445

Anatomy, Physiology, and Pathophysiology of

Erectile Dysfunction
jsm_1624

445..475

Christian Gratzke, MD,* Javier Angulo, PhD, Kanchan Chitaley, PhD, Yu-tian Dai, MD, PhD,
Noel N. Kim, PhD, Jaw-Seung Paick, MD, PhD,** Ulf Simonsen, MD, PhD, Stefan ckert, PhD,
Eric Wespes, MD, PhD, Karl E. Andersson, MD, PhD, Tom F. Lue, MD,*** and
Christian G. Stief, MD, PhD*
*Department of Urology, Ludwig-Maximilians-Universitt, Mnchen, Germany; Department of Urology, Hospital Gregorio
Maranon, Madrid, Spain; University of Washington, Seattle, WA, USA; Department of Urology, Nanjing, China; Institute
for Sexual Medicine, San Diego, CA, USA; **Department of Urology, Seoul National University, Seoul, South Korea;

Department of Pharmacology, University of Aarhus, Denmark; Department of Urology, Hannover Medical School,
Hannover, Germany; Department of Urology, Centre Hospitalier Universitaire, Charleroi, Belgium; Wake Forest
University, Institute for Regenerative Medicine, Wake Forest, NC, USA; ***Department of Urology, University of California
at San Francisco, San Francisco, CA, USA
DOI: 10.1111/j.1743-6109.2009.01624.x

ABSTRACT

Introduction. Signicant scientic advances during the past 3 decades have deepened our understanding of the
physiology and pathophysiology of penile erection. A critical evaluation of the current state of knowledge is essential
to provide perspective for future research and development of new therapies.
Aim. To develop an evidence-based, state-of-the-art consensus report on the anatomy, physiology, and pathophysiology of erectile dysfunction (ED).
Methods. Consensus process over a period of 16 months, representing the opinions of 12 experts from seven
countries.
Main Outcome Measure. Expert opinion was based on the grading of scientic and evidence-based medical
literature, internal committee discussion, public presentation, and debate.
Results. ED occurs from multifaceted, complex mechanisms that can involve disruptions in neural, vascular, and
hormonal signaling. Research on central neural regulation of penile erection is progressing rapidly with the
identication of key neurotransmitters and the association of neural structures with both spinal and supraspinal
pathways that regulate sexual function. In parallel to advances in cardiovascular physiology, the most extensive efforts
in the physiology of penile erection have focused on elucidating mechanisms that regulate the functions of the
endothelium and vascular smooth muscle of the corpus cavernosum. Major health concerns such as atherosclerosis,
hyperlipidemia, hypertension, diabetes, and metabolic syndrome (MetS) have become well integrated into the
investigation of ED.
Conclusions. Despite the efcacy of current therapies, they remain insufcient to address growing patient populations, such as those with diabetes and MetS. In addition, increasing awareness of the adverse side effects of commonly
prescribed medications on sexual function provides a rationale for developing new treatment strategies that minimize
the likelihood of causing sexual dysfunction. Many basic questions with regard to erectile function remain unanswered and further laboratory and clinical studies are necessary. Gratzke C, Angulo J, Chitaley K, Dai Y-T, Kim
NN, Paick J-S, Simonsen U, ckert S, Wespes E, Andersson KE, Lue TF, and Stief CG. Anatomy,
physiology, and pathophysiology of erectile dysfunction. J Sex Med 2010;7:445475.
Key Words. Erectile Function; Penis, Corporal Smooth Muscle; Nitric Oxide; Cavernous Nerve; Endothelial
Dysfunction

2010 International Society for Sexual Medicine

J Sex Med 2010;7:445475

446
Brain, Autonomic Nervous System,
and Neurotransmission

enile erection is initiated after central processing and integration of tactile, visual, olfactory, and imaginative stimuli. Signals to the
peripheral tissues involved are generated, and the
nal response is mediated by coordinated spinal
activity in the autonomic pathways to the penis
and in the somatic pathways to the perineal striated muscles. The central regulation of penile
erection involves many transmitters and transmitter systems, the details of which are still incompletely known. Some of the anatomical areas of the
brain that relate to sexual function have been
dened, including the medial amygdala, medial
preoptic area (MPOA), paraventricular nucleus,
the periaqueductal gray, and ventral tegmentum
[13]. In rats, electrical stimulation of the MPOA
[4], the paraventricular nucleus [5], or the hippocampal formation [6] can elicit an erectile response.
Spinally, there seems to be a network consisting
of primary afferents from the genitals, spinal interneurons, and sympathetic, parasympathetic, and
somatic nuclei. This network appears capable of
integrating information from the periphery and
eliciting reexive erections, and also to be the
recipient of supraspinal information [7]. The
degree of preservation of sensory function in
the T11-L2 dermatomes could be used to determine the potential for psychogenic erectile
responses in men with spinal cord injury [8].
Peripherally, the balance between factors that
control the degree of contraction of the smooth
muscle of the corpora cavernosa determines the
functional state of the penis. Many details of neurotransmission, impulse propagation, and intracellular transduction of signals in penile smooth
muscles remain to be elucidated. However, the
information on central control mechanisms
involved in erection is rapidly expanding, and new
details are continuously added [1,916].

Central Neuromediation
The central mechanisms controlling erection
include supraspinal as well as spinal pathways. The
current knowledge about these mechanisms is
largely based on experimental data from animals
(mainly, rats).
Dopamine
Central dopaminergic neurons project to the
MPOA and the paraventricular nucleus [17]. Furthermore, dopaminergic neurons have been identied that travel from the caudal hypothalamus to
J Sex Med 2010;7:445475

Gratzke et al.
innervate the autonomic and somatic nuclei in the
lumbosacral spinal cord [18,19]. Thus, dopamine
can be expected to participate in the regulation of
both the autonomic and somatic components of
the penile reexes.
Both the two major families of dopamine receptors, D1-like (D1, D5) and D2-like (D2, D3, D4)
receptors [20], have been associated with central
erectile functions; however, the D2-like receptor
subtype seems to have the predominating effect.
The nonselective dopamine receptor agonist, apomorphine, when administered systemically to male
rats, was found to induce penile erection [21],
simultaneously producing yawning and seminal
emission. Similarly, low-dose systemic administration of other dopamine agonists initiates erection
[1]. The effects of these agonists can be attenuated
by centrally but not peripherally acting dopamine
receptor antagonists.

Oxytocin
Oxytocinergic spinal projections from the
supraoptic and paraventricular nuclei of the hypothalamus are likely to inuence the sacral autonomic outow more than the somatic outow
[22,23]. The nding that immunoreactive
oxytocin-containing spinal neurons associate with
sacral preganglionic neurons supports the idea that
oxytocin has an important role in the autonomic
spinal circuitry that mediates penile erection
[24,25]. Oxytocin is a potent inducer of penile
erection when injected into the lateral cerebral
ventricle, the paraventricular nucleus, or the hippocampus of laboratory animals; intrathecal oxytocin can also initiate an erection. These erections
can be blocked by the administration of oxytocin
antagonists given intracerebroventricularly (i.c.v.)
or intrathecally, or by electrolytic lesion of the
paraventricular nucleus. Additionally, noncontact
erections can be reduced by a selective oxytocin
receptor antagonist administered into the lateral
ventricles, which supports the view that oxytocin
mediates this response [26].
Adrenocorticotropic Hormones (ACTH) and
Related Peptides
Administered i.c.v., the ACTH and a-melanocytestimulating hormones (a-MSH) are able to induce
penile erection, along with grooming, stretching,
and yawning [1,2,27]. These effects are most probably mediated via stimulation of melanocortin
(MC) receptors, of which ve different subtypes
have been cloned and characterized [28,29].
Alpha-MSH/ACTH seem to act in the hypothalamic periventricular region, and grooming,

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

stretching, and yawning, but not penile erection,
was reported to be mediated by MC4 receptors
[27,30]. It is unclear, however, what MC receptor
subtype(s) can be linked to the erectile responses.
For example, the MC3 receptor is found in high
density in the hypothalamus and limbic systems
[31], regions known to be important for erectile
functions. The site and mechanism of action
responsible of a-MSH/ACTH seem to be different from those involving dopamine or oxytocin
[15].
Martin et al. [32] concluded that current evidence indicates that the MC4 receptor subtype
contributes to the pro-erectile effects observed
with MC pan-receptor agonists. However, the
putative receptor subtypes, pathways, and mechanisms implicated in mediating the pro-erectile
effects of MCs remain to be fully elucidated. Melanotan II, a synthetic analogue of a-MSH, when
given subcutaneously, was shown to have proerectile effects in men with psychogenic impotence [33]. Still, the therapeutic potential of
a-MSH analogues remains to be established
[3436].

447

injected into the paraventricular nucleus [4244].

Furthermore,
NMDA,
amino-3-hydroxy-5methyl-isoxazole-4-propionic acid, or trans-1amino-1,3-cyclo-pentadicarboxylic acid increases
intracavernosal pressures (ICPs) when injected
into the paraventricular nucleus [45]. The effect of
NMDA was prevented by intracerebroventricular
administration of an oxytocin antagonist [42]. The
NOS signal transduction pathway is considered to
mediate the effect of NMDA. Injection of the
amino acid leads to an increased concentration of
NO metabolites in the paraventricular nucleus
[46], and the administration of NOS inhibitors
into the paraventricular nucleus and i.c.v. blocked
the NMDA effect [42,47].

Nitric Oxide (NO)

Several investigators have shown that within the
central nervous system, NO can modulate sexual
behavior and penile erection [3741]. NO may act
in several discrete brain regions, e.g., in the
MPOA [40,41] and the paraventricular nucleus
[5,30]. NO production increases in the paraventricular nucleus of male rats during noncontact
penile erections and copulation, conrming that
NO is a physiological mediator of penile erection
at the level of the paraventricular nucleus [39].
As mentioned previously, injection of NO synthase (NOS) inhibitors i.c.v. or in the paraventricular nucleus prevents penile erectile responses
induced by dopamine agonists, oxytocin, and
N-methyl-D-aspartate (NMDA) in rats. NO may
also mediate the actions of ACTH/a-MSH and
5-HT2C agonists, which elicit erections when
injected into the intracerebroventricular system,
according to mechanisms unrelated to oxytocinergic neurotransmission [38]. The inhibitory effect
of NOS inhibitors was not observed when these
compounds were injected concomitantly with
L-arginine, the substrate for NO [38].

Serotonin
Neurons
containing
serotonin
(5hydroxytryptamine, 5-HT) can be found in the
medullary raphe nuclei and ventral medulla reticular formation, including the rostral nucleus
paragigantocellularis, and bulbospinal neurons
containing 5-HT project to the lumbar spinal cord
in the rat and cat [1]. Some serotonergic bers
occur in close apposition with sacral preganglionic
neurons and motoneurons, and synapses were
demonstrated at the ultrastructural level [25].
These morphological ndings support the
involvement of 5-HT in both the supraspinal and
spinal pharmacology of erection, with participation in both the sympathetic and parasympathetic
outow mechanisms.
In animals, 5-HT seems to exert a general
inhibitory effect on male sexual behavior [48],
although the amine may be inhibitory or facilitatory depending upon its action at different sites
and at different 5-HT receptors within the central
nervous system [49,50]. This may explain conicting reports of 5-HT agonists either enhancing or
depressing sexual function. Yonezawa et al. [51]
found that p-chloroamphetamine, an indirect serotonin (5-HT) agonist, elicited both penile erection
and ejaculation simultaneously in anesthetized
rats. It was suggested that these effects were
mainly produced by the release of 5-HT as limited
to the lower spinal cord and/or peripheral sites.
The use of selective 5-HT receptor agonists and
antagonists can reveal different components of
male copulatory behavior [9].

Excitatory Amino Acids

Microinjections of L-glutamate into the MPOA
elicits an increase in intracavernous pressure [4],
and behavioral studies have shown that NMDA
increases the number of penile erections when

Gamma-Aminobutyric Acid (GABA)

Cumulative data resulting from investigations on
the role of GABA in penile erection indicate that
this neurotransmitter may function as an inhibitory modulator in the autonomic and somatic
J Sex Med 2010;7:445475

448
reex pathways involved in penile erection [52].
Activation of GABAA receptors in the paraventricular nucleus of male rats reduced penile erection and yawning in response to apomorphine,
N-methyl-D-aspartate (NMDA), and oxytocin
[52]. Dorfman et al. examined age-related changes
of the GABAB receptor in the lumbar spinal cord
of Sprague Dawley rats of different ages using
quantitative autoradiography [53]. GABAB receptor afnity showed signicant age-dependent and
regional increases. The GABAB receptor decrease
in aged rats did not seem, however, to be related to
the inhibitory function in penile erection.

Cannabinoids
Administration of endogenous and exogenous cannabinoids was shown to be associated with changes
in penile erection and modulation of male sexual
behavior [54,55]. The cannabinoid CB1 receptor
antagonist SR 141716A was shown to potentiate
the penile erection responses to apomorphine in
rats [56]. Also, it was shown that cannabinoid CB1
receptors present in the paraventricular nucleus
may inuence erectile function and sexual activity
possibly by modulating paraventricular oxytocinergic neurons mediating erectile function [57]. It
was also demonstrated that SR 141716 induced
penile erection by a mechanism involving excitatory amino acid neurotransmission causing activation of neuronal NOS (nNOS) in paraventricular
oxytocinergic neurons [58].
Opioid Peptides
Available information supports the hypothesis that
opioid m-receptor stimulation centrally prevents
penile erection by inhibiting mechanisms that
converge upon central oxytocinergic neurotransmission [1]. In rats, morphine injected into the
paraventricular nucleus prevents noncontact
penile erections (i.e., when penile erection is
induced in the male by the presence of an inaccessible receptive female) and impaired copulation.
These morphine effects are apparently mediated
by prevention of the increased NO production
that occurs in the paraventricular nucleus during
sexual activity [59]. Morphine also prevents
apomorphine-,
oxytocin-,
NMDAand
noncontact-induced penile erection and yawning
by inhibiting NOS activity in the paraventricular
nucleus [6062].
Prolactin
Long-term hyperprolactinemia can depress sexual
behavior, reduce sexual potency in men, and
depress genital reexes in rats [50,63]. Acute and
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Gratzke et al.
chronic central prolactin treatment in rats,
however, may have stimulatory and inhibitory
effects on male sexual behavior, respectively [64].
Correspondingly, striatal dopaminergic activity
was shown to be increased and decreased by acute
and 5-day central prolactin treatment [64], supporting the view that the effects of prolactin are
associated with changes in striatal dopaminergic
activity. Prolactin has been shown to inhibit the
dopaminergic incerto-hypothalamic pathway to
the MPOA [65]. In humans, it is still unclear
whether the negative effects of hyperprolactinemia
on erectile function are mediated centrally by way
of reduction in sexual interest and sex drive [66], or
through a direct effect of prolactin on corpus cavernosum smooth muscle contractility. In dogs, a
direct effect on the corpus cavernosum was suggested [67]. In any case, the effect seems independent of circulating testosterone levels and gonadal
axis function [68].

Sexual Hormones
Androgens, particularly testosterone, are necessary (although not sufcient) for sexual desire in
men. They are essential in the maintenance of
libido and have an important role in regulating
erectile capacity [6973]. In men with normal
gonadal function, however, there is no correlation
between circulating testosterone levels and measures of sexual interest, activity, or erectile function [74]. Following castration in the male (which
may reduce plasma testosterone levels by 90%
[75]), or other causes leading to a reduction in
androgen levels, there is generally a decline in
libido, and sometimes in erectile and ejaculatory
functions. Testosterone administration restores
sexual interest and associated sexual activity in
hypogonadal or castrated adult men [7678].
The testosterone doseresponse relationships for
sexual function and visuospatial cognition differ in
older and young men, higher testosterone doses
needed in the elderly for normal sexual functioning [72]. El-Sakka et al. [79] assessed the pattern of
age-related testosterone depletion in patients with
erectile dysfunction (ED). They found a signicant decrease in testosterone level throughout the
4-year follow-up in patients with ED. Patients
with decreasing testosterone were older than
patients with a steady testosterone level. When
castration has been performed in humans, the
resultant sexual function may range from a complete loss of libido to continued normal sexual
activity. Thus, the role of androgens in erectile
function is complex, and androgen deprivation

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

may not always cause erectile impotence, either in
man [80], or in rats [81].

Perspectives and Conclusions

Ongoing and future studies assessing the efcacy
and tolerability of centrally acting agents for male
sexual dysfunction will reveal which targets are the
most promising. Based on current literature, clinical trials have shown benets for some drugs
acting on mediator systems discussed above.
However, today, none of the available agents can
be regarded as a major player in the practical treatment of ED. In light of the relatively large fraction
of the ED patients that does not respond to or
does not tolerate phosphodiesterase type 5 (PDE5)
inhibitors, additional centrally acting drugs modulating sexual responses may be a potential solution.
It cannot be expected that these drugs will work in
patients with severe end-organ damage; however,
they may potentially add to existing therapy by
modifying arousability and sexual desire. The
central regulation of the erectile process is still
only partly known. Central transmitter systems,
which seem to be dependent on androgens as well
as NO, may be the targets of future drugs aimed at
the treatment of ED. Increased knowledge of the
central (and peripheral) changes associated with
ED may lead to an increased understanding of
these pathogenetic mechanisms and therefore new
treatments and possibly even prevention of the
disorder.
Regulation of Smooth Muscle Function

The penile corpora cavernosa are highly specialized vascular structures that are morphologically
adapted to their function of becoming engorged
during sexual arousal. The trabecular smooth
muscle constitutes approximately 4050% of
tissue cross-sectional area, as assessed by histomorphometric analysis [82,83]. Most of the
remaining cavernosal tissue area is occupied by
extracellular matrix, which provides a bro-elastic
framework and consists predominantly of collagen
types I, III, and IV, and elastin [8487]. Collagen
types V and XI are also synthesized by the cavernosal smooth muscle at detectable levels. Although
smaller in number, endothelial cells and neurons
play critical roles in maintaining and regulating
vascular smooth muscle cell (VSMC) tone.
This complex architecture is maintained by the
active and dynamic expression of numerous
growth factors. Well established as a regulator of
limb morphogenesis, sonic hedgehog (Shh) has

449

also been identied in the penis [88,89]. Studies

indicate that inhibition of Shh in the adult leads to
rapid atrophy and disorganization of the corpus
cavernosum [88,89], suggesting that Shh is a critical protein in the development and maintenance of
penile cavernosal tissue structure. In addition, Shh
has been shown to stimulate the expression of vascular endothelial growth factor (VEGF) and NOS
in the penis [89]. Numerous other growth factors
are expressed in the penis and are also likely to play
important roles in maintaining cavernosal tissue
structure and function. However, most studies
have examined the use of exogenously applied
growth factors in therapeutic capacities, rather
than investigating the roles of endogenously produced growth factors.
As a major constituent and primary effector of
the vascular structures in the genitals, the VSMC
is highly adaptable and multifunctional. The two
primary functions of VSMCs are contraction and
synthesis/maintenance of extracellular matrix.
However, these two categories are considered to
be extremes that are manifested under in vitro
conditions and it is likely that a range of intermediary phenotypes exist in any given tissue in vivo
[90,91].

Mechanism of Smooth Muscle Contraction

Changes in smooth muscle tone are crucial for
regulating erectile function. Unlike striated
muscle, the molecular contractile units of interdigitating actin (thin) and myosin (thick) laments
are not regularly aligned with one another and can
be oriented in multiple directions [9294]. Smooth
muscle myosin is a large hexameric protein, consisting of two heavy chains and four light chains.
The heavy chains are identical and have both
globular and linear domains. The linear domains
form coiled structures that result in the tail of the
myosin molecule, while the globular domains
possess actin-binding sites and ATPase catalytic
activity. Actin laments are composed of two long
strands of globular actin that intertwine into a
double helical arrangement.
The contractile response of the smooth muscle
cell is tightly associated with the intracellular
concentration of free Ca2+ and its regulatory
action through calmodulin. Calmodulin-activated
myosin stimulates phosphorylation events that initiate cross-bridge movement along the actin lament and generation of force. Myosin light chain
phosphatase (MLCP) dephosphorylates myosin
and inactivates cross-bridge movement. At any
given level of intracellular Ca2+, the contractile
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450
apparatus may become further sensitized by the
inhibition of MLCP, increasing the efciency of
myosin phosphorylation by myosin light chain
kinase.
The activity of MLCP can be modulated by a
variety of factors. A well-recognized mechanism
involves the Rho/Rho kinase pathway. Rho proteins are small GTPases and can be activated by the
binding of agonists to G-protein-coupled receptors
[95]. Activated Rho can in turn activate Rho kinase,
a serine/threonine kinase. Rho kinase can then
phosphorylate multiple substrates including
MLCP, the 17 kD protein kinase C-potentiated
inhibitor protein, and myosin light chain (MLC20)
[96,97]. In genital smooth muscle, the RhoA/ROK
pathway and its effects on MLCP have been shown
to play an important role in regulating smooth
muscle contractility in both male and female genital
smooth muscle, whereas the importance of MLC20
phosphorylation by Rho kinase remains unclear
[98101].

Pathways Regulating VSMC Tone

Pathways that regulate smooth muscle contractility ultimately inuence intracellular Ca2+ levels
and/or alter the calcium sensitivity of the contractile proteins (Figure 1). Vasoactive substances induce changes in smooth muscle tone by
pharmacomechanical coupling and/or changes in
cell membrane potential via electromechanical
coupling.
Pharmacomechanical Coupling
Inositol 1,4,5-trisphosphate (IP3), 1,2diacylglycerol (DAG), and protein
kinase C (PKC)
The binding of vasoconstrictor agonists, such as
norepinephrine (NE), endothelin-1 (ET-1), angiotensin II (AT-II), prostaglandin (PG) F2a and
thromboxane (Tx) A2, to their respective receptors

Gratzke et al.
stimulates phospholipase C beta (PLC-b). This
membrane-bound enzyme hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to liberate IP3
and DAG. IP3 binds to specic receptors (IP3R) on
the smooth endoplasmic reticulum (SER) to
stimulate the release of Ca2+ from intracellular
stores. IP3Rs act as Ca2+-activated Ca2+ channels.
Binding of IP3 to these receptors not only activates
the channel, but also increases the sensitivity of the
IP3R to Ca2+ and facilitates Ca2+-induced release of
Ca2+ [102]. Upon dissociation of agonists from
their receptors, free Ca2+ is recycled back into the
SER by the SER Ca2+-ATPase pump. It restores
intracellular Ca2+ levels to the basal state and
thereby is an important mechanism of signal
termination.
DAG is also an important intracellular second
messenger generated by PLC. DAG directly activates PKC. With regard to smooth muscle tone,
PKC can regulate ion channels or phosphorylate
multiple substrates to facilitate contraction
[93,103]. PKC may also mediate Ca2+-independent
contraction, since several of the PKC isoforms are
insensitive to Ca2+ while still being activated by
DAG. In VSMCs, termination of DAG/PKC signaling is accomplished predominantly by hydrolysis of DAG by lipases to yield free fatty acids and
glycerol [103].

Cyclic Nucleotides
Generation of cyclic nucleotides (cyclic guanosine
monophosphate [cGMP] and cyclic adenosine
monophosphate [cAMP]) by guanylyl and adenylyl
cyclases is a primary mode of mediating penile
vascular and nonvascular smooth muscle relaxation. Vasodilators such as vasoactive intestinal
polypeptide (VIP) and PGs E and D activate
G-protein (Gs)-coupled receptors that can stimulate plasma membrane-associated adenylyl cyclase,
whereas soluble guanylyl cyclase (sGC) can be
directly activated by NO or carbon monoxide (CO)

Figure 1 Signal transduction pathways regulating smooth muscle tone. Pathways mediating contraction are shown in panel
A and pathways mediating relaxation are shown in panel B. Red arrows indicate association, binding, and/or activation,
whereas yellow arrows indicate inhibitory regulation. Indirect or putative interactions are indicated by dashed arrows.
AM = actin-myosin contractile apparatus; BKCa = calcium-activated maxi-K+ channel; CaM = calmodulin; CaMK = calmodulindependent kinase; cAK = cAMP-dependent protein kinase; cGK = cGMP-dependent protein kinase; CO = carbon monoxide;
DAG = 1,2-diacylglycerol; IP3 = inositol 1,4,5-trisphosphate; IP3R = IP3 receptor; IRAG = IP3R-associated cGK substrate;
KATP = ATP-dependent K+ channel; MLCP = myosin light chain phosphatase; MLCK = myosin light chain kinase; NO = nitric
oxide; PI3K = phosphoinositide 3-kinase; PIP2 = phosphatidylinositol 4,5-bisphosphate; PIP3 = phosphatidylinositol 3,4,5trisphosphate; PKC = protein kinase C; PLCb = phospholipase C beta; PLmb = phospholamban; ROC = receptor-operated
channel; SER = smooth endoplasmic reticulum; SERCA = SER calcium ATPase. Adapted from Kim NN. Vascular physiology
of erectile function. In: Carson CC, Kirby RS, Goldstein I, Wyllie MG, eds. Textbook of erectile dysfunction, 2nd edition. New
York: Informa Healthcare; 2009.

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Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

Contractile
Agonist

Ca2+

ROC
PIP2

Ca2+

aq

SOC

L-Type Ca2+
Channel

PLCb

Na+
Ca2+

DAG

Gq

Ca2+
Ca2+
CaM

SERCA
(inhibited)

MLCK-like
Kinase?

IP3

PLmb

Na+
Ca2+
Depol.

PKC

IP3R

Ca2+

Ca2+

SER

CaM

ERK
MLCK

MLCK

PIP3

CONTRACTION

PI3Kg

AM
a
Rh

Contractile
Agonist

MLCP
o

L-Type
Ca2+
Channel

Ca2+
AM- P

NSCC

Ca2+

bg

MLCP- P
(inactive)

Rho-Kinase

PIP2

G
Contractile
Agonist

B
CO

K+

NO
as

Gs
Guanylyl
Cyclase

GTP

NO

Ca2+

Vasodilatory
Agonists
Adenylyl
Cyclase

BKCa

Ca2+
ATPase

KATP

Ca2+

ATP

K+

K+

Hyp

cAMP

erpo
+
lariz
atio K
n

cGKI

GTP

cAK

cAK
cGMP

cGKI

HSP20

Ca2+

Lower
Affinity
for CaM

PLmb

Desensitization

(inactive)

MLCK- P

SERCA

(inactive)

AM- P

Hi Ca2+

Ca2+

SER

CaMK II

MLCK

RELAXATION

AM

cGMP
cGMP - cGKI IP3R - IRAG
Complex
(inactive IP3R)

MLCP
cGKI

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452
by binding to the heme moiety of the enzyme.
Increased levels of intracellular cAMP and cGMP
cause the activation of cAMP-dependent and
cGMP-dependent protein kinases (cAK and cGK)
[104106]. Thus, in addition to specic activation,
there is potential cross-activation of cAK (also
called protein kinase A) and cGK (also called
protein kinase G), which may be a mechanistic basis
for signal cross talk. However, it has been postulated that activation of cGK by cGMP is the main
mechanism to mediate relaxation of penile erectile
smooth muscle. cGK are derived from two different
genes that encode type I (cGKI) and type II
(cGKII). In smooth muscle, only cGKI is expressed
and exists as two splice variants (cGKI alpha and
cGKI beta). While specic roles of the two different cGKI isoforms are an area of continuing investigation, there is evidence that both isoforms differ
considerably in their functional properties [107
109]. Immunoprecipitation studies indicate that in
smooth muscle cells, cGKI is associated with IP3R
and a protein known as IP3R-associated cGK substrate (IRAG), both of which act as substrates for
the kinase [110]. Phosphorylation of IP3R and
IRAG decreases agonist-induced Ca2+ release from
the SER [111]. In addition, cGKI is known to
phosphorylate phospholamban, a small membraneassociated protein that constitutively inhibits the
SER Ca2+-ATPase. Phosphorylation of phospholamban inactivates its inhibitory control of ATPase
activity and increases Ca2+ reuptake into the SER,
where Ca2+ is bound to proteins such as calsequestrin. Protein kinase A can also phosphorylate phospholamban to increase Ca2+ reuptake [112]. Thus,
the combined actions of cGKI and cAK can inhibit
Ca2+ release from intracellular stores or stimulate
Ca2+ re-uptake.
Additional and perhaps equally important pharmacomechanical mechanisms by which cGMP
and/or cGKI may cause relaxation also involve
inhibition of Rho kinase and stimulation of MLCP
[113]. Some studies suggest that Rho kinase and
MLCP can both be phosphorylated by cGKI to
antagonize Rho kinase activity and stimulate
MLCP. In the penis, immunostaining for cGKI
alpha and cGKI beta has been observed within the
smooth musculature and the endothelium of cavernous arteries and sinusoids. Double-staining
protocols revealed the colocalization of alphaactin, cGMP, endothelial NOS (eNOS), and cGKI
isoforms [114]. Findings from in vitro functional
studies are also in support of a signicance of the
cGKI in the control of human penile erectile tissue
[115,116].
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PDEs
One of the main mechanisms by which cyclic nucleotide signaling is terminated is by the action of
PDEs, a heterogenous group of hydrolytic
enzymes. PDEs are classied according to their
preference or afnity for cAMP and/or cGMP,
kinetic parameters of cyclic nucleotide hydrolysis,
relative sensitivity to inhibition by various compounds, allosteric regulation by other molecules,
and chromatographic behavior on anion exchange
columns. Out of 11 families of PDEs consisting of
more than 50 isoenzymes identied to date [117
119], six (PDE 1, 2, 3, 4, 5, and 11) have been
proven to be of pharmacological importance. Since
the distribution and functional signicance of PDE
isoenzymes varies in different tissues, isoenzymeselective inhibitors have the potential to exert specic effects on the target tissue. Preferential
expression of PDE5 in the corpus cavernosum and
the cGMP-mediated relaxation of the cavernous
smooth muscle during sexual stimulation have
made inhibition of this enzyme by sildenal, vardenal, or tadalal a clinical benet in the management of ED. The puried protein is a homodimer
of 99.6 kDa subunits and binds two zinc atoms per
monomer which are necessary for catalysis.
Since PDEs form a biochemically and structurally diverse family of proteins, there might be
more than one PDE isoenzyme or isogene serving
as potential drug target in the treatment of ED. In
the 1990s, the presence of PDE isoenzymes 2, 3, 4,
and 5 was reported in cytosolic supernatants of
human erectile tissue [120]. In addition, the
expression of mRNA transcripts specically
encoding for 14 different human PDE isoenzymes
and isoforms in human cavernous tissue was shown
by means of real-time polymerase chain reaction
(RT-PCR) and Northern blot analysis: PDE1A,
PDE1B, PDE1C, PDE2A, and PDE10A, which
hydrolyze both cAMP and cGMP; the cAMPspecic PDE isoenzymes PDE3A, PDE4 (A-D),
PDE7A, and PDE8A, and the cGMP-specic
PDEs PDE5A and PDE9A [121]. The intracellular level of cAMP in human erectile tissue is
mainly regulated by the cAMP-degrading PDE
isoenzymes 3 and 4. Results obtained in vitro
suggest that PDE3 and PDE4 might be the predominant isoenzymes in the human corpus cavernosum [122]. Interestingly, it has also been shown
that the reversion of tension mediated by an
alpha1-adrenoceptor of isolated human corpus
cavernosum induced by sildenal and tadalal was
reversed by the cAK inhibitor Rp-8-CPT-cAMPS,

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

suggesting an involvement of cAMP-mediated
mechanisms in the action of PDE5 inhibitors
[115]. On the basis of these observations, an
important complementary role might be considered for the adenylyl cyclase/cAMP/cAK pathway
in the control of cavernous smooth muscle tone.

Electromechanical Coupling
Pathways that regulate VSMC tone and that are
associated with changes in membrane potential are
dened as electromechanical coupling mechanisms. The primary electromechanical mechanism
of contraction in VSMCs involves depolarization
and the opening of voltage-gated L-type Ca2+
channels to allow inux of extracellular Ca2+. Contractile responses caused by NE, ET-1, and AT-II
are partly mediated by L-type Ca2+ channels [123
125]. Recent studies indicate that L-type Ca2+
channels can be activated by phosphatidylinositol
3,4,5-trisphosphate (PIP3) which is derived from
PIP2 through the action of phosphoinositide
3-kinases (PI3K) [123]. PI3Ks are associated with
the plasma membrane and can be activated by
G-protein-coupled receptors or tyrosine kinases.
A major mechanism of VSMC relaxation is the
activation of K+ channels. Activation of cGK and
cAK has been associated with the opening of Ca2+activated maxi K+ (BKCa) channels in the plasma
membrane, causing hyperpolarization. Various
mechanisms involving direct and indirect
phosphorylation/dephosphorylation events mediated by cGK or cAK have been postulated for the
activation of BKCa channels in smooth muscle from
different vascular beds. However, the precise
mechanisms remain undened. Hyperpolarization
mediated by BKCa channels has been shown to be an
important mechanism of NO-cGK-dependent
relaxation in the cavernosal smooth muscle of the
penis [126]. Some vasodilators that stimulate cAMP
production have also been shown to activate ATPsensitive K+ channels in penile cavernosal tissue and
resistance arteries [127,128]. Collectively, changes
in membrane potential due to increased K+ efux
inactivate L-type Ca2+ channels to inhibit Ca2+
inux. NO may also cause VSMC hyperpolarization independent of cGMP and cGK. In aortic
smooth muscle cells, NO has been shown to
directly activate BKCa channels [129].
Endogenous Regulators of Penile Cavernosal
VSMC Contractility
NO
NO is the primary mediator of nonadrenergic,
noncholinergic (NANC) parasympathetic input

453

and endothelium-dependent relaxation in the

corpus cavernosum [1]. NO can regulate a wide
array of physiological functions in mammals. It is
synthesized on demand from the amino acid
L-arginine and molecular oxygen by a family of
enzymes known as NOS. Three distinct isoforms
of NOS have been identied which were originally named after the tissues in which they
were rst described. nNOS (NOS type I) and
eNOS (or NOS type III) are Ca2+/calmodulindependent, constitutive isoforms. Inducible NOS
(iNOS or NOS type II) is a Ca2+-independent
isoform that is mainly expressed in macrophages
and tissues following an immunological stimulus
[130]. NO can readily cross plasma membranes to
enter target cells and promote the synthesis and
accumulation of cGMP by the activation of the
sGC. sGC is a heterodimeric protein that contains
a prosthetic heme attached to a histidine residue
of the b-subunit, which is required for the activation of the enzyme. Although the binding of NO
occurs in the b-subunit, both subunits are
required for the stimulation of enzyme activity
[131,132].

PGs
PGs are produced by the action of cyclooxygenases on the common precursor arachidonic acid
[133]. Human corpus cavernosum smooth muscle
cells in culture have been shown to produce prostaglandin E (PGE2) and PGF2a. It has been demonstrated that prostanoids can induce both
relaxation and contraction in penile corpus cavernosum. PGE is the only endogenous PG that
appears to elicit relaxation of human trabecular
smooth muscle, the others causing constriction or
having no effect on smooth muscle tone. Exogenous PGE1 and PGE2 relax isolated cavernosal
tissue at submicromolar concentrations, while
PGE2 causes contraction at concentrations of
10 mM or greater. Prostaglandin E receptor (EP)
receptors, which mediate the response to PGE,
have been the most extensively studied and are
categorized into four pharmacologic subclasses
(EP1EP4) [134,135]. Several different isoforms of
the EP3 receptor have been identied and arise
from alternative splicing of a single gene product.
In general, the EP1, EP3I, and EP3III receptors
mediate smooth muscle contraction by stimulating
phosphatidylinositol hydrolysis or inhibiting adenylyl cyclase, while EP2, EP3II, and EP4 receptors
mediate smooth muscle relaxation by coupling to
Gs protein and stimulating adenylyl cyclase to
increase intracellular cAMP [136].
J Sex Med 2010;7:445475

454

Peptide RegulatorsVIP and ET

The density and distribution of VIPergic nerves
within the penis has led many to postulate that
VIP, in addition to NO, is an important NANC
neurotransmitter regulating penile erection. VIPimmunoreactive nerves are widely distributed
throughout the male genitourinary system, and
VIP and NOS containing nerves are often colocalized in penile tissue [1]. Isolated corpus cavernosum tissue from various species, including human,
exhibits relaxant responses to VIP. These effects
are accompanied by an increase in tissue levels of
cAMP. The role of endogenous VIP in mediating
penile erection is further supported by the observations that anti-VIP antibodies and VIP receptor
antagonists inhibit nerve-mediated relaxation in
isolated cavernosal tissue strips [1]. However, the
role of VIP as a modulator of trabecular smooth
muscle tone remains inconclusive since the effects
of the peptide in vivo are not necessarily consistent
with ex vivo or in vitro ndings. Intracavernosal
administration of VIP in humans has yielded
varying results, ranging from no effect to partial
tumescence to full erection. Thus, while descriptive studies are supportive of VIPs potential role
in mediating or enhancing the onset and maintenance of penile erection, the mechanisms underlying its regulation and action have yet to be
completely elucidated.
ET-1 is one of the most potent vasoconstrictors
yet described [137,138]. This peptide has also been
shown to have growth factor activity, stimulating
mitogenesis in broblasts, smooth muscle, and
endothelial cells. Similar to NO, ET release from
the intimal lining of blood vessels can be induced
by shear stress. In human corpus cavernosum,
ET-1 is synthesized by the endothelium and elicits
strong, sustained contractions of corpus cavernosum smooth muscle [139,140]. Both ET receptor
subtypes (ETA and ETB) have been identied in
penile corpus cavernosum. They are distributed on
both the endothelium and the smooth muscle and
are distinguished by their binding afnity for ET-3
[141]. Exogenous ET-1 or ET-2 cause equipotent
contraction in isolated cavernosal tissue strips,
whereas ET-3 induces much weaker contraction in
corpus cavernosum. While the receptor-binding
afnity of ET-1 and ET-2 is not necessarily greater
than that of other contractile factors, the rate of
dissociation is signicantly slower than many
ligands [141]. This may account for the unique
ability of ETs to maintain long-lasting, sustained
contraction in corpus cavernosum smooth muscle.
It has been suggested that ET may also exert
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Gratzke et al.
vasodilatory effects at low concentrations through
a super-high afnity form of the ETB receptor.
Although this vasodilatory role of ET in penile
erection remains unclear, it has been demonstrated
in the rat that ET-3 and submaximal doses of ET-1
increase ICP, potentially by stimulating NO production [142].

Noncontractile Responses in VSMCs

Changes in VSMC growth and extracellular
matrix production can have a profound impact on
the function of genital tissues. The extracellular
matrix itself is a dynamic structure that plays an
important role in modulating cell morphology,
movement, growth, differentiation, and survival by
regulating cell adhesion, cytoskeletal machinery,
and intracellular signaling. It has been postulated
that smooth muscle cells may transform from contractile to synthetic cells (or vice versa) in response
to changes in their environment (e.g., chronic
disease states or acute injury). Alternatively, there
may be an inherently heterogeneous population of
VSMCs in a given vascular tissue at any one time.
In addition to growth factors and cytokines, vasoactive factors have also been shown to have trophic
effects in the vasculature, suggesting that many of
the same intracellular mediators that cause contraction or relaxation are also involved in trophic
responses in VSMCs.
Synthetic VSMCs are primarily characterized
by a signicantly decreased expression of contractile proteins. Thus, activation of signaling pathways that may have mediated tonic responses in
contractile VSMCs can modulate cell growth or
matrix production in a synthetic VSMC. However,
the specic mechanisms regulating gene expression and cell growth remain, in large part, to be
elucidated. For example, the NO-cGK pathway
and its effects on gene expression is an area of
active study. While it appears that cGKI modulates
the exracellular signal-regulated kinase (ERK)
pathway (also called mitogen-activated protein
kinase or MAP kinase) to modulate proliferation
and migration of VSMCs, the molecular targets of
ERK that eventually control gene transcription
have not been clearly dened [143].
Many growth factors stimulate cell surface
receptors with intrinsic tyrosine kinase activity in
their cytoplasmic domains. This tyrosine kinase
activity is considered essential to regulating cell
growth. Several of these receptors have been
linked with the activation PLC-g. Also, phospholipase D (PLD) may be more important for mediating trophic responses than contractile responses.

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

Some variations in responses to growth factors and
vasoactive substances may be due to the different
mechanisms of activation for different PLC isoforms. Stimulation of PKC has been shown to
have both proliferative and antiproliferative effects
to platelet-derived growth factor, epidermal
growth factor, and AT-II [103]. While the reasons
for this variability remain unclear, it must be
stressed that multiple isoforms of PKC exist and
each isoform has numerous substrates. PKC has
also been shown to modulate DNA synthesis,
potentially through the phosphorylation of transcription factors [103].

Summary and Perspective

An impressive amount of knowledge has been
accumulated regarding smooth muscle biology
and vascular physiology. Future concepts in genital
tissue pharmacology will benet from these
insights. To date, it is widely accepted that several
disorders of the male sexual response, such as male
ED and orgasmic dysfunctions, can be therapeutically approached by inuencing the function of the
vascular and nonvascular smooth musculature of
the genital tract. In order to achieve a pronounced
drug effect without signicant adverse events,
especially on the cardiovascular system, a certain
degree of tissue selectivity is mandatory. Selective
intervention in intracellular pathways regulating
smooth muscle tone has become a promising strategy to modulate tissue function.

Diabetes and MetS

Diabetics are at increased risk for maladies, including retinopathy, neuropathy, nephropathy, and
vascular disease. ED is often characterized in part
by insufcient NANC nerve stimulus, and/or an
inability to dilate feeder arterioles of the penis
resultant from vascular disease. As the diabetic
population is susceptible to these changes, ED is
indeed prevalent in this cohort. Although PDE5
inhibitors have revolutionized the eld of ED
treatment, these drugs are less effective in certain
subsets of the population, including diabetics. For
the sake of this amended chapter, the work outlined will review mainly type 2 diabetic ED and
the MetS, highlighting studies of type 1 diabetic
ED when relevant. Some valuable reviews include:
Hidalgo-Tamola et al. [144], Moore et al. [145],
Vrentzos et al. [146], Musicki et al. [147], and
DiSanto [148].

455

Epidemiolgic Data
Diabetes Mellitus
Diabetes mellitus is a common chronic disease,
affecting 0.52% worldwide. The prevalence
of diabetes as a comorbidity has remained at
2025%, irrespective of whether treating clinics
are endocrine based or andrology based [149,150].
ED in diabetics is more common than retinopathy
or nephropathy [151]. The Massachusetts Male
Aging Study reported that up to 75% of men with
diabetes have a lifetime risk of developing ED,
much higher rates than 52% (4070 years of age)
[152154]. The onset of ED occurs in the earlier
age for those with diabetes, presenting within 10
years of the diabetic onset in more than 50% of
patients with any type of diabetes [155].
MetS
MetS, which is also called insulin resistance syndrome or syndrome X, includes glucose intolerance, insulin resistance, obesity, dyslipidemia, and
hypertension. Several epidemiological data have
identied MetS as potential risk factors of ED.
Grover et al. [156] evaluated the effect of various
cardiovascular risk factors on ED in a primary care
setting. ED was found in 49.4% according to a
score of less than 26 on the International Index of
Erectile Function-erectile function (IIEF-EF)
domain in a cross-sectional survey of 3,921 Canadian men. The presence of diabetes (odds ratio
3.13), undiagnosed hyperglycemia (odds ratio
1.46), impaired fasting glucose (odds ratio 1.26),
and MetS (odds ratio 1.45) were identied as independent risk factors for ED.
Clinical Findings
Diabetes Mellitus
In 12% of type 1 diabetic men, ED was the rst
symptom of diabetes [157]. The prevalence of coronary artery disease (CAD) (20%) and peripheral
vascular disease (5%) among men with diabetes is
far higher than in the general population. Pathologic changes in the cavernous arteries [158], ultrastructural changes in the cavernous smooth muscle
[159],andimpairedendothelium-dependentrelaxation of the corporeal smooth muscle [160] have also
been noted in penile specimens from diabetic men
with ED.
The presence of ED in diabetic patients could be
the harbinger of fatal cardiovascular disease. Gazzaruso et al. [161] demonstrated a higher prevalence of ED in diabetic patients with silent CAD
than those without any evidence of myocardial
ischemia. ED was associated with more than 14
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456

Gratzke et al.

times higher risk for silent CAD in diabetic men. In

a subsequent study, ED was associated with higher
major cardiovascular morbidity and mortality in
diabetic patients with silent CAD [161].
Hemoglobin (Hb)A1c levels have been shown
to increase with the severity of ED [162,163] and
was found to be an independent predictor of the
EF score in 78 men with type 2 diabetes [164].
However, there have been conicting results about
the benecial effects of strict glycemic control on
erectile function. Some studies reported improved
erectile function following the reduction of
HbA1c, while others reported no signicant
change despite the aggressive blood sugar control
[165,166].
Hypogonadism is often associated with diabetic
ED patients. Corona et al. found hypogonadism in
24.5% of men with diabetes and ED vs. 12.6% in
the rest of the men with ED [167]. Testosterone
supplementation in human diabetics with ED
receiving pharmacological treatment might be
advantageous in the diabetic men in whom PDE5
inhibitors given for ED do not work [168].

serum T showed a strong negative correlation. To

assess the effect of BMI on vasculogenic ED, the
authors examined this relationship in the absence
of other risk factors and found that for a BMI <25,
three out of 13 men (23.1%) had vasculogenic ED
as compared with 32 out of 54 men (59.3%) with a
BMI 25.
Currently, no direct pharmacologic therapy for
MetS is available. Esposito et al. [174] assessed the
effect of weight loss and increased physical activity
on men with ED associated with obesity. BMI
decreased signicantly in the intervention group,
and was associated with a decrease in serum concentrations of interleukin-6 and CRP. Erectile
function scores improved signicantly with lifestyle intervention but remained stable in the
control group. In multivariate analyses, changes in
BMI, physical activity, and CRP were independently associated with erectile function improvement. Thus, lifestyle changes are associated with
improved sexual function and lowered inammation in obese men with ED.

MetS
MetS and increased waist-to-hip ratio have been
associated with a higher proportion of moderateto-severe ED in men older than 50 years [169].
Conversely, ED may be predictive of MetS presence in men with a body mass index (BMI) of
<25 kg/m [145,170]. These interesting ndings
suggest that ED may be a warning sign for MetS in
men otherwise considered at low cardiovascular
risk.
Studies indicated the possible role of inammation and endothelial dysfunction in the development of ED for patients with MetS. Men with
MetS had an increased prevalence of ED, reduced
endothelial function score, and higher circulating
concentrations of high sensitivity C-reactive
protein (CRP) compared with men without metabolic disorders [171]. This and other studies
clearly showed the relationship between MetS, the
inammatory endothelial activation, and the
prevalence of ED [171,172].
As mentioned earlier, low circulating androgen
levels are clearly a risk factor for MetS and the
reverse relationship is true as well. ED might
occur as a possible consequence of hypogonadism
and MetS. A recent study by Zhody et al. [173]
elegantly related hypogonadism to ED and MetS
by analyzing BMI measurements in 158 obese
men. With increasing BMI, the frequency of
hypogonadism and ED increased, while total

Basic Science Mechanisms

The majority of basic science studies, to date, that
examine mechanisms of diabetic ED have done so
using animal models of type I diabetes. Available
studies outlining ED in animal models of type 2
diabetes and MetS have recently been reviewed
[144].

J Sex Med 2010;7:445475

Nitrergic Dysfunction
Erection is activated by NO release from nNOS at
NANC nerve terminals. Maintenance of cavernosal vasodilation is thought to occur through the
activation of eNOS in endothelial cells, presumably in response to shear stress. Impaired vasodilator signaling often results from NANC nerve
dysfunction and/or endothelial dysfunction,
leading to ED. Numerous studies have demonstrated type I diabetic animals to have impaired
cavernosal relaxation to electrical eld stimulation
as well as decreased ICP following electrical cavernosal nerve stimulus, indicative of nitrergic dysfunction [175181]. Decreased penile nNOS
content was detected in various rodent models of
type 2 diabetes [182184]. Impaired nitrergicmediated relaxation in type 2 diabetic mice has
also been reported; however, the extent of the
impaired relaxant response was modest, leading
the authors to question the true pathophysiologic
relevance of this nding to the ED phenotype
[185].

457

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

Endothelial Dysfunction
Endothelial dysfunction is characterized by
lowered NO bioavailability resulting from
decreased eNOS expression or activity, or
increased NO scavenging. It is clear that an
attenuation of endothelium-dependent vasodilation of cavernosal tissue is present in several
animal models of type 1 and type 2 diabetes
[144,147,184186]. The activation of eNOS can
occur by hemodynamic stimuli, such as shear
stress, as well as through protein signaling, such as
by VEGF, leading to eNOS phosphorylation on
serine 1177 [147,187]. In addition to phosphorylation events, eNOS activity and subsequent NO
production are regulated by substrate concentration, cofactor availability, and enzyme coupling.
Relevance of dysfunctional eNOS enzyme regulation remains speculative in regard to diabetic ED
(see citation [147] for review).
Oxidative Stress
Chronic hyperglycemia induces free radical production through formation of advance glycation
end-products (AGE), lipid peroxidation, polyol
pathway activation, superoxide production, and
activation of PKC [188]. Increased penile and
serum AGE and reactive oxygen species (ROS)
levels have been detected in type I diabetic rodents
[189,190]. Impairments in NO-mediated cavernosal relaxation in these rodents are prevented with
superoxide dismutase or a peroxynitrite decomposition catalyst, supporting a delirious role of ROS
in type I diabetic ED [191193].
Studies examining oxidative stress in animal
models of type 2 diabetes or MetS are scant.
Decreased antioxidant levels, such as glutathione
(GSH), may result in elevated ROS/oxidative
stress in type 2 diabetic men. Kovanecz et al. found
prolonged treatment with pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-g
agonist said to have anti-inammatory effects and
to improve the glutathione/glutathione disulphide
(GSH/GSSH) ratio [194], suggesting that
glycemic-stabilizing agents may also have benet
in decreasing damaging ROS.
Cavernosal Hypercontractility
Increased contractile function of the cavernosum
can result from heightened sympathetic activation
or potentiated intracellular contractile signaling of
smooth muscle cells. Many animal models of diabetic ED have pointed to cavernosal hypercontractility as a pertinent mechanism underlying the
disease phenotype. A recent review extensively

outlines potential pro-signaling pathways in the

penile smooth muscle cell that may contribute to
diabetic ED [148].
Studies by Carneiro et al. and Luttrell et al.
have suggested the presence of increased contraction in response to sympathetic activation in type
II diabetic ED [185,195]. Wingard et al. found the
heightened contractile signaling in the type 2 diabetic rodent in response to phenylephrine and
ET-1 to be mediated by overactivity of PKC and
Rho kinase, two primary kinases mediating
smooth muscle cell tone [186].

Veno-occlusive Dysfunction
The limiting of blood outow through mechanical
compression of the emissary veins against the
tunica albuginea is essential for the maintenance of
elevated corporal pressures and a rigid erection.
Studies in animal models of type 2 diabetes have
suggested that a veno-occlusive disorder may
underlie the ED phenotype. Kovanecz et al. found
Zucker diabetic fat rats to have an inability to
sustain adequate intracorporal pressure after the
cessation of penile saline infusion, suggesting the
presence of a veno-occlusive disorder [194]. These
studies have recently been validated in the db/db
mouse model of type 2 diabetes [185].
Conclusions
The numbers of patients with type 2 diabetes and
MetS continue to rise. Current pharmacologic
treatments remain insufcient for these populations, and the need for improved therapeutics is
evident. Organic ED in these cohorts is underlined by multifaceted, complex mechanisms,
involving nerve, vascular, and hormonal signaling
at its core. It is clear that more clinical and basic
science studies are warranted.

ED and Cardiovascular Disease

The vascular system is responsible for providing

adequate blood supply to the erectile tissue facilitating the corporo-veno-occlusive mechanism
required for erection. Thus, any alteration of the
vascular system may compromise erectile function.
Vascular disease in arteries supplying blood to the
penis obviously impedes erectile function by limiting blood ow, but systemic vascular dysfunction
is also intimately related to ED. Cardiovascular
disease shares with ED the same risk factors,
namely hypertension, hypercholesterolemia, diabetes, and smoking [152,196].
J Sex Med 2010;7:445475

458

Atherosclerosis/Vascular Ischemia and ED

Association of ED to systemic vascular diseases is
clear. On one hand, there is a high prevalence of
ED in patients having CAD [197,198], peripheral
arterial disease [199], and cerebrovascular disease
[200]. In addition, the prevalence of ED seems to
be increased as the severity of vascular disease augments [201]. Patients with lesions in two or more
coronary arteries had worse erectile function than
patients with normal coronary arteries or singlevessel CAD [202].
On the other hand, cardiovascular diseases are
prevalent among patients with ED. In fact, CAD
has been revealed in patients reporting ED
without any other symptomatology of vascular
disease [203]. ED has also been associated to the
presence of peripheral atherosclerotic lesions.
Among patients with ED, 66.4% presented atherosclerotic lesions, while lesions were only
present in 36.5% of patients without ED [204]. In
most cases, ED symptoms preceded CAD symptoms [197,201]. Thus, ED would be a sentinel
symptom that warns of a probable underlying systemic vascular disease [205].
Chronic ischemia provoked by atherosclerotic
stenosis of the proximal iliac artery in rabbits is
also associated with functional changes in the
distal part of the penile vasculature such as
decreased NOS activity, increased production of
contractile Tx, and PG formation. Neurogenic
contractions were potentiated, while endotheliumdependent and neurogenic NO-mediated relaxations were reduced in cavernosal tissue [206,207].
A time-dependent reduction of the expression of
nNOS and eNOS in the cavernosal tissue from
these animals, with a parallel increase of the
expression of iNOS, was demonstrated [208].
Reduced NOS activity and impaired endotheliumdependent and neurogenic NO-mediated relaxation of cavernosal tissue have been conrmed in a
rabbit model of cavernosal ischemia without
hyperlipidemia [209]. An elevation of the cavernosal content of endogenous inhibitors of NOS
was proposed to be responsible for these effects
[209]. The apolipoprotein E knockout mouse, a
known experimental model of atherosclerosis,
shows reduced erectile responses and impaired
NO/cGMP pathway [210,211].
Hyperlipidemia and ED
Association of ED to hyperlipidemia has been
found in several clinical studies. High concentrations of low-density lipoprotein seem to be related
to ED [212], although low levels of high-density
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Gratzke et al.
lipoproteins have been shown to be predictive of
ED [213]. Hypercholesterolemia at baseline was
also shown as a predictor of ED 25 years later
[214]. In contrast, a survey of 1,899 men aged
3079 years in Boston area revealed the absence of
association of untreated hyperlipidemia and ED
[215].
Chronic
hypercholesterolemia
reduces
endothelium-dependent relaxations, but not the
endothelium-independent relaxations in rabbit
corpus cavernosum [216,217]. In contrast, the neuronal vasodilation does not appear affected in these
animals [207]. The selective action of the endothelial NO/cGMP pathway in hypercholesterolemia
could be due to increased superoxide production
[217] by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [218] or to increased
plasma levels of asymmetric dimethylarginine
(ADMA), an endogenous inhibitor of NOS [219].
VEGF and VEGF receptor 2 are downregulated in
corporal tissue of rats high-cholesterol diet [220].
Intracavernosal administration of VEGF and broblast growth factor-2 improved endothelial function, increased the expression of nNOS, and
activated eNOS [221,222].

Hypertension and ED
The analysis of a representative care claims database identifying 273,325 patients with ED in the
United States revealed that the prevalence of
hypertension in this ED population was as high as
41.6% [223]. Conversely, a high prevalence of ED
is generally observed in hypertensive patient populations [224226]. However, hypertension is a risk
factor not only for ED but also for cardiovascular
disease. Then, the impact of hypertension on erectile function is contributed by the cardiovascular
complications following hypertension are associated to even higher prevalence of ED [152,227].
Some studies have detected lower levels of serum
testosterone in hypertensive patients [228,229], a
fact that could be relevant to the development of
ED in these patients. In hypertensive population,
ED was associated to older age, longer duration of
hypertension, and a more severe hypertension. ED
was also related to the antihypertensive therapy
[224].
Erectile responses were markedly inhibited in
spontaneously hypertensive rats (SHR) after normalization by mean arterial pressure (MAP),
although moderately reduced absolute increases in
ICP were observed [230,231]. Reduction of ICP/
MAP response in SHR preceded the development
of hypertension. The impairment of cavernosal

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

endothelium-dependent and NO donor-induced
relaxations also occurred before systemic vascular
alterations were manifested [231]. This suggests
that erectile tissue is at the front line of the development of endothelial dysfunction and would be
an early target end organ. Oxidative stress may
play a signicant role in the alterations caused by
hypertension on erectile function. In fact, an augmented production of superoxide anions could
result from increased activity of NADPH oxidase
driven by AT-II [232].

Cigarette Smoking and ED

Cigarette smoking is clearly related to ED. Active
and passive smokers are at higher risk for ED than
men not exposed to smoke, and the risk increases
as the exposure increases [233,234]. Some studies
suggest that smoking is associated to ED independently of cardiovascular disease [235,236].
Although a causative effect cannot be proven in
cross-sectional studies, this hypothesis is supported by the doseresponse shown in several
studies [234,236,237] and the fact that erectile
function is improved after smoking cessation
[238,239].
A reduction of penile NOS activity and nNOS
expression was observed after passive smoking in
rats, although erectile responses were not reduced
[240]. Cigarette smoking would be related to
downregulation of NO/cGMP pathway in penile
tissue, probably related to increased oxidative
stress [241,242], although an elevated activity and
expression of arginase together with an increase of
the content of the endogenous NOS inhibitor,
ADMA, could participate [243]. On the other
hand, acute nicotine administration caused a signicant reduction of physiological erectile
responses to erotic lms in healthy nonsmoker
men [244].
Pathophysiological Mechanisms in Vascular ED
Increased Vasoconstriction
RhoA/Rho kinase pathway plays an important role
in calcium sensitization and tonic contraction of
smooth muscle. Cardiovascular diseases are associated with an enhancement of RhoA/Rho kinase
activity [245]. RhoA and Rho kinase expression is
elevated in the cavernosal tissue from hypertensive
rats, possibly contributing to reduced erectile
function in these rats [246]. ET-1 levels are
elevated in plasma from patients with hypertension and hypercholesterolemia [247,248]. Patients

459

with organic ED also show higher venous and

cavernosal ET-1 levels [249]. In cavernosal tissue
from DOCA-salt hypertensive rats (specic animal
model), contractile responses to ET-1 were
increased and relaxation caused by ETB activation
was reduced [250]. A decrease in ETB receptors in
cavernosal tissue from hypercholesterolemic
rabbits was also detected [251]. AT-II has been
detected in endothelial and smooth muscle cells of
human corpus cavernosum [252] and caused its
contraction [253]. AT-II converting enzyme
expression is upregulated in rats with arteriogenic
ED [254]. In fact, administration of an AT1
antagonist has been shown to improve erectile
function in hypertensive patients [255].

Impaired Neurogenic Vasodilatation

Impaired neurogenic relaxation of cavernosal
tissue has been observed in a rabbit model of cavernosal ischemia [209], in SHR, affecting both NO
neurotransmission and CO neurotransmission
[256] and after cigarette extract administration
[241] while was unaffected in a rabbit model of
hypercholesterolemia [207].
Endothelial Dysfunction
Coronary endothelial dysfunction has been
associated with the presence of ED [257].
Endothelium-dependent ow-mediated dilation
(FMD) of the brachial artery was signicantly
reduced in ED patients, although nitroglycerineinduced dilation was also impaired [258,259]. The
impairment of FMD correlates to the severity of
ED [260]. Endothelium-dependent penile blood
ow increases generated by reactive hyperemia
were reduced in patients with ED. At the same
time, endothelial function in the forearm vasculature was not signicantly altered in ED patients
[261].
Penile Structural Alterations
Objective reduction of smooth muscle cells has
been demonstrated in patients with organic ED
[262]. A decrease in cavernous trabecular smooth
muscle and an increase in connective tissue are
correlated with diffuse venous leakage and a failure
of the veno-occlusive mechanism, hence resulting
in ED [263,264]. SHR show hyperproliferation of
smooth muscle in cavernosal tissue and penile vasculature, which correlates with blood pressure
values. Increased brosis was also observed [265].
Hypertension-induced alterations were improved
after antagonism of type 1 AT-II receptors (AT1)
[266].
J Sex Med 2010;7:445475

460
Drugs Causing ED

ED is a common symptom among older men and

will inevitably coexist with other physical conditions prevalent in this population such as depression, diabetes, and cardiovascular disease which
are themselves risk factors for ED [152,227,267].
In addition, sexual symptoms related to medication can involve a combination of complaints concerning sexual desire, arousal, and orgasm rather
than being concentrated on ED alone. Selfreported and questionnaire data concerning ED as
a side effect of medication should therefore be
interpreted with caution.

Cardiovascular Drugs and Erectile Function

ED and heart disease have common risk factors
[214,227], but comparing untreated and treated
patients with heart disease or hypertension
revealed that medication increases the relative risk
for development of ED [268].
Treatment of Hypertension and ED
Current recommendations for treatment of hypertension suggest thiazide diuretics as rst-line
therapy, while angiotensin-converting enzyme
(ACE) inhibitors, AT1 receptor antagonists,
calcium channel blockers, and beta-adrenoceptor
antagonists are indicated as rst-line agents in specic high-risk conditions [269]. Often, two or more
antihypertensive medications will be required to
achieve a blood pressure <140/90 mm Hg (or
<130/80 mm Hg in diabetic patients) in hypertensive patients [269]. All drugs have ED listed as a
potential side effect, but well-designed controlled
clinical trials give conicting results concerning
causative relationships [270]. Animal studies do
suggest possible mechanisms using in vitro and in
vivo methodology [271].
Diuretics
This class of drug has been extensively studied
following early trials which showed a high prevalence of self-reported ED. Possible mechanisms
include decreased vascular resistance and lowered
zinc levels leading to reduced androgen production. Appropriate controlled studies with ED as an
end point give consistent results despite trends
toward lower-dosage schedules [225]. Similar ndings were documented from the Treatment of
Mild Hypertension Study (TOMHS) where the
prevalence of ED at 2 years in men taking a lowdose thiazide was twice that of both the placebo
group and those on alternative agents [272]. Interestingly, after 4 years of treatment, prevalence of
J Sex Med 2010;7:445475

Gratzke et al.
ED in the placebo group approached that of the
thiazide group, a nding not fully explained by
dropouts. It may be that thiazide therapy unmasks
latent ED at an earlier stage rather then being
directly causal. Thus, it is likely that thiazide
diuretics are associated with ED in men with
hypertension, although this may represent
unmasking of an existing problem and the effect
can be reduced by lifestyle changes.

b- and a-Adrenoceptor Antagonists

In penile tissue, activation of b-adrenoceptors leads
to corporal relaxation [1] and vasodilation of penile
arteries [273]. This response is attenuated in vitro
by nonselective drugs such as propanolol, possibly
by blocking postjunctional b2-adrenoceptors
[273,274], but not by cardiac selective agents such
as practolol and atenolol. Depending on the lipophilicity of the b-adrenoceptor antagonists (e.g.,
propranolol is hydrophobic, while atenolol is
hydrophilic), they may also exert an inhibitory
effect within the central nervous system, perhaps
leading to lowered sex hormone levels [275]. The
effect of b-adrenoceptor antagonists on erectile
function to a large degree can be explained by
their mechanisms of action (e.g., they are either
general b-adrenoceptor antagonists, selective b1adrenoceptor antagonists, or also possess vasodilatatory properties) (Figure 2). Nonselective drugs
such as propanolol were associated with higher
prevalence of ED compared with patients treated
with placebo or ACE inhibitors [276,277]. Later
trials using agents with higher selectivity for the
b1-adrenoceptor such as acebutolol have shown a
substantial reduction in ED as a side effect with no
difference being found against the placebo and
ACE inhibitor groups [272]. This also applies to
the use of selective b1-adrenoceptor antagonists
in the prophylaxis of angina [278]. The general
b-adrenoceptor antagonists which also cause
vasodilation by blocking a1-adrenoceptors,
e.g., carvedilol, have, in a crossover study, been
reported to be associated with worsening in sexual
function [279]. Some of the recently introduced
b1-adrenoceptor antagonists such as nebivolol have
also vasodilatatory effects mediated by release of
NO. In crossover studies, nebivolol, in contrast to
the selective b1-adrenoceptor antagonists, metoprolol, and atenolol, did not decrease sexual intercourse activity in hypertensive men, and may even
have positive effects on erectile function [280,281].
In clinical trials, a1-adrenoceptor antagonists
(e.g., doxazosin) used to treat hypertension [272]
or lower urinary tract symptoms [282] are not

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

461

Figure 2 b-adrenoceptor antagonists and erectile function. Propranolol is a general b-adrenoceptor antagonist, while
carvedilol and labetalol also block a1-adrenoceptors. Metoprolol, bisoprolol, and atenolol are selective b1-adrenoceptor
antagonists, and nebivolol, in addition, leads to release of nitric oxide (NO).

associated with complaints of ED and indeed had

lower rates than placebo groups. Drugs stimulatory to the a2-adrenoceptors such as clonidine
result in diminished erectile function both clinically and experimentally by peripheral and central
mechanisms [274,283].
ACE Inhibitors and AT1 Receptor Antagonists
In addition to circulating AT-II, ACE and chymase
are expressed in erectile tissue, and functional as
well as binding studies suggest that AT-II induces
contraction by activation of AT1 receptors [270].
Moreover, AT-II increases during the detumescence phase in man [284]. The ACE inhibitor captopril does not cause any signicant adverse effect
on sexual function in awake rats [274], and enalapril may even improve erectile function in SHR
[285]. This is also supported by clinical studies
comparing an ACE inhibitor with other agents
and placebo. All three studies found either no difference compared with placebo or improved sexual
function from baseline compared with other antihypertensive drugs [272,275,276,286].

In studies of hypertensive animals, AT1 receptor

antagonists (e.g., losartan, valsartan, and candesartan) reverse structural changes in the penile vasculature and appear to conserve erectile function
[285,287289]. Moreover, in clinical crosssectional studies, AT1 receptor antagonists, in contrast to other antihypertensive drugs, even tend to
improve erectile function [225]. In direct comparison with the b-adrenoceptor antagonist carvedilol,
valsartan has a benecial effect on existing sexual
dysfunction at baseline and has no adverse sexual
effects during 12 months of treatment [279]. In the
case of losartan, 3-month treatment was also
reported to improve sexual function [290].
Calcium Channel Blockers
Smooth muscle contraction requires increased
cytosolic calcium derived from internal stores and
extracellular uid. It would, therefore, be anticipated that calcium channel blockers would have a
permissive effect on penile erection but might
inhibit bulbospongiosal contraction during ejaculation. This is supported by ndings of in vitro
J Sex Med 2010;7:445475

462
studies which demonstrated a modest relaxant
effect on isolated cavernosal smooth muscle [283]
and penile arteries [291]. Clinical studies have
demonstrated no adverse effect on erection and
ejaculatory complaints seem short-lived [275]. In
the TOMHS, there was no signicant excess risk
of ED in the amlodipine group compared with
placebo-treated patients [272]. Another study also
showed no increase in the prevalence of ED when
hypertension was treated with diltiazem alone or
in combination with an ACE inhibitor [292]. A
comparative study of two calcium channel antagonists showed that neither had any signicant effect
on sexual function, although two patients withdrew from the nifedipine arm because of reduced
libido [293].

Treatment of Heart Disease and ED

ED is highly prevalent among patients with heart
failure, because of neurohumeral changes, an
imbalance of circulating vasomodulators, reduced
cardiac capacity, depression, and potential adverse
effects of heart failure medical treatment [294]. An
array of drugs is applied for the treatment of heart
disease. In most cases, a multiple drug regimen is
applied for conditions such as chronic heart
failure, where patients are treated with diuretics
for removal of surplus liquid, ACE inhibitors
and/or AT1 receptor antagonists to cause peripheral vasodilation, digoxin as positive inotropic
agent, antithrombotics, antiarrhythmics, anticoagulants, and hypolipidemic drugs. In addition,
the aldosterone receptor antagonists, spironolactone and eplerenone, and b-adrenoceptor antagonists such as metoprolol, bisaprolol, carvedilol,
and recently, nebivolol have been found to
enhance survival in patients suffering from heart
failure [295297]. Standard heart frequency
therapy with b-adrenoceptor antagonists, digoxin,
and thiazide diuretics may worsen sexual dysfunction owing to medication side effects, but evidence
regarding the effect on erectile function of most of
these drugs is sparse [270].
Lipid-Lowering Drugs (Fibrates, Statins)
ED was reported to be a frequent side effect of
treatment of hyperlipidemic subjects using clobrate [298] or gembrozil [299]. In patients
referred to a clinic for primary hyperlipidemia, an
increased risk of ED was also observed in patients
treated with brates [300]. Fibrates interact with
PPARs [301], which in the liver stimulates
microsomal esterication of estradiol and testJ Sex Med 2010;7:445475

Gratzke et al.
osterone [302]. That may explain the increased
prevalence of ED reported in patients treated with
brates.
In patients with hyperlipidemia and treated
with statins such as simvastatin and pravastatin and
referred to a clinic for primary hyperlipidemia, an
increased risk for ED was reported [300,303]. It is
controversial whether simvastatin is associated
with ED [304306], and so far, in patients treated
with simvastatin, underlying diseased vasculature
rather than the drug appears to be the cause of ED.
In contrast to simvastatin, positive effects on erectile function was reported for atorvastatin on erectile function [307310]. These reported positive
effects of atorvastatin, in contrast to simvastatin,
on erectile function suggest that the effect of
statins is not a class effect of statins. Moreover, in
an observational prospective study, it was reported
that differences in dose, relative efcacy, or relative
lipophilicity of statin did not show correlation with
changes in IIEF score over a 6-month period
[311]. However, statins are structurally a heterogenous group of compounds and, therefore, other
mechanisms than the lipid-lowering effects may
have signicance for the effect of a statin on erection [246,312,313].

Aldosterone Receptor Antagonists

Treatment with spironolactone and eplerenone
increased survival in systolic chronic heart failure.
In addition to being an aldosterone receptor
antagonist, spironolactone also blocks androgen
receptors (ARs) and that may explain why it is
associated with sexual dysfunction. In contrast,
the newer aldosterone receptor antagonist,
eplerenone, is devoid of effects on sex hormone
receptors.
Psychotropic Medication
Antipsychotics
It is difcult to separate disease from drug effect, as
well as to obtain reliable information from patients
with psychotic illness. There is a paucity of controlled studies. Mainly, older antipsychotic drugs
result in decreased erection and anorgasmia, while
newer antipsychotics appear to have lower incidence of sexual dysfunction. Among newer antipsychotics, risperidone appears to have highest rate
of sexual dysfunction, while there are insufcient
data on aripiprazole and ziprasidone.
Antidepressive and Anxiolytic Drugs
Depression by itself makes it difcult to separate
effect of illness from additive effect of drugs, as

Anatomy, Physiology, and Pathophysiology of Erectile Dysfunction

mood disorders may lead to lack of interest and
emotional withdrawal from the sexual partner.
Antidepressants can have numerous effects on
sexual function including altered sexual desire,
erection difculties, and orgasm problems. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine can negatively affect all the steps of the
male sexual response cycle (desirearousal
excitementorgasm). Bupropion, nefazodone, and
mirtazapine have lower rates of sexual dysfunction
than SSRIs. The evidence has been summarized in
a recent Cochrane review of 15 randomized
studies [314]. The main conclusion regarding
comedication to correct ED was an effect of
sildenal in three of the clinical trials, while the
available evidence was insufcient regarding other
strategies for correction of ED. Anxiolytic agents
such as bupropion, acting mainly by inhibiting
dopamine reuptake, and buspirone, which acts on
5-HT1A receptors, are not associated with sexual
side effects in placebo-controlled trials [315] and
can be used to alleviate sexual symptoms caused by
other antidepressant medication [316]. There are
insufcient randomized data assessing effect of
dose reduction, e.g., drug holidays, on sexual function in patients treated with antidepressants.

Opiates
Long-term intrathecal administration of opiates
results in hypogonadotropic hypogonadism and
associated sexual dysfunction that can be restored
with appropriate supplementation [317]. Administration of opioid antagonists to older men with
ED, however, did not improve erectile function
measured objectively by nocturnal penile tumescence monitoring [318]. Opioids do have a generalized depressant effect on sexual function when
directly administered to the MPOA in rat brain,
but treatment with the opioid receptor antagonist,
naloxone, had no sexual effect on healthy male
volunteers [283].
Anti-Androgens
These drugs cause partial or near-complete blockade of circulating androgens by inhibiting production or antagonism at the AR. Nonsteroidal drugs
such as utamide and bicalutamide have relatively
pure effects on the AR, while the steroidal antiandrogen, cyproterone acetate, also has inhibitory
effects on the hypothalamus. Even at a low dose of
50 mg, bicalutamide therapy resulted in half the
patients in one placebo-controlled study suffering
loss of erectile function [319]. In summary, antiandrogen drugs produce the expected effects of

463

sexual desire and erection commensurate with the

degree of androgen ablation achieved.
Corresponding Author: Christian Stief, MD, PhD,
Department of Urology, University-Hospital Grosshadern, Ludwig-Maximilians-Hospital Munich, 81377
Munich, Germany. Tel: +49 89 7095 2971; Fax: +49 89
7095 8890
Conict of Interest: T.F. Lue, Speakers Bureau for Pzer,
Bayer, AMS, Medtronic and Lilly; J. Angulo, Speakers
Bureau for Pzer; N.N. Kim, Employee Alagin
Research LLC, Research Funding from Pzer, and
Advisory Board for Boehringer-Ingelheim.
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