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- Review -
Insights of priapism mechanism and rationale treatment for recurrent priapism
Jiuhong Yuan, Rowena DeSouza, O. Lenaine Westney, Run Wang
Departments of Urology, University of Texas Health Science Center and MD Anderson Cancer Center, Houston, TX 77030,
Priapism is defined as abnormal prolonged penile erection occurring beyond or unrelated to sexual interest. The
disorder is enigmatic yet devastating because of its elusive etiology, irreversible erectile tissue damage, and resultant
erectile dysfunction (ED). Current management strategies suffer from a poor understanding of the pathophysiology,
especially at the molecular level. The traditional treatments are based more on empirical rather than evidence-based
knowledge. The outcomes for restoration of normal erectile function are poor, especially for stuttering priapism.
Therefore, it is critical to understand priapism from a molecular level, to formulate treatment strategies and to
establish rational prevention strategies for high-risk populations, such as sickle cell disease (SCD) patients and cases of the
stuttering variant. This review focuses on the recent advances at the molecular level in priapism and penile erection,
and applies the recent knowledge to the treatment of stuttering priapism.
(Asian J Androl 2008 Jan; 10: 88_101)
Keywords: priapism; stuttering priapism; molecular mechanism; treatment
Correspondence to: Run Wang, MD, FACS, Departments of Urology, University of Texas Health Science Center and MD Anderson Cancer
Center, 6431 Fannin Street, Suite 6.018, Houston, TX 77030, USA.
Tel: +1-713-500-7337 Fax: +1-713-500-0546
1 Overview of priapism
Priapism is a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation .
Typically, only the corpora cavernosa are affected . In the American Urological Association's Guidelines on the
Management of Priapism, the definition is restricted to erections of greater than 4 hours in duration . Priapism
requires prompt evaluation and might require emergency management .
The term priapism was derived from the Greek god Priapus . Priapus was revered as the god of fertility 
and his giant phallus was a symbol of male power . The ritualistic worship of Priapus was prevalent in Italian
fertility cults of the 18th and 19th centuries. Worshippers attributed magical therapeutic powers to genitals displayed
or worn as an effigy . Priapism has been reported in Pharaonic Egypt and prescriptions for its treatment are found
in Ebers Papyrus . The earliest record of priapism in modern literature was by Petraens in 1616, in an article
entitled "Gonorrhoea, Satyuriasis et Priapisme"  and the first account of priapism appearing in English literature
was by Trife in 1845 . Subsequently, there have been isolated case reports of this mysterious illness and various
unsuccessful attempts at management. In 1914, Hinman  published his seminal article on the pathophysiology of
this unique condition. Frank Hinman Jr., his son, postulated that venous stasis, combined with increased blood
viscosity and ischemia, played an important part in the development of the condition . In 1960, Burt
et al.  reported the first case of the high flow variant of priapism, which developed after traumatic coitus in a young man.
Two decades later, Hauri et al. , using penile arteriography and cavernosography, described the concept of high
arterial inflow and the non-ischemic nature of this type of priapism. Priapism has been associated with genitourinary
infection, urinary retention, failed ejaculation, psychosis,
sickle cell disease (SCD), thallasemia, leukemia,
metabolic disorders, tumors, medication and bites from
insects [2, 11_17]. However, its underlying mechanism
remains obscure. Over the past two decades, advances
in our understanding of the molecular mechanism of
penile erection have enlightened our concept of this
1.3 Epidemiology and etiology
Priapism is a relatively uncommon disorder . It
has an incidence of 1.5 per 100 000 person-years and
can occur in all age groups from newborn to elderly .
Typically, there is a bimodal peak of incidence, between
5 and 10 years in children and 20 to 50 years in adults
. SCD is the most common etiology in childhood,
whereas pharmacological agents are responsible for the
majority of cases in adults . There are a wide
variety of other causes, however, including recreational
drugs, hematological disorders, metabolic disorders,
total parental nutrition, trauma, tumors, neurological
disorders, medication, and bites from insects [12_17].
Besides these established causes, almost half of cases
are idiopathic .
Traditionally, priapism has been classified as
primary/idiopathic and secondary . Hemodynamically,
priapism can be separated into two distinct types: ischemic
(veno-occlusive, low flow) and nonischemic (arterial,
high flow) . Priapism can also present as acute,
intermittent (recurrent/stuttering), or chronic (usually in
the high-flow variant) . The American Urological
Association Guidelines on the Management of Priapism
divides priapism into three categories: nonischemic,
ischemic, and stuttering .
1.4.1 Nonischemic (arterial, high flow) priapism
Nonischemic (arterial, high flow) priapism is a
nonsexual, persistent erection caused by unregulated
cavernous arterial inflow. Cavernous blood gases are
not hypoxic or acidotic. Typically, the penis is neither
fully rigid nor painful. Antecedent perineal trauma is the
most commonly described etiology. Nonischemic priapism does not necessarily mandate emergency
urological treatment. Resolution of nonischemic priapism is
characterized by a return to a completely flaccid penis .
1.4.2 Ischemic (veno-occlusive, low flow) priapism
Ischemic (veno-occlusive, low flow) priapism is a
non-sexual, persistent erection characterized by little or
no cavernous blood flow and abnormal cavernous blood
gases (hypoxic, hypercarbic and acidotic). The corpora
cavernosa are rigid and tender to palpation. Patients
typically report pain. A variety of etiologic factors may
contribute to failure of the detumescense mechanism in this
condition. Ischemic priapism is an emergency.
Resolution of ischemic priapism is characterized by the penis
returning to a flaccid, nonpainful state. However, in many
cases persistent penile edema, ecchymosis and partial
erection can occur and may mimic unresolved priapism.
Resolution of priapism can be verified by measurement
of cavernous blood gases or blood flow measurement
by color duplex ultrasonography .
1.4.3 Stuttering (intermittent)
Stuttering (intermittent) priapism is a recurrent form
of ischemic priapism in which unwanted painful
erections occur repeatedly with intervening periods of
detumescence. This historical term identifies a patient
whose pattern of recurrent ischemic priapism encourages
the clinician to seek options for prevention of future
2 Pathophysiology and molecular mechanism
We will follow the classification of the American
Urological Association Guidelines on the Management of
Priapism to review the mechanisms of the three types of
2.1 Mechanism of nonischemic priapism
Nonischemic priapism has been classified only recently, and is usually traumatic in origin. This form of
priapism displays high blood oxygen levels and lower
intracavernous pressures which are different from
ischemic priapism [9, 10, 20_23]. Initially, the
mechanism of nonischemic priapism was postulated to be
related to disrupted arteriogenic regulation based on the
high blood flow and blood gas values similar to an
arterial overflow for a normal erection. However, with
penile angiography, cavernosography and selective
embolization, investigators determined that trauma
induced-fistula formation between the cavernous artery and lacunar
spaces of the cavernous tissue, which allows blood to
bypass the normal high resistance helicine arteriolar bed,
is the key factor in the development of nonischemic
priapism [24_26]. Even after years of nonischemic priapism,
there can be no detrimental homeostasic changes or
ultrastructural tissue damage . Based on this
mechanism, initial conservative management and, if the
condition persists, highly-selective arterial embolization in
most cases achieve desired results [3, 12]. Erectile
dysfunction (ED) after interventional embolization has been
reported in 11%_20% of cases .
2.2 Mechanism of ischemic priapism
2.2.1 Pathophysiology of ischemic priapism
In modern medicine, Frank Hinman was the first person to demystify priapism and develop a rational
management for the mysterious urologic condition . In
his 1914 seminal article, he classified priapism into two
subtypes: mechanical and nervous . The mechanic
type, associated with 80% of presentations, referred to
mechanical effects disturbing blood flow in the penis and
was etiologically related to "thrombosis of the veins of
the corpora" . Clinical conditions grouped within this
type were pelvic abscess, penile tumorous growths,
perineal, or genital injuries and hematological dyscrasias
. The nervous type, considered to be primary in only
20% of cases, referred to known or suspected neurological disorders that supposedly affected erectile
centers of the nervous system . This category included
infections such as syphilis, brain tumors, epilepsy,
intoxication, and brain and spinal cord injury . Frank
Hinman Jr. postulated that vascular stasis and decreased
venous outflow were the primary circumstances that
physically interfered with detumescence . His
contention stemmed mainly from the invariable finding of
dark, viscous blood in the corpora cavernosa when priapic
penes were incised or aspirated . Additional support
for the venous congestion hypothesis was provided by
clinical examples of priapism, in which mechanical
factors were ostensibly responsible for impeding penile
venous drainage, including occlusive erythrocytes in
patients with SCD, thickened blood in patients on dialysis,
malignant cell infiltration of the corporeal bodies in
patients with leukemia, and vascular disruption in patients
sustaining trauma to the pelvis or penis . Hinman Jr.
reasoned that deoxygenated blood combined with venous
congestion to enhance blood viscosity in all idiopathic
presentations and increased the deformity of erythrocytes
locally in the penis. This notion is supported by the
occurence of edema of the trabecular septa a few days
after priapism onset, and fibrosis of the penile tissue and
finally ED .
Further investigations have verified Hinman Jr.'s
hypothesis. Kim et al.  demonstrated that the penis
in the flaccid state is exposed to a relative hypoxia
(20_40 mmHg), which is randomly interrupted by sudden
increases in oxygen tension (80_100 mmHg) linked to
sex activity and to spontaneous nocturnal erection.
Therefore, each episode of priapism begins in a hyper
oxygenated state . For high flow priapism, the high
oxygenated status can be maintained indefinitely, and the
afflicted penis still has the potential to become erect .
However, with ischemic priapism, hypoxia and the
accumulation of acidic metabolic products develop as soon
as 4 hours after the onset [22, 28] and trabecular
interstitial edema develops at approximately 12 hours. By 24
hours thrombi form in the sinusoidal spaces and smooth
muscle cells undergo necrosis or may be transformed
into fibroblast-like cells [20, 29, 30]. This kind of tissue
damage is not observed in high flow nonischemic
Based on our understanding of the physiological
equilibrium of the penis, we know that smooth muscle tone
is critical to penile tumescence or detumescence.
Functional response to erectile stimuli are determined by the
interplay of diverse neuroeffectors, hormones,
vasoactive substances, signal transduction systems, and
corporeal tissue cellular and molecular factors [31_33]. It
is widely accepted that autonomic nerve controlled
acetycholine/NO/cGMP/PKG, norepinephrine, and
RhoA/Rho-kinase delicately control smooth muscle cell (SMC)
tone (Figure 1) [32_37]. Compared to normal erection,
the turning point for ischemic priapism is the disruption
of the SMC tone control system, which is induced by
obviously cause-effect pharmaceutical agents, inexplicit
SCD, and other hematological dyscrasias, and obscure
causes. We review the mechanism under two categories,
peripheral-acting pharmaceutical-induced ischemic
priapism and non-pharmaceutical-induced ischemic priapism.
2.2.2 Mechanism of peripheral-acting
pharmaceutical-induced ischemic priapism
Priapism resulting from drug usage has a well
documented cause-and-effect relationship [12, 38, 39] with
drugs being the leading cause of priapism in adults .
Kulmala et al.  report that in 21% of cases priapism
was caused by intracavernosal injection of a vasoactive
drug. The incidence of priapism with intracavernosal
injection therapy depends on the particular injected
vasoactive agent and the dose, which indicates different
signal pathway involved and at variant depth. Papaverine,
which inhibits all of PDE2/3/5 (involving both
cGMP/PKG and cAMP/PKA pathways), has been associated
with a 5% risk of priapism at initial diagnostic testing
. Intracavernosal prostaglandin E1 (PGE1) (only
involving cAMP/PKA pathway) has been associated with
a much lower risk of priapism: less than 1% . The
incidence of the priapism can be reduced by dose
reduction . Intraurethrally administered alprostadil 
and oral sidenalfil  have been rarely reported as the
cause of priapism.
Pharmaceutical agents alter the balance of the SMC
control system towards SMC relaxation, which prolongs
erection. When the penis is in a rigid state, inflow and
outflow of blood is halted . Corporal oxygen partial
pressure progressively decreases with the duration of
erection ; therefore, at 4 hours the corporal blood
gas becomes hypoxic . Without oxygen, the
anaerobic mechanism takes over and acidic metabolites
accumulate , glucose substrate decreases, and the
intracavernous blood changes to glucopenic . Therefore, prolonged erections over 4 hours induce
hypoxia, acidosis and glucopenia [21, 44]. A rabbit
ischemic priapism model, established by breathing low
oxygen tension gas (resulting in a mean systemic
oxygen saturation of 60%) and pelvic nerve electrical
stimulation, reveals that ischemia significantly increases
myeloperoxidase activity, lipid peroxidation (both
indicators of tissue injury induced by reactive oxygen
metabolites) , and polymorphonuclear leukocyte
infiltration . In a dog priapism model, induced by
intracavernosal papaverine injections, microscopic
changes observed included sporadic endothelial defects,
loss of plasma membrane integrity and cytoplasmic
condensation . Gene expression studies show that
TGF-β1, which is a mediator of fibrosis, dramatically increases
. In a rat ischemic model, this fibrotic effect was
counteracted by TGF-β1 neutralizing antibodies .
Collectively, all of these studies demonstrate that
prolonged erection triggered by pharmaceutical agents alter
penile homeostasis resulting in hypoxia, acidosis,
glucopenia, and eventual penile tissue injury.
Over the short-term, prolonged erections cause hypoxia, acidosis and glucopenia which reduce SMC
contraction. In rabbit in vitro experiments, Muneer
et al.  demonstrated that hypoxic, acidotic and
glucopenic conditions in the penis, alone or in combination, cause a sustained reduction in SMC tone,
which is linked to reduced adenosine triphosphate (ATP)
or energy production. ATP catabolism produces
adenosine during ischemia/hypoxia . Adenosine is a
bi-directional signal molecule. It may have a positive
function to maintain homeostasis or detrimental repercussions
on the cavernosal cells. Which effect dominates depends
on the adenosine level and the tissue receptor subtype(s)
. Our research clearly shows that elevated
adenosine has a detrimental effect in the adenosine deaminase
knockout (ADA-/-) mouse and can result in priapism via
adenosine A2B receptor .
Hypoxia has a dramatic effect on Endothelin-1 (ET-1)
function in the penis. ET-1, expressed by endothelial
and stromal cells of the human penis , is considered
the most potent stimulator of trabecular SMC
contractility . It is reported in human , rat  and
bovine  penile preparations that the endothelin A (ETA)
receptor subtype mediates the contractile effect of
ET-1. In contrast, endothelin B (ETB) receptor activation
induces a nitric oxide (NO)-dependent decrease in penile
vascular tone [52, 53] and in other vascular beds [54,
55]. However, during hypoxic conditions ET-1 induces
SMC relaxation via a number of counter-regulatory mechanisms in penile tissue, including downregulation
of the RhoA/ROK pathway and upregulation of ETB .
Early hypoxia increases ET-1 , which, via ETA receptors, induces eNOS downregulation which, in turn,
induces NO/cGMP downregulation (Figure 1). Downregulated NO/cGMP decreases RhoA expression in SMC
through the inhibition of RhoA transcription and protein
stability  to reduce SMC contraction. With prolonged
hypoxia (over 24 hours), ETB receptors are activated
 inducing NO formation [52_55] and perpetuating
SMC relaxation . In contrast to arterial relaxation,
ET-1 induces venous contraction via
H2O2, which is increased by ET-1 in veins not in arteries in the rat
thoracic aorta and vena cava model . Increased ET
induces reactive oxygen species (ROS), such as super
oxide and H2O2 . ROS induces tissue injury  and
studies have shown that allopurinol protects rat corporal
tissue against damage . Collectively, hypoxia induces
ET-1 and ETB activation which promotes SMC relaxation in arteries, contraction in veins, and eventually
tissue damage via ROS, all of which disrupt the normal
penile homeostasic mechanism.
A decrease in α-receptor affinity under hypoxic and
acidotic conditions has been reported. Animal studies
have shown that corporal smooth muscle tone,
spontaneous contractile activity, and the contractile response
to α-agonists and field stimulated relaxation depended
on a normal state of corporal oxygenation . The
inability of α-stimulation to induce a tonic contraction
of corporal smooth muscle under anoxia conditions
in vitro parallels the failure of penile injection of
α-adrenergic agonists to relieve ischemic priapism over longer
periods of time . Munarriz et al.  report that
doses of phenylephrine higher than previously reported
are necessary to overcome this decreased affinity in
acidosis associated with ischemic priapism. Under these
conditions, high-dose intracavernosal phenylephrine
administration is safe and effective in the management of
ischemic priapism .
All of the above demonstrate that altered homeostasis
shifts the SMC control balance to relaxation (Figure
2: coarse line shows the dominant signal pathway) [43, 56,
61_65]. This situation is self-perpetuating, leading to
progressive deterioration of the normal mechanism and
the clinical manifestation of pain. This requires
emergent medical intervention to interrupt the cycle of
unchecked SMC tone .
Taken together, we postulate that in this subtype of
ischemic priapism, pharmaceutical agents initially disturb
the balance of the SMC tone, triggering prolonged erections, which induce the disruption of homeostasis
of penile vascular tissue. The latter further deteriorates
the SMC tone control system. They aggravate each other
by amplifying effects, setting the stage for a pernicious cycle.
2.2.3 Mechanism of non-pharmaceutics induced ischemic
Most cases of non-pharmaceutical-induced ischemic
priapism are associated with SCD, other hematological
dyscrasias, or may be idiopathic.
Emerging scientific evidence reveals the importance
of aberrant NO activity in the penis, which alter
molecular determinants of the erectile response . Not only
is NO a main regulatory molecular in penile erection, it is
a critical component in vascular homeostasis [67_69].
Any factor that disturbs vascular homeostasis, such as
hemolysis in SCD or other hematologic dyscrasis, might
induce aberrant NO activity  or reduce penile NO
bioavailability [63, 70]. Tonically deficient endothelial
NO in the penis causes a downregulation of
cGMP-specific protein kinase I (PKG, a downstream effector of
the NO signal transduction pathway) (see Figure 1) .
According to the cGMP-dependent feedback control mechanism, phosphodiesterase type 5 (PDE-5) is also
expressed at low levels (Figure 1) [66, 71, 72].
RhoA/Rho-kinase, a vasoconstrictive pathway that opposes the
NO signal transduction pathway functions (see Figure
1), is dependent on a tonic release of NO in the vascular
SMC . The evidence to support this is: (i) NO/cGMP
kinase positively regulates RhoA expression in SMC
through stimulation of RhoA transcription and protein
stability ; and (ii) rats chronically treated with an
NOS inhibitor showed a 70% decrease in RhoA gene expression in the aorta . Therefore, in the presence
of tonically deficient endothelial NO, RhoA/Rho-kinase
also exhibits downregulated expression and activity via
the feedback control mechanism . Because the entire
SMC tone control system is functioning at a low level, the
response to a normal erection stimulus (nocturnal,
psychogenic, or reflexogenic)  is accentuated,
causing a prolonged erection. The same outcome occurs in
the aforementioned situations: hypoxia, acidosis, glucopenia, especially in SCD and other hematological
dyscrasias, the malformed blood cells in the
deteriorating environment contributes an additional burden to the
pathophysiologic state further disturbing the impaired
2.2.4 Summary of ischemic priapism mechanism
In review, the mechanism of ischemic priapism is a
result of interaction between delicate, integrated smooth
muscle contraction/relaxation balance and erectile tissue
homeostasis. In certain circumstances, such as
vasoactive injection induced priapism, the imbalance of SMC
control initiates and perpetuates deterioration of penile
homeostasis. In other cases, such as SCD-induced
ischemic priapism, the altered homeostasis of penile tissue
impairs the balance of the contraction/relaxation control
system in SMC, which triggers a prolonged erection.
The latter effect further disrupts penile homeostasis. In
both instances, the impaired SMC tone control system
and deteriorating homeostasis stimulate one another. If
the cycle is not broken by intervention, the resulting
disorder causes extreme tissue injury, including denudation
of the endothelium, SMC necrosis or transformation to
fibroblast-like cells [20, 29, 30]. These changes
ultimately cause loss of erectile potency .
2.3 Mechanism of stuttering priapism
Stuttering priapism is a special type of ischemic
priapism . A leading proposal for its molecular
mechanism is similar to the mechanism implicated in
non-pharmaceutical-induced ischemic priapism: tonically deficient
endothelial NO in the penis which causes downregulation
of cGMP-specific protein kinase I, PDE-5 (Figure 1)
[66, 71, 72], and RhoA/Rho-kinase . Under these
conditions, the control of SMC tone is running at a low set
point. In the presence of sex-related or unrelated (nocturnal)
stimulation, SMC will overrespond with a prolonged erection.
With appropriate management, the priapism will subside,
but the low set point of SMC tone remains. Therefore, this
form of priapism occurs repeatedly.
3 Rationale for the treatment of stuttering
The treatment of stuttering priapism requires
differentiating between ischemic and non-ischemic types
(Figure 3) [1, 12]. In non-ischemic priapism,
conservative approaches are the first line therapy; selective
embolization and surgery are for refractory or severe
traumatic cases. In contrast, ischemic priapism
necessitates immediate intervention, such as aspiration,
aspiration with irrigation and α-receptor agonist penile injection,
or surgical shunt procedures for persistent priapism. The
objective is to resolve the erection rapidly to prevent
damage to the erectile tissue. However, the management of
stuttering priapism can be challenging. Below, we present
the various approaches.
3.1 Hormonal manipulation
Hormonal manipulation for stuttering priapism aims
at downregulation of the pituitary gland (GnRh agonists),
suppressing serum testosterone levels by feedback
inhibition (diethylstilbestrol), blocking androgen receptors
(antiandrogens) and reducing adrenal and testicular
androgen production (ketoconazole).
Hormonal manipulation to prevent stuttering priapism
is effective. Research demonstrates that long-term
androgen deficiency with testosterone levels below the
threshold value (10% of the normal physiological plasma
testosterone concentration) will induce ED by: (i)
diminishing mRNA, protein expression and enzymatic
activities of NOS isoforms (eNOS and nNOS) and PDE-5 in
penile tissue; (ii) promoting differentiation of precursor
cells into adipocytes and/or facilitating
trans-differentiation of SMC into adipocytes; and (iii) developing venous
leakage correlated with the loss of SMC . Other
studies reveal that both androgen and its rival estrogen are
directly involved in control of SMC tone. Wingard
et al.  report that cavernosal tissues show increased RhoA
and Rho-kinase protein levels after castration and that
ED induced by this can be reduced by Rho-kinase
inhibition (Figure 1). Chrissobolis et al.  show that
estrogen also suppresses Rho-kinase function in
vivo. Although the data came from the cerebral circulation of
women, it demonstrates estrogens are involved in SMC
tone via regulation of Rho-kinase.
Even with the aforementioned evidence, the role of
androgen in erection is still controversial. In a classic
paper Bancroft et al.  showed that androgen
deficiency does not disturb erections induced by visual sexual
stimulation ; although, androgen deficiency does
diminish nocturnal erections and libido . Unfortunately,
most of the clinical data are from case reports; there is a
lack of data regarding the efficacy and safety of these
agents and none has been investigated using controlled
3.1.1 GnRH analogues
Levine and Guss  report on a patient with SCD
and recurrent priapism who was treated successfully for
more than a year with monthly gonadotropin-releasing
hormone analogue therapy after failure of standard
medical management. Steinberg et al.  report similar
results in a case report in 1995 regarding a 32-year-old
man with recurrent priapism. The patient was initially
placed on intracavernous self-injections with epinephrine.
However, he desired a more convenient form of
treatment with preservation of libido and sexual function and
was placed on 7.5 mg of leuprolide acetate monthly. His
libido remained stable during the 2 months of leuprolide
therapy. Four months after cessation of therapy,
erections continued to be adequate for intercourse without
prolonged erection. This was the first case report of a
non-SCD patient who was successfully treated with GnRH analogues .
Serjeant et al.  conducted a double-blind,
placebo-controlled crossover study in 11 patients in
Kingston, Jamaica with stuttering priapism and
homozygous SCD (SS) and demonstrated that a estrogen,
stilbestrol 5 mg daily, was superior to placebo in preventing
attacks. The paper did not discuss an intention-to-treat
analysis. The quality of this study was not sufficient to
allow firm conclusions about treatment for priapism in
SCD to be made here .
Reported anti-androgen therapy includes bicalutamide
and flutamide chlormadinone acetate. Dahm et
al.  report 3 cases of men with SCD and recurrent priapism
refractory to other medical therapy. The first patient
was started on a dose of 50 mg of bicalutamide daily,
which was later reduced to every other day. He has been
episode-free for 2.5 years. The second patient also failed
other treatments and was placed on 50 mg bicalutamide
daily. Both patients reported no change in libido or
ability to have sexual intercourse. Treatment with oral
antiandrogens resulted in a significant improvement in all
three patients with refractory priapism . Hoffman
et al.  report in one case that a combination of
α-adrenergic agonist and bicalutamide prevented recurrent
priapism with impotence despite good libido. Costabile
 also reported a successful treatment of stuttering
priapism with oral flutamide (125_250 mg t.i.d.).
Yamashita  reports a case of recovery of
detumescence in a 56-year-old Japanese man with stuttering
priapism using antiandrogens. The patient was started on a
low dose of anti-androgen (chlormadinone acetate 50
mg/day) and tried self-injection of an α-adrenergic
sympathomimetic agent when priapism occurred. He next tried
baclofen therapy. Finally, the patient was started on 100
mg of chlormadinone acetate treatment. His total
testosterone decreased to 0.43 ng/mL. Subsequently, the
patient stopped taking the medication after it caused ED.
The erectile function gradually recovered and he had no
additional recurrences of priapism. In this patient, a dose
of the anti-androgen sufficient to lower his testosterone
to the castrate level was effective for both prevention of
priapism and detumescence . At this time, the
duration of androgen deprivation treatement had not been
established but should be determined by clinical course
and patient quality of life.
Anti-androgens, compared to GnRH analogues, are
not associated with a temporary rise in testosterone levels,
which could theoretically increase the risk of priapism.
The side-effect profile is significantly more favorable than
that of stilbestrol, which has been associated with deep
venous thrombosis and pulmonary embolism. The efficacy, durability, and side-effect profile needs further
investigation in a prospective and controlled manner.
Ketoconazole is structurally similar to imidazole, and
interferes with the fungal synthesis of ergosterol, the main
constituent of fungal cell membranes (mammalian cell
membranes contain no ergosterol). It is usually prescribed
for infections such as athlete's foot, ringworm,
candidiasis and jock itch.
As with all azole antifungal agents, ketoconazole
works principally by inhibition of an enzyme, cytochrome
P450 14-alpha-demethylase (P45014DM), which converts lanosterol into ergosterol in the sterol biosynthesis
in adrenal and testicular androgen production. Besides
its antifungal action, one of the side effects of
ketoconazole is reduction in testosterone. This effect is
exhibited in treating metastatic prostate cancer, preventing
post-operative erections following penile surgery, and
treating Cushing's disease. Based on the same
mechanism, it is suggested to treat recurrent priapism. However,
there is no evidence-based publication regarding its
efficacy for this indication. Patients should receive
prednisone daily when receiving ketoconazole because of the
complete blockage of adrenal steroid production.
3.2 Other oral agents
Baclofen is an agonist of gamma aminobutyric acid
(GABA) receptor though its precise mechanism of action is unknown. Baclofen is capable of inhibiting both
monosynaptic and polysynaptic reflexes at the spinal level,
possibly by hyperpolarization of afferent terminals,
although actions at supraspinal sites may also occur and
contribute to its clinical effect. Although baclofen is an
analog of the putative inhibitory neurotransmitter GABA,
there is no conclusive evidence that actions on the GABA
systems are involved in the production of its clinical
effects. Several studies in both rats and men have
inferred that baclofen might inhibit penile erection and
ejaculation. Denys et al.  studied nine men with
spinal cord injury (SCI) or multiple sclerosis who were
receiving intrathecal baclofen therapy for spasticity. Of
the nine patients, eight reported a decrease of erection
rigidity and/or duration subsequent to intrathecal baclofen
therapy with follow-up of 44.4 months. More importantly,
abrupt cessation of intrathecal baclofen can provoke a
withdrawal syndrome during which priapism can occur.
Benefits of baclofen therapy include its cost-effectiveness.
Adverse effects include nausea and drowsiness. There
have been few trials using Baclofen as an oral agent.
Vaidinaythan et al.  report a case of a 46-year-old
male C4 SCI patient who 12 weeks post-injury was
experiencing persistent stuttering priapism with even the
slightest manipulation. This was bothersome and
embarrassing to the patient. The patient was prescribed
baclofen 10 mg t.i.d. Ultimately, the penile erections
occurred less frequently and each episode lasted a shorter
period of time . Likewise, Rourke et
al.  treated a 41-year-old man with nocturnal priapism and noted
complete alleviation of symptoms with an oral dose of
40 mg daily of baclofen. His response lasted at least 12
months post-therapy with preservation of normal sexual
Digoxin is an inhibitor of sodium/potassium
adenosine triphosphatase (sodium pump), a plasma membrane
enzyme that has a role in regulating smooth muscle tone.
Digoxin use is associated with ED. Gupta et
al. demonstrate that in vitro digoxin caused contraction of
corporal smooth muscle by inhibition of sodium pump
activity. Therapeutic concentrations of digoxin inhibit
corporal smooth muscle relaxation induced by
acetylcholine and electrical field stimulation, which releases
nitric oxide from corpus cavernosum endothelial cells
and nonadrenergic noncholinergic nerves, respectively.
They also conducted an in vivo prospective double-blind,
placebo controlled, cross-over investigation in six healthy
male volunteers and demonstrated that digoxin diminished
penile rigidity during visual sexual stimulation and
nocturnal penile tumescence testing compared to the
placebo without influencing libido or serum testosterone,
estrogen or luteinizing hormone levels. The authors
suggest using digoxin for treatment of recurrent priapism
states . Unfortunately, there is no published study
on the use of digoxin in treating stuttering priapism.
Perimenis et al.  managed three men with
refractory idiopathic priapism with oral gabapentin. They
responded to treatment within 48 hours (gabapentin 400
mg q.i.d., third case increased to 2 400 mg daily; after
complete response, continued 300 mg t.i.d.). Two of
the men no longer exhibited stuttering priapism while
being treated with lower doses of gabapentin for 16 and
24 months, respectively. The third, after a successful
treatment for 6 months, stopped gabapentin and his
priapism recurred. He responded to treatment again and
continued to be free of episodes for 9 months while on
treatment. Gabapentin may be a safe alternative for the
management of refractory idiopathic priapism .
Gabapentin is a drug with anticonvulsant, antinociceptive and anxiolytic properties, widely used as an
analgesic and antiepileptic agent, with an unknown
mechanism of action. The rationale for the treatment of
priapism with this medication was based on the reported
sexual dysfunction possibly caused by gabapentin. Some
patients treated with gabapentin for epilepsy complained
of decreased potency and anorgasmia, which improved
when the dosage of gabapentin was tapered or the
medication replaced with other antiepileptic drugs. Studies
of gabapentin's effect on the rat hippocampus and
neocortex have suggested that gabapentin selectively
inhibits Ca2+ influx by inhibiting voltage-operated
Ca2+ channels in a subset of excitatory and inhibitory presynaptic
terminals, thereby attenuating synaptic transmission.
Although the molecular targets of gabapentin remain
unknown, the inhibition of Ca2+ efflux from muscle cells
in the corpora, with a consequent inhibition of smooth
muscle relaxation, may explain the effectiveness of
gabapentin in the management of refractory priapism.
Another study showed that gabapentin treatment in rats
significantly reduced testosterone and follicle
stimulating hormone levels. This might be another mechanisim
of gabapentin in priapism treatment . An interesting
issue is the ability of these men to have normal erections,
although treated with gabapentin. Further studies are
necessary to determine whether gabapentin interferes
with these erections, as occurs in men with stuttering
priapism treated with estrogens or antiandrogens. All of
these treatments, aiming at the feedback inhibition of
testosterone, blocking androgen receptors or downregulation of the pituitary gland, appear to be effective
and most patients are still able to engage in sexual life.
Clearly, the preliminary study involved only three cases,
and it is difficult to affirm that the medication is
reproducibly effective for this condition. To elucidate
gabapentin's clinical efficacy and mechanism of action,
a larger series of patients is needed and, possibly,
histological in vitro studies need to be conducted specifically
of the cavernous tissue.
Terbutaline is an β-adrenergic receptor agonist.
In vitro and in vivo pharmacologic studies demonstrate that
terbutaline exerts a preferential effect on β2-adrenergic
receptors. Ahmed et al.  report on a case of an
11-year-old boy with recurrent and persistent erections for
greater than 6 hours. He was given 3 mg of oral terbutaline while in the hospital and then placed on 1.5
mg of oral terbutaline t.i.d. for 1 week and had no reported
episodes after 6 months . In a placebo-controlled
study of terbutaline and pseudoephederine in
management of PGE1-induced priapism performed by Lowe
et al. , detumescence occurred in 36% of those
patients who received terbutaline, 28% of those who
received pseudoephedrine and 12% of the placebo group
(P < 0.05) . The results of this study suggest that oral
terbutaline can be considered in the initial management of
pharmacologically-induced prolonged erections. It is
contraindicated in patients with diabetes, hypertension and
hyperthyroidism or in patients with a history of seizures.
3.2.5 Hydroxyurea (HU)
HU is a small molecule that blocks the synthesis of
DNA by inhibiting ribonucleotide reductase, thus
arresting cells in the S-phase. It is routinely used for the
management of many neoplastic diseases, in particular
those affecting the blood cells, including chronic
myeloid leukemia and polycythaemia rubra vera; however, it
now has an established role in ameliorating the disease
and improving life expectancy for most SCD patients
. There are side-effects and risks of HU treatment
in SCD; but for moderate and severely affected patients,
the benefits can be significant . Saad ST et
al.  report five cases of SCD patients with stuttering
priapism that benefited from HU treatment . HU was
introduced at the initial dose of 10 mg/kg, and as the HU
dosage increased, the number or length of priapism
episodes decreased. One to two months after the maximal
dose (25_35 mg/kg) was introduced, the episodes disappeared. Of the five cases, four retained normal
sexual activity. The fifth patient, using 20 mg/kg had a
6-year remission of priapism after HU administration,
experienced stuttering priapism 1 month before a major
attack, which progressed to impotence. During that
month, he did not seek medical attention. The data
suggests that HU might prevent stuttering priapism in SCD,
probably at higher doses than usually prescribed for use
in painful crisis prevention . A random controlled
clinical trial is needed to verify its general efficacy for
stuttering priapism in SCD patients.
3.2.6 PDE-5 inhibitors
In physiological erection, autonomic nerve controlled
acetycholine/NO/cGMP/PKG is the main pathway to relax SMC  (Figure 1). PDE-5 is a natural occurring
enzyme within the corpus cavernosum that breaks down
cGMP and, therefore, acts as delicate counter balance to
regulate SMC tone (Figure 1) . The PDE-5 inhibitors,
sildenafil, vardenafil or tadalafil, improve erections
through decreased cGMP breakdown to maintain SMC relaxation and penile erection . Recent basic science
investigation has determined that a mechanism of
priapism involves PDE-5 downregulation in the penis, caused
by altered signaling of the NO/cGMP/PKG pathway .
Accordingly, during normal sexual stimulation or
nocturnal erection, cGMP is generated and exerts an
unchecked action because of relative PDE-5 deficiency, so
the buildup of cGMP causes a prolonged erection. Interestingly, in 2002, Bialecki and Bridges  reported
that 50 mg sildenafil taken as needed relieved acute
priapism and prevented recurrence of priapism in patients
with SCD . Champion et al.  establish priapism
phenotypic mice with eNOS deficiency. The phenotype
is associated with downregulated PDE-5 activity in the
penis (known as a reverse nitrate tolerance mechanism).
Chronic use of sildenafil in this phenotype resulted in
upregulation of the PDE-5 in the penis and, subsequently,
fewer priapistic episodes [71, 72]. Burnett et
al.  administered 25 mg sildenafil daily and switched to 5 mg
tadalafil three times weekly in a series of men with
sickle-cell related recurrent priapism and achieved long-term
priapism relief in most of the cases. More intriguing, all
of the cases were after the management options currently available for recurrent priapism were applied
unsuccessfully . Thus, low dose PDE-5 inhibitor
therapy has become a paradoxical treatment for priapism
(i.e. using a medication that is normally prescribed to
enhance erections). Whether PDE-5 inhibitor therapy
will be useful in treating recurrent priapism in other
conditions awaits additional study.
3.3 Intracavernosal injections
3.3.1 Sympathetic amines
There are various medications that have been
prescribed intracavernosally that exhibit benefit in
preventing stuttering priapism. McDonald and Santucci 
published a case report of the successful treatment of
priapism using intracavernosal injection of metaraminol
in a 38-year-old African-American male with sickle cell
trait and recurrent priapism . The patient injected
once a week using 5_10 mg of metaraminol. The patient
reported complete detumescence within 3_10 min after
injection. Metaraminol is a potent sympathomimetic
amine, a long-acting vasoconstricting amine that is
considered safer than epinephrine . Overdosage is
associated with hypertension, which can result in flash
pulmonary edema, coronary ischemia, cardiac
arrhythmia and death. The drug is not Food and Drug
Administration approved for the treatment of priapism, although
neither are other sympathomimetics in common use .
Ralph et al.  describe a drug delivery implant
that enables self-administered intracavernosal
phenylephrine for recurrent priapism, a long-acting
vasoconstricting amine that is also considered safer than
epinephrine. They report the case of a 28-year-old man
with a 3-year history of painful, nocturnal prolonged
erections. The patient was successfully treated with
the implantation of a drug delivery system to deliver
phenylephrine. Through a lateral penoscrotal incision,
the Brindley drug delivery implant was placed with the
cannula inserted into the lateral aspect of the right
corpus cavernosum and sutured to the tunica albuginea
with a non-absorbable suture. The combined reservoir
was filled with saline and positioned in a dependent
position in the scrotum. After an initial titration period,
50 mg phenylephrine solution (10 mg/mL) diluted with
normal saline to a volume of 8 mL was percutaneously
instilled into the reservoir. The patient was instructed
on how to squeeze the pump so that one squeeze
delivered 0.13-mL phenylephrine solution into the corpus
cavernosum. The patient used the device for 4 months
and was successful in reversing his prolonged painful
3.3.2 Tissue plasminogen activator (TPA)
TPA is a secreted serine protease that converts the
proenzyme plasminogen to plasmin, a fibrinolytic enzyme.
Increased enzymatic activity causes hyperfibrinolysis,
which manifests as excessive bleeding; decreased
activity leads to hypofibrinolysis, which can result in
thrombosis or embolism. Recombinant TPA is used in
diseases that feature blood clots, such as myocardial
infarction and stroke. Hinman  suggests that
"thrombosis of the veins of the corpora" is related to priapism,
and others report success with thombolytic therapy.
Rutchik et al.  discuss the successful use of a single
intracorporeal injection of TPA to treat patients with
recalcitrant priapism. They reported on a 35-year-old
schizophrenic man with a twice daily history of
persistent painful erections. After attempts at detumescence
with corporeal irrigation, phenlylephrine and Al-Ghorab
shunt, 15 mg TPA was injected via the right coporum
cavernosa, and 80% detumescence was observed after
15 min. The use of TPA might be preferable to other
thrombolytic agents because it possesses a half-life of
only 5 min. However, this is definitively an in-house
hospital therapy with a limited application for
self-administration secondary to the risk of uncontrolled
Another self-injection therapy that has been reported
is intracavernosal etilefrine. Etilefrine is a
sympathomimetic α1-selective agonist with a potent vasoconstrictor
effect, usually used in the management of postural
hypotension and post-esophagectomy chylothorax and
chyloperitoneum. It has minimal cardiovascular effect
when used as an intracavernous injection. Teloken
et al. reported on a case of a 27-year-old man who
presented with a 1-year history of prolonged painful erections.
The patient failed oral terbutaline therapy. Therefore,
emergent drainage and irrigation with etilefrine 5 mg
diluted in 500 mL of plain saline were applied.
Intracavernosal self injection of 5 mg etilefrine was proposed. The
patient was instructed to inject 1 hour after a
spontaneous erection and to repeat the injection every 15 min
until detumescence was achieved. He has not had
recurrent priapism since this treatment was established and
he has been sexually active without ED. Self injection
protocols are well suited to allow for expeditious
management of the acute priapism episodes. However,
concerns persist regarding the long-term effect on
hypertension, ED and scarring at the site of the injection.
3.3.4 Methylene blue (MB)
MB is a guanylate cyclase inhibitor. It is widely
recognized that NO released by nonadrenergic/noncholinergic (NANC) neurotransmission and from the
endothelium is the principal neurotransmitter mediating
penile erection. NO diffuses into smooth muscle cells,
where it activates soluble guanylyl cyclase, producing
cGMP, which in turn cause the activation of cGMP-specific protein kinase, resulting in the phosphorylation
and inactivation of myosin light-chain kinase, thereby
causing dissociation of myosin and actin and smooth
muscle relaxation (Figure 1) . Intracavernosal
injection MB paralyzes the guanylate cyclase enzyme;
therefore, the amount of cGMP is diminished, blocking
the effect of NO on the SMC. The efficacy of MB intracavernosal injection has been demonstrated in rats
, rabbits  and humans (100 mg) [103_105]
and has been claimed to combat all forms of priapism
; however, there is no evidence-based publication
regarding its use in stuttering priapism.
3.4 Surgical management: penile prosthesis
At the Institute of Urology in London, 8 patients
presented with acute low flow priapism of variable
etiologies . All patients were refractory to conservative
management. The patients were assessed by penile
Doppler ultrasonography and blood gas analysis, which
confirmed low-flow priapism with ischemic features. All
patients underwent placement of a penile prosthesis. At
a mean follow-up of 17 months, seven of the eight
patients were successfully engaging in sexual intercourse.
Detumescence and preservation of potency are important measures of outcome in the treatment of priapism
. Previous studies show that both these criteria are
only met in fewer than half of patients. Kulmala and
Tamella  show that within 24 hours, most cases
respond to aspiration and α-adrenergic drugs with no
consequent corporeal fibrosis; however, beyond this time,
patients usually do not respond to medication and
develop varying degrees of intracavernosal fibrosis .
Sundaram et al.  presented a 40-year-old patient
with refractory priapism. Options for the treatment of
refractory priapism that were considered included caverno-spongiosal shunt, caverno-saphenous shunt and
the placement of a penile prostheses. The patient
selected placement of the penile prosthesis. In the event
that a patient's priapism is refractory to all other forms
of treatment, a penile prosthesis is a viable option. It
offers the benefit of management of future erectile
dysfunction and avoids the possible complications of shunt
procedures (urethral fistulae or purulent cavernositis
following the Quackels shunt  and pulmonary
embolism following the Grayhack procedure ). The
immediate insertion of a penile prosthesis offers a solution
for both painful priapism and the ensuing ED .
The mechanism of nonischemic priapism is documented, along with its treatment; whereas the
mechanism of ischemic priapism is still somewhat unclear. The beginning of ischemic priapism as a
nonischemic state, just like nonischemic priapism and
normal erection are clear. Peripheral-acting
pharmaceuticals break the delicate SMC contraction/relaxation
balance to prolonge erections, with time it induces hypoxia,
acidosis, and glucopenia. In non-pharmaceutical-induced
ischemic priapism, whether the disruption of delicate SMC
contraction/relaxation balance induces hypoxia, acidosis,
and glucopenia is the first step is unclear. In some
patients, hematological abnormalities may be the inciting
event that disturbs penile vascular homeostasis,
impairing the delicate balance of the smooth muscle tone
control system and altering SMC signaling. Regardless of
the initiating event, prolonged erection induces hypoxia,
acidosis, glycopenia, which induce ATP catabolism into
adenosine, and increase ET1, ETB receptor, decrease
α-receptor affinity; all of these promote SMC relaxation
and enhance prolonged erections (Figure 2). The cycle
is self-perpetuating with long-term deleterious effects on
the penile smooth muscle. Strategies need to focus on
prevention and maintenance of normal smooth muscle
tone. Treatment modalities must break the pernicious
cycle and allow the normal mechanisms to regain
balance of smooth muscle tone as rapidly as possible.
Although these different medications for prevention
of stuttering priapism have been used in various forms
over the years, there is no proven superior choice.
However, these medications and their specific action
should be kept in the armentarium of every urologist when
confronted with the challenge of treating men with
stuttering and recurrent priapism. For practical use, we have
designed a basic algorithm that demonstrates the various
options for treating stuttering priapism (Figure 3) and
summarized all of the treatments in Table 1. There is a
need for well-designed, adequately powered,
multi-institutional randomized trials to evaluate the efficacy of
specific interventions for stuttering priapism. Advances in
basic research on priapism will hopefully allow us to
manage the dilemma of the enigmatic priapism.
The authors would like to thank Dorothy Stradinger
for her editorial assistance.
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