PHYSIOLOGY OF PENILE ERECTION
AND PATHOPHYSIOLOGY OF
ERECTILE DYSFUNCTION
Campbell’s Chapter 21
Roc McCarthy, DO
Physiology of Penile Erection
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Historical Aspects
First description of erectile dysfunction dates from about 2000 BC
types: natural - the man is incapable of accomplishing sex
supernatural - evil charms and spells
- Two
Aristotle- three nerves carry spirit and energy to the penis, erection is
produced by influx of air
Leonardo da Vinci (1504) noted a large amount of blood in the erect penis
of hanged men and cast doubt on the concept of the air-filled penis
Many theories have since been added to explain the hemodynamic events
during erection and detumescence.
-In the
19th century, venous occlusion was thought to be the
main factor in
achieving and maintaining erections
Much of the current understanding of erectile physiology wasn’t gained until
the 1980s and 1990s
Functional Anatomy of the Penis
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3 cylindrical structures
- paired corpora cavernosa
corpus spongiosum (which houses the urethra),
covered by
a loose subcutaneous layer and skin.
Flaccid length is controlled by the contractile state of the
erectile smooth muscle (varies considerably)
- depending on emotion and outside temperature
Neither age nor the size of the flaccid penis accurately
predicts erectile length
Tunica Albuginea
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Tunica affords great flexibility, rigidity, and tissue strength to
the penis
Tunica covering of the corpora cavernosa- bilayered
structure with multiple sublayers.
- Inner-layer bundles support and contain the
cavernous tissue and are oriented circularly.
Radiating from this inner layer are intracavernous
pillars
that act as struts, provide support
Outer-layer bundles are oriented longitudinally
Corpus spongiosum lacks the outer layer and intracorporeal
struts
Tunica Albuginea
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Emissary veins run between the inner and outer layers for a
short distance, often piercing the outer bundles obliquely
Variability in tunical thickness and strength
6-7 o'clock positions, thickness is 0.8 ± 0.1 mm
-9
o'clock position, 1.2 ± 0.2 mm
-11
o'clock position, 2.2 ± 0.4 mm
The most vulnerable area is located on the ventral groove
(between the 5 and 7 o'clock positions), where the
longitudinal outer layer is absent; most prostheses tend to
extrude here
External Penile Support
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2 ligamentous structures:
1. fundiform ligament arises from Colles'
fascia and is lateral, superficial, and not
adherent
to the tunica albuginea of the
corpora
2. suspensory
ligament arises from Buck's
fascia and consists of
two lateral bundles and one median bundle, which
circumscribe the dorsal vein of the penis. Its main
function is to attach the tunica albuginea of the
corpora cavernosa to the pubis
Corpora Cavernosa, Corpus
Spongiosum, and Glans Penis
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Septum between the two corpora cavernosa is
incomplete
Flaccid state, the blood slowly diffuses from the
central to the peripheral sinusoids and the blood
gas levels are similar to those of venous blood.
Erect, the rapid entry of arterial blood to both the
central and the peripheral sinusoids changes the
intracavernous blood gas levels to those of arterial
blood
Arteries
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Penile blood supply- the internal pudendal artery (off
internal iliac artery) → common penile artery
3 branches- dorsal, bulbourethral, and cavernous
Dorsal artery is responsible for engorgement of the
glans during erection
Veins
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Venous drainage from the three corpora originates in
tiny venules leading (from sinusoids) exiting as the
emissary veins
Hemodynamics and Mechanism of
Erection and Detumescence
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Corpora Cavernosa
In the flaccid state, these smooth muscles are tonically contracted, allowing
only a small amount of arterial flow for nutritional purposes
Phases of erection:
(1) dilation of the arterioles and arteries by increased blood flow
(2) trapping of the incoming blood by the expanding sinusoids (3)
compression of the subtunical venous plexuses, reducing
venous
outflow
(4) stretching of
the tunica to its capacity, which occludes the
emissary veins
(decreases venous outflow to a minimum) (5) PO2 increases- 90 mm Hg
(6) Intracavernous pressure
increases
to 100 mm Hg
(7) Penis raises to erect state
Blood flow and intracavernous pressure changes during the seven
phases of penile erection and detumescence
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0, flaccid; 1, latent; 2, tumescence; 3, full erection; 4, rigid erection; 5, initial detumescence; 6, slow
detumescence; 7, fast detumescence.
Corpus Spongiosum and Glans Penis
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During erection, the arterial flow increases in a
similar manner
- however, the pressure in the corpus
spongiosum and glans is only one third to
one half that in the corpora cavernosa
- No
outer longitudinal tunic layer (no
venous
occlusion)
Neuroanatomy and Neurophysiology of
Penile Erection
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Peripheral Pathways
Innervation of the penis is both autonomic (sympathetic
and parasympathetic) and somatic (sensory and motor)
Sympathetic and parasympathetic nerves merge to form
the cavernous nerves
- effect the
neurovascular events during
erection and
detumescence
Somatic nerves- 1° responsible for
sensation and
the contraction of the bulbo/ischio-cavernosus muscles
Autonomic Pathways
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Sympathetic pathway originates from the 11th
thoracic to the 2nd lumbar spinal segments
Parasympathetic pathway arises from S2-S4
Cavernous nerves are branches of the pelvic plexus
that innervate the penis
cavernous nerves are easily damaged during
radical excision of the rectum, bladder, and
prostate
Autonomic Pathways
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Stimulation of the PNS cavernous nerves induces
erection, whereas stimulation of the sympathetic trunk
causes detumescence
Sacral spinal cord injury retain psychogenic erectile
ability even though reflexogenic erection is abolished
No psychogenic erection occurs in patients with lesions
above T9
Somatic Pathways
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The somatosensory pathway originates at the sensory receptors in
the penile skin, glans, and urethra and within the corpus cavernosum
The free nerve endings are derived from thin myelinated Aδ and
unmyelinated C fibers
Nerve fibers from the receptors converge to form bundles of the
dorsal nerve of the penis, which joins other nerves to become the
pudendal nerve
Onuf's nucleus in the second to fourth sacral spinal segments is the
center of somatomotor penile innervation
Contraction of the ischiocavernosus muscles produces the rigiderection phase. Rhythmic contraction of the bulbocavernosus muscle is
necessary for ejaculation
Neurotransmitters
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α-Adrenergic nerve fibers and receptors
norepinephrine has generally been accepted as the
principal neurotransmitter to control penile flaccidity
and detumescence
Endothelin, a potent vasoconstrictor produced by the
endothelial cells, has also been suggested to be a
mediator for detumescence
Flaccidity and Detumescence
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Intracorporeal smooth muscle in a semicontracted (flaccid)
state results from three factors:
1) Intrinsic
myogenic activity
2) Adrenergic
neurotransmission
3) Endotheliumderived contracting factors such as
angiotensin II,
PGF2α, and endothelins
Detumescence after erection may be a result of cessation of
NO release, the breakdown of cyclic guanosine
monophosphate (cGMP) by phosphodiesterases, or sympathetic
discharge during ejaculation
Erection
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NO released from nonadrenergic, noncholinergic
neurotransmission and from the endothelium is the
principal neurotransmitter mediating penile erection
NO increases the production of cGMP, which in turn
relaxes the cavernous smooth muscle
VIP
Central Neurotransmitters and
Neural Hormones
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A variety of neurotransmitters (dopamine, norepinephrine, 5hydroxytestosterone [5-HT], and oxytocin) and neural hormones (oxytocin,
prolactin) have been implicated in regulation of sexual function.
Dopamine- Apomorphine, which stimulates both D1 and D2 receptors,
induces erection that is unaccompanied by sexual arousal
Serotonin- 5-HT pathways inhibit copulation but that 5-HT may have both
facilitory and inhibitory effects on sexual function
Norepinephrine- Central norepinephrine transmission seems to have a
positive effect on sexual function
γ-Aminobutyric acid (GABA), Opioids, Oxytocin, Nitric Oxide,
Melanocortins, Prolactin
Molecular Mechanism of Smooth
Muscle Contraction
Molecular Mechanism of Smooth
Muscle Relaxation
KEY POINTS: SMOOTH MUSCLE
RELAXATION CAUSES ERECTION
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Relaxation of the cavernous smooth muscle is the key to penile
erection.
Nitric oxide release initiates the erection process, and helps
maintain erection.
Upon entering the smooth muscle cells, NO stimulates the
production of cGMP.
Cyclic GMP activates protein kinase G, which in turn opens
potassium channels and closes calcium channels.
Low cytosolic calcium favors smooth muscle relaxation.
The smooth muscle regains its tone when cGMP is degraded by
phosphodiesterase
PATHOPHYSIOLOGY OF ERECTILE
DYSFUNCTION
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Incidence and Epidemiology
Diokno and associates reported that 35% of married men aged 60 years
and older suffer from erectile impotence
MMAS study, between the ages of 40 and 70 years, the probability of
complete ED increased from 5.1% to 15%, moderate dysfunction
increased from 17% to 34%, and mild dysfunction remained constant
at about 17%.
Worldwide prevalence of ED, 24 international studies were reported
between 1993 and 2003
- Before age 40 the rate was 1% to 9%
- From 40 to 59 it ranged from 2% to 9% to as high as 20% to
30%
Risk Factors for ED
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General health status
Diabetes mellitus
Cardiovascular disease
Concurrence of other GU diseases
Psychiatric or psychological disorders
Chronic diseases
Smoking
Medications
Hormonal factors also serve as well-defined risk factorassociated conditions
Classification of Male Erectile
Dysfunction
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Organic I. Vasculogenic, Arteriogenic, Cavernosal, Mixed
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II. Neurogenic
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III. Anatomic
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IV. Endocrinologic
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Psychogenic
I. Generalized
A. Generalized unresponsiveness
1. Primary lack of sexual arousability
related decline in sexual arousability
Generalized inhibition
1. Chronic disorder of sexual intimacy
II. Situational
A. Partner-related
1. Lack of arousability in specific relationship
2. Lack of arousability owing to sexual object preference
3. High central inhibition owing to partner conflict or threat
B. Performance-related
Associated with other sexual dysfunction/s (e.g., rapid ejaculation)
Situational performance anxiety (e.g., fear of failure)
Psychological distress- or adjustment-related
negative mood state (e.g., depression)
2. AgingB.
1.
2.
C.
1. Associated with
Psychogenic
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Previously, psychogenic impotence was believed to be most common,
thought to affect 90% of impotent men
Two possible mechanisms have been proposed to explain the
inhibition of erection in psychogenic dysfunction:
1) direct inhibition of the spinal erection center by the
brain as an exaggeration of the normal suprasacral
inhibition
2) excessive
sympathetic outflow or
elevated
peripheral catecholamine
levels
Neurogenic
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10% to 19% of ED is neurogenic
MPOA, the PVN, and the hippocampus are important integration centers for sexual
drive and erection, and pathologic processes in these regions, such as Parkinson's
disease, stroke, encephalitis, or temporal lobe epilepsy, are often associated with
ED.
In men with a spinal cord injury, its nature, location, and extent largely determine
erectile function
Reflexogenic erection is preserved in 95% of patients with complete upper cord
lesions
Introduction of nerve-sparing radical prostatectomy has reduced the incidence of
impotence from nearly 100% to 30% to 50%
- Recovery of
erectile function after radical pelvic surgery can take 6 to 24 months. Early
treatment with intracavernous alprostadil or oral
sildenafil has been shown
to improve recovery
Endocrinologic
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Hypogonadism is a not-infrequent finding in the impotent population
Mulligan and Schmitt (1993) concluded that testosterone
(1)
enhances sexual interest
(2)
increases the frequency of sexual acts
(3) increases
the frequency of nocturnal erections but has
little or no effect on
fantasy-induced or visually
stimulated erections
Treatment with flutamide, estradiol, or a gonadotropin-releasing hormone
antagonist in addition to castration further depresses the erectile response
Hyperprolactinemia, whether from a pituitary adenoma or drugs, results in
both reproductive and sexual dysfunction
Arteriogenic
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Atherosclerotic or traumatic arterial occlusive disease of the hypogastriccavernous-helicine arterial tree can decrease the perfusion pressure and
arterial flow to the sinusoidal spaces, thus increasing the time to maximal
erection and decreasing the rigidity of the erect penis
Common risk factors associated with arterial insufficiency include
hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, blunt
perineal or pelvic trauma, and pelvic irradiation
Focal stenosis of the common penile or cavernous artery is most often seen
in young patients who have sustained blunt pelvic or perineal trauma
Long-distance cycling is also a risk factor for vasculogenic and neurogenic
ED
Hypertension
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Hypertension is an independent risk factor for ED
Cardiovascular complications such as ischemic heart disease and renal failure are
associated with even higher ED prevalence
Mechanism of Vascular Erectile
Dysfunction
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Increased peripheral vascular resistance
Enhanced basal and myogenic tone has been
observed in arteries
Cavernous (Venogenic)
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Failure of adequate venous occlusion has been proposed as one of the most
common causes of vasculogenic impotence
Veno-occlusive dysfunction may result from a variety of pathophysiologic
processes: degenerative tunical changes, fibroelastic structural alterations,
insufficient trabecular smooth muscle relaxation, and venous shunts.
Degenerative changes (Peyronie's disease, old age, and diabetes) or traumatic
injury to the tunica albuginea (penile fracture) can impair the compression of the
subtunical and emissary veins
Structural alterations in the fibroelastic components of the trabeculae, cavernous
smooth muscle, and endothelium may result in venous leakage
Loss of compliance of the penile sinusoids associated with increased deposition
of collagen and decreased elastic fiber may be seen in diabetes,
hypercholesterolemia, vascular disease, penile injury, or old age
Antihypertensive Agents
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Diuretics- Thiazides showed a significant increase in ED when compared with
placebo
- Treatment of Mild Hypertension Study (TOMHS), in which the prevalence of
ED at 2 years in men taking low-dose thiazide was twice that of those taking
placebo or alternative agents (Grimm et al, 1997). (After 4 years of treatment, the
prevalence of ED in the placebo group approached that of the thiazide
group……may be that thiazide therapy, rather than causing ED directly, unmasks it
at an earlier stage
β-Adrenergic Blockers- 10% of adrenoceptors in the penile tissue are of the β
type, and their stimulation is thought to mediate relaxation
-β
antagonists also exert an inhibitory effect within the CNS, perhaps leading to
lowered sex hormone levels
- nonselective
drugs such as propranolol were associated with a
higher prevalence of ED
than placebo or ACE inhibitor.
- Newer agents with higher
selectivity for the β1 adrenoceptor, such
as acebutolol, have shown a
substantial reduction in ED
Antihypertensive Agents
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α-Adrenoceptor Blockers- positive effect on erection for α antagonists, particularly
those acting on the α1 receptor
- drugs such as
doxazosin were not associated with complaints of ED
Angiotensin-Converting Enzyme Inhibitors- Lack any easily appreciated
peripheral or central effect that would interfere with sexual function
- ACE inhibitor captopril did not cause any significant adverse effect on
sexual function
Angiotensin II receptor antagonists, have a beneficial effect on existing sexual
dysfunction at baseline
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Calcium Channel Blockers- no adverse effect on erection
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Antipsychotics- varies
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Antidepressants- neg
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Selective serotonin reuptake inhibitors (SSRIs)- SSRIs differ in their ability to cause ED.
A high incidence has been observed in patients treated with paroxetine (Kennedy et
al, 2000), and a lesser impact has been reported with citalopram
Antiandrogens
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These drugs cause partial or near-complete blockade of androgen's action
by inhibiting production of or antagonizing the androgen receptor (AR)
The effects of androgen deficiency on sexual activity are variable, ranging
from complete loss to normal function
the 5α-reductase inhibitor finasteride (5 mg daily) for prostatic symptoms,
approximately 5% complained of decreased desire and ED compared with
1% in the placebo group (Gormley et al, 1992). At the lower dose used to
treat male-pattern alopecia (1 mg daily), no sexual dysfunction was seen
Nonsteroidal antiandrogens when combined with an LHRH agonist, reduce
sexual desire occurs in up to 70% patients
Miscellaneous Drugs
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Digoxin
Statins?
Histamine H2 Receptor Antagonists
Opiates
Retroviral and Chemotherapeutic Agents
Tobacco and Alcohol
Diabetes Mellitus
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Common chronic disease, affecting 0.5% to 2% worldwide
Prevalence of ED is three times higher in diabetic men (28%
versus 9.6%)
In 12% of diabetic men, deterioration of sexual function can
be the first symptom
Chronic Renal Failure
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Sexual dysfunction has been reported in 20% to
50% of men with chronic renal failure
45% prevalence of self-reported severe ED among
men receiving hemodialysis
Uremia decreases NO bioavailability
Primary Erectile Dysfunction
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Primary ED refers to a lifelong inability to initiate or maintain
erections, or both, beginning with the first sexual encounter
Physical cause resulting from mal-development of the penis or
the blood and nerve supply
Micropenis- self explanatory
The End