxytocin had
no effect on appetitive, consummatory and refractory
sexual behaviour 67 despite anecdotal evidence indicat-
ing that intranasal oxytocin can facilitate orgasm in an
otherwise anorgasmic male.68 In summary, although
preclinical data suggests a role for peripheral oxytocin
receptors in the first part of the ejaculatory reflex (semen
emission) and for central receptors in several aspects of
male sexuality (including ejaculation), the clinical data
are scant and inconclusive. More studies that are suf-
ficiently large and powered to determine the effect of
oxytocin on the ejaculation reflex are, therefore, needed.
Adenohypophyseal hormones: prolactin
Human prolactin is a nonglycosylated protein composed
of 198 amino acids. Although the monomeric form of
the protein predominates in circulation, high-molecular-
weight forms of the protein are also present, such as
macroprolactin (>100kDa), a biologically inactive
complex of prolactin bound to IgG. 6971 Retrospective
analysis of patients with hyperprolactinaemia found
that approximately 40% have macroprolactinaemia.71
In women, prolactin controls breast development and
lactation.71 However, the role of prolactin in men is not
fully understood.
Deletion of PRL, or of the gene encoding the pro
lactin receptor (PRLR), does not affect male reproduc-
tive fitness,7274 despite the receptor being expressed in
the male brain, testis, accessory glands 72 and penis.75
However, the effects of the pathological elevation of
prolactin expression on both male reproductive and
sexual behaviour have been well clarified. 71,7678 Many
studies have demonstrated the marked inhibitory effect
of hyperprolactinaemia on sexual desire,76,7880 the under
lying mechanism of which is via action on hypothalamic
GnRH (and, therefore, on testosterone production) and/
or dopamine production and turnover.81 Several studies
have shown that prolactin levels increase following male
orgasm, 31,8284 which might exert negative feedback
control on sexual motivation, contributing to the post
orgasmic refractory period. However, the postorgasmic
rise in prolactin is modest (1015ng/ml) and similar in
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FOCUS ON SEXUAL MEDICINE
men and in women,83 who are less prone to postorgasmic
refractoriness and satiety. Additionally, prolactin levels
can increase during emotionally stressful or disturbing
events (including venipuncture) or following stimula-
tion of the nipple or areola in both men and women.85
The reported prevalence of mild hyperprolactinaemia
(defined as >420mU/l or 20ng/ml) in men with sexual
dysfunction varies, ranging from >13%86 to <2%.78 In
men with sexual dysfunction, severe hyperprolactinaemia
(defined as >735mU/l or 35ng/ml) is an infrequent event
(<1%).76,78 By contrast, mild forms of hyperprolactinaemia
do not contribute to the pathogenesis of male sexual dys-
function,76,78 but severe hyperprolactinaemia (defined as
>735mU/l or 35ng/ml) can have adverse effects on sexual
function, hindering sexual desire, erectile function and
testosterone production.31,7681
Prolactin secretion from the pituitary gland is nega-
tively influenced by hypothalamic dopaminergic neurons
and positively influenced by several factors, some of
which have not yet been identified. 87 Among these
prolactin-releasing factors (PRFs) are thyroid-releasing
hormone, oxytocin, vasopressin and vasoactive intestinal
polypeptide.87 A role for serotonin in the regulation of
prolactin secretion has also been identifiedascending
serotoninergic inputs from the dorsal raphe nucleus are
thought to be the major activators of PRFs in the para-
ventricular nuclei.88 Accordingly, treatment with both
selective and nonselective serotonin reuptake inhibitors
is associated with hyperprolactinaemia.78,89 Interestingly,
the serotoninergic system suppresses the ejaculatory
reflex at the hypothalamic level.510 In fact, both selective
serotonin reuptake inhibitors (SSRIs), which are com-
monly prescribed for anxiety and depressive symptoms,
and serotonin agonists (used in experimental models)
have roles in determining the extension of ejaculatory
latency.5,90 The most common adverse sexual effects asso-
ciated with SSRIs are delayed ejaculation and absent or
delayed orgasm.91 Furthermore, these effects on sexual
function are dose-dependent and can vary within the
group of SSRIs used according to which serotonin and
dopamine reuptake mechanisms are invoked, whether
prolactin release is induced, the presence of anti
cholinergic effects, inhibition of nitric oxide synthase
and the propensity for accumulation of the drugs.92 Some
long-acting 90,93 or specifically designed short-acting
SSRIs94 are currently used clinically to treat premature
ejaculation by virtue of their ejaculation-delaying effects.
A poor prolactin response to a serotonergic challenge
can be a reflection of impaired central serotonergic func-
tion95,96 and is associated with thickening of the carotid
artery. These associations suggest that differences in
central serotonergic responsivity are inversely related to
the likelihood of developing vascular disease.97 Indeed,
determination of even the basal prolactin level can be
used as an indicator of blunted central serotonergic
function.98 In the brain, serotonin modulates neuronal
activity and mediates cognitive function and behaviour,
including the ejaculatory reflex.99102 Men with anxious
symptoms and disorders commonly exhibit abnormali-
ties in serotonin function, therefore, 99 the serotonin
REVIEWS
a Adjusted r = 0.021; P = 0.044 b Adjusted r = 0.067; P = 0.029
2.24
2.22
Log10 (PRL) mU/l
2.20
2.18
2.16
2.14
I II III IV I II III IV
Free-floating anxiety symptoms SIEDY Scale 3 score quartiles
(MHQ-A score) quartiles
Figure 2 | The association with PRL levels and psychological and anxiety scores.
Data were derived from a consecutive series of 2,948 patients (mean age
51.313.1years) seeking medical care at the Sexual Medicine and Andrology
Unit and Department of Clinical Physiopathology, University of Florence, Florence,
Italy. Adjusted r values indicate the MHQ score, which is an index of mood and
anxious spectrum psychopathology and chronic disease score (a validated index of
associated morbidities) adjusted data after excluding subjects with
hyperprolactinaemia (defined as >735mU/l or 35ng/ml) or taking
antidepressants. a | PRL levels as a function of free-floating anxiety symptoms
(MHQA) score quartiles (IIV). b | PRL levels as a function of SIEDY scale 3 score
quartiles (IIV). Abbreviations: MHQ-A: Middlesex Hospital Questionnaire, anxiety;
PRL, prolactin.
system is unsurprisingly a major target for therapies
in this arena.103 The common belief that anxiety is sec-
ondary to serotonin overactivity has been debunked
by research that revealed different serotonergic neural
circuitry and receptorsrather than global serotonin
levelsare mediators of different aspects of anxiety.99
Specifically, genetic variations in the sodium-dependent
serotonin transporter, which is crucial to the regulation
of the serotonin system, and its effects on emotional
characteristics99 has provided a new level of understand-
ing of the neurobiological and genetic basis of emo-
tional regulation and anxiety disorders.103 Accordingly,
a meta-analysis of the available evidence clarified that
allele variants in the promoter region of the serotonin
transporter gene are associated with selective attention to
negative stimuli strongly implicated in the aetiology and
maintenance of anxiety disorders.104
Men with prolactin levels in the lowest quartile show
the highest level of free-floating anxiety 98 and the
highest level of SIEDY Scale 3 score (a validated index
of psychopathology in subjects with sexual dysfunction),
which supports the hypothesis that peripheral prolactin
might mirror central serotoninergic tone (Figure2). 105
Furthermore, such hypoprolactinaemia is, in men with
sexual dysfunction, related to psychobiological features
such as anxiety symptoms and premature ejaculation.98
Guiltiness during autoeroticism has also been associated
with low levels of prolactin.106 Waldingers neurobiologi-
cal hypothesis states that perturbation of the central
serotonin pathway (specifically, 5hydroxytryptamine
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2012 Macmillan Publishers Limited. All rights reserved
[serotonin] receptor2C hyposensitivity and/or sero
tonin receptor1A receptor hypersensitivity) might be
the origin of some cases of lifelong premature ejacula-
tion.10 This hypothesis has been supported clinically: low
prolactin levels were associated with a higher risk of pre-
mature ejaculation, even after adjusting for confounding
factors that include age, body mass index, medicaments
and smoking habit.98 However, no differences in pro
lactin levels were detected between men with lifelong
or acquired premature ejaculation.98 Thus, secondary
causes of premature ejaculation might primarily influ-
ence the serotonergic system of the brain, rather than
at the level of prolactin. 98,107,108 Additionally, central
modifications of a serotonergic nature, mirrored by low
prolactin levels both in lifelong and acquired premature
ejaculation, might actually be a resultnot a causeof
the loss of ejaculatory control in men with lifelong pre-
mature ejaculation. Prolactin levels have also been found
to be positively correlated with reported ejaculatory
latency (from severe premature ejaculation to anejacu-
lation), after excluding men with pathological hyper
prolactinaemia and adjusting for SSRI use (Figure3a).109
These data imply that low prolactin levels should be
taken into consideration when evaluating patients with
sexual dysfunction, as it can shed some light on ejacula-
tory behaviour and might reflect central serotoninergic
tone (Figure4).
Thyroid hormones
Thyroid hormone nuclear receptors are located in all
tissues including the male genital tract.110 Associations
between delayed and premature ejaculation with hypo-
thyroidism100 and hyperthyroidism,100,107,111 respectively,
have been widely documented in animal models and
humans.112,113 Hyperthyroidism in rats (induced by treat-
ment with lthyroxin) increases seminal vesicle contrac-
tion frequency and bulbospongiosus muscle contractile
activity, which indicates that hyperthyroidism can affect
the ejaculatory emission and expulsion phases. 112 In
that study, after a 28-day washout period (to determine
spontaneous recovery from hyperthyroidism) the afore-
mentioned alterations were reversed,114 confirming the
direct role of thyroid hormones in the control of ejacula-
tion. These results have been replicated in several clinical
studies in human patients. In a series of 755 consecutive
men seeking medical care for sexual dysfunction, includ-
ing premature ejaculation, the prevalence of suppressed
thyroid-stimulating hormone (TSH)which is a marker
of possible hyperthyroidismwas twofold higher in
patients with premature ejaculation than those reporting
normal ejaculatory timing.105
The first multicentre prospective study on this topic
showed that half of patients with hyperthyroidism also
have premature ejaculation,100 but curing the under
lying illness led to a drastic reduction in this proportion
(to 15%) and a doubling of ejaculatory latency period
(Table1). Premature ejaculation was observed in 72% of
men with hyperthyroidism, but was reduced upon treat-
ment of the underlying illness(es) in a subsequent pro-
spective single-centre study of premature ejaculation.111
 FOCUS ON SEXUAL MEDICINE

A positive correlation between TSH and IELT was also a

2.40 Adjusted r = 0.050; P = 0.003
observed.111 IELT could be increased threefold in men
with premature ejaculation (n=24) upon therapeutic 2.35
intervention to achieve euthyroidism at follow-up. 111
2.30

Log10 (PRL) mU/l

In the euthyroid state, Beck anxiety and International
Index of Erectile Function (IIEF) scores also signifi- 2.25
cantly improved (both P<0.05, Wilcoxon signed rank 2.20
test), which led the researchers to conclude that hyper
thyroidism is a novel and reversible aetiological risk 2.15
factor for premature ejaculation.111 Although Oztrk 2.10
etal.114 obtained similar results in their study of 107 men
consulting an outpatient clinic for premature ejaculation, 0.00
Waldinger etal.115 found no connection between TSH
levels and IELT in a cohort of Dutch subjects with lifelong b
0.30 Adjusted r = 0.046; P = 0.010
premature ejaculation without erectile dysfunction.
To disentangle the data, we conducted a meta-analysis 0.25

Log10 (TSH) mU/l

(Table1) of the available studies comparing the preva- 0.20
lence of hyperthyroidism in patients with premature
ejaculation and in those without (derived from healthy 0.15

men or the general population). In the same analysis, 0.10

we included unpublished data from 855 patients attend-
0.05
ing our clinic for premature ejaculation over 12years
(20002012), the characteristics of whom do not differ 0.00
significantly from the previous published sample.107
The prevalence of hyperthyroidism in this unpublished c
group was compared with that found in a sample of 433 19 Adjusted r = 0.042; P = 0.012
men enrolled, from the general population of the same 18
Testosterone (nmol/l)

geographical area, in the European Male Aging Study
(EMAS).116,117 EMAS is a multicentre survey of 3,369
community-dwelling men aged 4079years (mean
6011years) randomly selected from eight European
centres: Florence, Italy; Leuven, Belgium; Malm,
Sweden; Manchester, UK; Santiago de Compostela,
Spain; Lodz, Poland; Szeged, Hungary and Tartu,
Estonia. Upon analysis of the data of Oztrk etal.114 and
Waldinger etal.115as well as of our unpublished evi-
dencewe found that men with premature ejaculation
have a threefold increased risk of hyperthyroidism com-
pared with control subjects (Figure5). However, when
separate analyses were performed according to overall or
lifelong premature ejaculation status, the association was
not confirmed in subjects with lifelong premature ejacu-
lation (Table1, Figure5). Given that hyperthyroidism is a
risk factor for erectile dysfunction,100,117 populations with
abundant thyroid disorders that induce hyperthyroid-
ism (such as Graves disease, uninodular or multinodular
toxic goitre and drug-induced hyperthyroidism) might
be predisposed to acquired premature ejaculation, which
at least partially explains the difference.
To quantify the improvements to IELT in men with
premature ejaculation who achieved euthyroidism,100,111
we conducted a meta-analysis and found that treat-
ing hyperthyroidism increases IELT by 84.634.2s,
P=0.001 (Table1). In addition, Carani etal.100 demon
strated that treatment of hypothyroidism reduced ejacu-
latory latency twofold as well as the observed frequency
of delayed ejaculation. Thus, thyroid hormones likely
govern not only the ankle reflex (also known as the
Achilles reflex) but also the ejaculatory reflex. Similarly,
in a study that excluded subjects with low TSH caused by
17
16
15
14
13
12
11
0
Severe Moderate Mild No PE/DE Mild Moderate Severe Anejaculation
PE DE
Figure 3 | Hormone levels as a function of ejaculatory difficulties. Data were
derived from a consecutive series of 2,948 patients (mean age
51.313.1years) seeking medical care at the Sexual Medicine and Andrology
Unit and Department of Clinical Physiopathology, University of Florence, Florence,
Italy. Ejaculatory difficulties were categorized using an 8point scale that
corresponds to the continuum of the ejaculation latency.118 0=severe PE
(ejaculation within 15s or before penetration); 1=moderate PE (if ejaculation
within 30s); 2=mild PE (ejaculation within 60s); 3=no ejaculatory difficulties;
4=mild DE (ejaculation and climax possible, but only with great effort and after
prolonged intercourse); 5=moderate DE (ejaculation and climax possible only
with autoerotism in the presence of a partner, but not during coitus); 6=severe
DE (ejaculation and orgasm obtained only with autoerotism conducted in the
absence of a partner); 7=anejaculation. Adjusted r values indicate the MHQ
score, which is an index of mood and anxious spectrum psychopathology and
chronic disease score (a validated index of associated morbidities) adjusted data
after excluding subjects with hyperprolactinaemia (defined as >735mU/l or
35ng/ml) or taking antidepressants. a | PRL levels as a function of ejaculatory
difficulty. b | TSH levels as a function of ejaculatory difficulty. c | Testosterone
levels as a function of ejaculatory difficulty. Abbreviations: DE,delayed
ejaculation; MHQ, Middlesex Hospital Questionnaire; PE, premature ejaculation;
PRL, prolactin; TSH, thyroid-stimulating hormone.
pituitary diseases, TSH levels were found to be positively
correlated to reported ejaculatory latencies (Figure3b).118
Given that TSH levels are closely linked to thyroid

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2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
function by negative feedback, thyroid hormones might
also negatively effect ejaculatory latency (Figure4).
Hyperthyroidism, even in its subclinical form,
increased the risk of all-cause mortality in men (by
approximately 41%).119 Clinical screening and laboratory
confirmation of thyroid disease are, therefore, strongly
advised in men with ejaculatory dysfunction.
Adrenal and gonadal steroids
Glucocorticoids
The major corticosteroid in many mammalian species
cortisolis generally secreted in response to stressful
stimuli and also during arousal and ejaculation (at least,
in several animal models). For example, during sexual
excitement in stallions, cortisol is secreted in prepara-
tion for or in anticipation of the physical demands of
mounting and breeding. 120 Male animals, including
horses, boars and pigs,120,121 demonstrate a rise in cor-
tisol after exposure to a receptive (oestrous) female; at
least in horses this rise is independent of ejaculation.120
Boars trained to mount a stationary artificial sow and
ejaculate after digital pressure of the extended penis
demonstrated this increase in cortisol during ejacula-
tion (with digital pressure) and when ejaculation was
not permitted (without digital pressure).122 These data
suggest that sexual stimulation, but not ejaculation,
activates the limbic circuits and hypothalamic area that
control adrenocortical secretion. However, cortisol
increase could merely reflect the physical component of
sexual stimulation.
Late-onset rises in cortisol (30min after ejacula-
tion) has been described in horses34 and donkeys,123
the significance of which has yet to be established. In
anesthetized, captive Felidae species (cheetahs, tigers,
leopards and pumas) electroejaculation was associated
with a sharp rise in cortisol levels, that mimics the spike
elicited by adrenocorticotropic hormone,124,125 which
possibly reflects stress-induced maximal adrenal activ-
ity. Data from rhesus monkeys indicate that cortisol
increases considerably after exposure to a sexually recep-
tive female, although this rise was also independent of
ejaculation.126 In another primate study, cortisol levels
were correlated positively with the rate of contact and
mount as well as with the percentage of tests in which the
monkeys had erections.127 By contrast, the cortisol levels
were reduced in older animals, which was characterized
by reduced cortisol levels at night.127
Data of this sort in humans are scant. Blood cortisol
levels, drawn continuously while subjects viewed an
erotic film, did not significantly change in male subjects
during either arousal or orgasm.128131 Although decreased
libido is an often-reported sexual complaint of men with
hypercortisolism,132 no effect on orgasm or ejaculation
has been described thus far. By contrast, in men with
hypocortisolism (such as those with the autoimmune
Addisons disease) glucocorticoid and mineralocorti-
coid replacement therapy is associated with an overall
improvement in sexual function, including orgasm.133
Hence, although animal studies have documented
a possible role of adrenal hormones in regulating
514 | SEPTEMBER 2012 | VOLUME 9  www.nature.com/nrurol
2012 Macmillan Publishers Limited. All rights reserved
Low Ejaculation latency High
Testosterone
Premature Delayed
ejaculation ejaculation
Thyroid hormones
Prolactin
Hypo Control of ejaculation Hyper
Figure 4 | The hormonal regulation of the ejaculatory
continuum.
ejaculatory reflex, data in humans are too preliminary
to draw final conclusions. Larger studies are advisable to
better understand this topic.
Oestrogens
Oestrogens, in particular oestradiol, have roles in regu
lating the initial part of the ejaculatory reflexthe
emission phaseby acting on the epididymis.52 These
epididymal functions were originally attributed to the
high levels of oestrogen measured in rete testis fluid. 134
In fact, P450 aromatase activity, which is partly respon-
sible for the irreversible transformation of androgens
to oestrogen, is localized in the testis of several animal
species135 and in the epididymis of rabbits,44 monkeys,136
rats137 and humans.138 The epididymis synthesizes and
responds to oestrogensboth oestrogen receptor and
(ER and ER) are expressed in the epididymis of several
animal species,135 including rabbits.44 ER and ER are
profusely localized in the peritubular smooth muscle
compartment of the cauda, but are irregularly expressed
in the epithelial cells of the corpus, at least in mice. 139
This differential expression of the oestrogen receptors
likely accounts for the two major roles attributed to
the oestrogens in the epididymis: regulation of luminal
fluid reabsorption and sperm concentration (typical of
the caput epithelium)140 and regulation of epididymal
contractility (typical of the muscular compartment of
epididymal cauda).
The oestrogenic regulation of fluid reabsorption and
sperm concentration has been reviewed elsewhere.140
Briefly, the disruption of EReither by complete
genetic knockout or by treatment with a pure anti
oestrogenresults in dilution of cauda epididymal
sperm, disruption of sperm morphology, inhibition of
sodium transport and subsequent water reabsorption,
increased secretion of chloride ions and an eventual
decrease in fertility.140
With respect to the oestrogenic regulation of epididy-
mal contractile activity, two distinct animal models of
oestrogen deprivation (inducing hypogonadotropic
hypogonadism and blocking aromatase activity using
letrozole) have been used to show that endogenous oes-
trogens are necessary for the epididymal responsiveness
to the contractile agents oxytocin and endothelin1.44,49
This epididymal hyporesponsiveness in hypogonadal
 FOCUS ON SEXUAL MEDICINE

Table 1 | Outcome variables for men with lifelong or acquired premature ejaculation*
Population characteristics Mean age (years) Prevalence of Mean IELT (s)
hyperthyroidism
Waldinger etal.115 (2005)
Study population (n=620): men with LPE NR 14/620 (2.2%) NR
Control population (n=620): general Dutch population NR 16/620 (2.5%) NR
Carani etal.100 (2005)
Study population (n=34): men with hyperthyroidism 43.2 34/34 (100%) 124 30
240 30
Control population: NR NR NR NR
Cihan etal.111 (2009)
Study population (n=43): men with hyperthyroidism 48.0 43/43 (100%) 75.8 99.3
123.2 96.4
Control population: NR NR NR NR
Oztrk etal. 114
(2012)
Study population (n=107): outpatients with premature ejaculation 45.1 14/107 (8.4%) NR
Control population (n=94): healthy men 48.1 4/94 (4.25%) NR
Corona etal. (2012)||
Study population (n=855): outpatients with premature ejaculation 51.3 LPE 17/322 (5.3%) NR
APE 13/533 (2.5%)
Control population (n=433): EMAS study Florentine sample111 60.1 3/433 (0.5%) NR
*Whenever possible the prevalence of hyperthyroidism in a control population was also reported. Men with hyperthyroidism. Men treated for hyperthyroidism.
||
Unpublished work. EMAS is a multicentre survey performed on a sample of 3,369 community-dwelling men aged 4079years. Subjects were randomly
selected from eight European cities: Florence, Italy; Leuven, Belgium; Malm, Sweden; Manchester, UK; Santiago de Compostela, Spain; Lodz, Poland; Szeged,
Hungary; and Tartu, Estonia. Only the Florentine sample was considered in this analysis. Abbreviations: APE, acquired premature ejaculation; EMAS, European
Male Aging Study; IELT, intravaginal ejaculation latency time; LPE, lifelong premature ejaculation; NR, not reported.

animals could be normalized by supplementation with
oestradiol valerate or with tamoxifena selective oes-
trogen receptor modulatorbut not with testosterone
enanthate, confirming the direct role of oestrogens.
Tamoxifen came to market 30years ago as an empiric,
off-label treatment for idiopathic oligospermia, 141
and has since been cited by the WHO as the first-line
treatment for the condition.142 As well as its purported
central effect in stimulating gonadotropin release,141,142
tamoxifen might also act as an oestrogen agonist in the
epididymis, 143 stimulating epididymal sensitivity to
oxytocin and endothelin1.36,44,58 Such an effect would
explain, at least in part, the benefit to patients tamoxifen
has in normogonadotropic idiopathic oligospermia.144
Oestrogens could positively regulate endothelin1-
mediated and oxytocin-mediated contractility either
by inducing the expression of oxytocin receptors or by
activating a calcium-sensitizing transforming protein
RhoA/Rho-associated protein kinase (Rho/ROCK)
system,39 which is a common downstream effector of the
contractile mechanisms in the epididymis.
Overall, these data uphold the hypothesis that the
epididymis is a target for oestrogens in males. Oestrogens
act by regulating the expression of proteins involved in
fluid reabsorption in the efferent ductule epithelium and
epididymal motility via conditioning the responsiveness
of the contractile hormones and local peptides.
Androgens
Testosterone affects male sexual response at both the
central and peripheral level,145 motivating sexual contact.
Several studies in hypogonadal men have definitively
demonstrated positive effects of testosterone substitution
on restoring sexual desire, spontaneous sexual thoughts
and attractiveness to erotic stimuli.146 Androgens also
have an effect at the penile level, regulating the forma-
tion and degradation of cGMP, which has central role
in penile erection. Indeed, testosterone regulates the
activity of nitric oxide (NO) synthase activity as well as
the expression and activity of cGMP-specific 3',5'-cyclic
phosphodiesterase (also known as type 5 phosphodi
esterase, PDE5); the integrated NOPDE5 system is one
of the most important factors involved in the contractil-
ity of the male genital tract.145,146 Accordingly, PDE5 was
immunolocalized in all the muscular layers of both the
human and rabbit vas deferens and was found to be nega-
tively involved in regulating NO-induced relaxation.147
Moreover, the time-course of PDE5 expression during
fetal development parallels the pattern of testosterone
receptor expression,148 which confirms the close relation-
ship between androgens and PDE5 system. Accordingly
the dependency of PDE5 expression and activity on
testosterone has been shown in other areas of the male
genital tract such as vas deferens, which indicates a role
for the androgen in semen emission and ejaculation.147
Low levels of testosterone accompanying hypogonadal
symptoms are associated with a lower tendency to ejacu-
late.107,109,118,149 Indeed, testosterone can affect the ejacula-
tory process109,118 and androgens have extensive influence
on sexual behaviour in men because of their ability to
act on the central and peripheral nervous system, many
areas of which are connected to the ejaculatory reflex.

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REVIEWS
Difference 95% CI Odds ratio for
in mean hyperthyroidism
Corona et al.* 5.419 [1.21624.144]
Oztrk et al.114 2.066 [0.6156.944]
Overall PE 3.029 [1.1827.766]
Waldinger et al.115 0.872 [0.4221.803]
Corona et al.* 12.011 [2.75552.371]
Overall 2.983 [0.22938.796]
lifelong PE
Overall 3.024 [1.2507.317]
0.1 1 10
Favours euthyroidism Favours hyperthyroidism
Figure 5 | Weighted odds ratio of hyperthyroidism between men with PE and a
control population. *Unpublished work. Abbreviation: PE, premature ejaculation.
Box 1 | Levels of control in mammalian ejaculation
Central control
Testosterone regulates the central serotonin pathway in a rat animal
models.151 In particular, chronic testosterone treatment has been reported
to considerably decrease serotonin and its metabolite, 5hydroxyindoleacetic
acid at the level of the hypothalamus level.151 This observation can explain, at
least in part, the higher levels of testosterone observed in patients reporting
premature ejaculationa condition associated with an impairment of serotonin
pathway.109,118 However, no specific data are available in humans.
Spinal control
Animal studies performed in cats and dogs have demonstrated that androgens
regulate the spinal nucleus of the bulbocavernosus nerve152 as well as muscles of
the pelvic floor involved in the ejaculatory reflexsuch as the bulbocavernosus,
ischiocavernosus and levator ani muscle.155 No specific evidence has been
reported in humans.
Peripheral control
A study of a rabbit model has documented that testosterone regulates the
integrated system of nitric oxide and type 5 phosphodiesterase, one of the most
important factors involved in the contractility of the male genital tract in the
emission phase.147 These data have been recapitulated in humans.147
Furthermore, the medial preoptic area, bed nucleus of
the stria terminalis, median amygdala and posterior thal-
amus, which are all involved in the supraspinal control
of ejaculation, express androgen receptors.150 Animal
models have exemplified these central roles for testo
sterone in mediating sexual behaviour and responses.
For example, rats treated for extended periods with
testosterone expressed considerably lower levels of sero
tonin in the brain (Box1).151 Even at the spinal cord
level, nuclei critically involved in controlling ejacula-
tion, such as the spinal nucleus of the bulbocavernosus,
are androgen-dependent.152 At least in mature cats, cir-
culating androgens can drastically alter the expression
of gastrin-releasing peptide in the lower spinal cord,153
which mediates the ejaculatory reflex by innervating the
bulbocavernosus spinal nucleus.154 Interestingly, bulbo-
cavernosus muscle is specifically androgen-dependent,
as are other muscles of the pelvic floor involved in the
ejaculatory ejection of the seminal bolus (namely, the
ischiocavernosus and levator ani muscles). Indeed,
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2012 Macmillan Publishers Limited. All rights reserved
hypertrophic action on the levator ani is a good invivo
predictor of androgen action.155
The emission phase of the ejaculatory reflex, which
relies on the NOPDE5A system, is also influenced by
testosterone. In an experimental model of hypogonado-
tropic hypogonadism, the vas deferens of testosterone-
deficient rabbits displayed decreased cGMP degradation
and decreased PDE5 expression and activity.147 However,
testosterone administration wholly reversed these
conditions, 147 which suggests that hypogonadism-
associated delayed ejaculation is caused by elevated
inhibitory nitrergic tone on the smooth muscle cells
100
of the male genitalia. Testosterone is converted to an
active oestrogen17-oestradiolby cytochrome
P450 aromatase, which is widely expressed throughout
the male genital tract (in particular, the epididymis). 52
In the epididymis, testosterone and 17-oestradiol can
reverse hypogonadism-induced downregulation of the
Rho/ROCK pathway to restore contractility.39 Thus, low
testosterone levels must be evaluated in all patients with
delayed ejaculation.
Testosterone also facilitates the control of the ejacu-
latory reflex.109,118 Different testosterone levels can be
linked to different subsets of ejaculatory disturbances
(Figure3c). Although delayed ejaculation is associated
with reduced testosterone levels, abnormally high levels
are an indication of premature ejaculation. Overall, these
data suggest that androgens have some part in the mech-
anism of ejaculation.109,118 Mechanical action of testos-
terone in ejaculatory control can also be hypothesized.
For example, a hypogonadism-induced reduction in
semen volume149 can disturb the dynamics of the seminal
bolus propulsion and explain why some men have ejacu-
lation difficulties. Furthermore, low testosterone levels
directly reduce ejaculate volume, which might reduce
stimulation of the accessory glands (such as the prostate
and seminal vesicles) that are known androgen targets.
Finally, testosterone differences could be the result
of sexual disturbances, particularly erectile dysfunc-
tion, which, in turn, might reflect differences in sexual
behaviour that include copulation frequency.156
In summary, several mechanisms link andro-
gens to the complex ejaculation process (Figure4).
Further studies are necessary to completely under-
stand these mechanisms and how these can be targeted
to treat men with premature ejaculation and other
sexual dysfunctions.
Conclusions
Evidence amassed on the endocrine control of ejacula-
tion is largely derived from preclinical observations and
small clinical trials. However, the evidence is compel-
ling and suggests that hormones do indeed modulate
the ejaculatory reflex. The notion that premature ejacu-
lation and delayed ejaculation can be considered two
ends of a single continuum has been confirmed experi-
mentally.118,157 The endocrine milieu (primarily com-
prising testosterone, thyroid hormones and prolactin)
has an effect on the ejaculatory process by altering its
overall latency (Figure4). Although our understanding
 FOCUS ON SEXUAL MEDICINE

of endocrine regulation of the ejaculatory reflex is still
under development, emerging data are providing insight
into frequently occurring and rarely studied conditions
such as ejaculatory disturbances. Considering that
hormone production, release, action and metabolism
can be easily manipulated by severalalready avail-
ablestrategies, understanding the complete endocrine
role is absolutely essential for the successful treatment of
men with sexual disorders such as premature ejaculation.
Perhaps endocrine therapy of ejaculatory disorders will
improve both the sexual life and the general health of
these patients, as was the case in disorders of the thyroid
and testis.
Review criteria
An extensive MEDLINE search was performed including the
following words oxytocin, prolactin, thyroid hormones,
adrenal steroids, estrogens, testosterone,
hormones and ejaculation. Results were limited to
English-language articles published up to 1 April 2012.

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Author contributions
G. Corona, L. Vignozzi, G. Rastrelli and M. Maggi
researched the data for the article. G. Corona,
E.A.Jannini, L. Vignozzi and M. Maggi contributed
substantially to the discussion of the article content.
G. Corona and M. Maggi wrote the article. G. Corona,
E. A. Jannini, L. Vignozzi and M. Maggi edited the
manuscript before submission.