Ketoconazole and Prednisone to Prevent Recurrent

Ischemic Priapism

Michael R. Abern and Laurence A. Levine*,†

From Rush University Medical Center, Chicago, Illinois

Purpose: To our knowledge no standard therapy exists for the prevention of Abbreviations
recurrent ischemic priapism. We used ketoconazole and prednisone with dosing and Acronyms
titrated according to serum testosterone levels to suppress sleep related erections bid ⫽ twice daily
in an attempt to prevent recurrent episodes.
ED ⫽ erectile dysfunction
Materials and Methods: Eight patients with recurrent ischemic priapism were
treated with ketoconazole and prednisone. Two patients had sickle cell anemia IIEF ⫽ International Index of
Erectile Function
and 6 had idiopathic recurrent ischemic priapism. Testosterone was measured on
initial presentation, and ketoconazole and prednisone dosing was titrated to KP ⫽ ketoconazole and
approximately 200 ng/dl testosterone and based on the presence or absence of prednisone
recurrent ischemic priapism epiosodes. The International Index of Erectile Func- NOS ⫽ nitric oxide synthase
tion-5 questionnaire was administered to evaluate for erectile dysfunction. Pa- PDE5 ⫽ phosphodiesterase type 5
tients were seen monthly and therapy was withdrawn after 6 months. REM ⫽ rapid eye movement
Results: Mean testosterone before and after treatment was 468 and 275 ng/dl, RIP ⫽ recurrent ischemic priapism
respectively. Mean followup was approximately 1.5 years. One patient had 2
SCA ⫽ sickle cell anemia
recurrent ischemic priapism episodes while on ketoconazole and prednisone
treatment. Another patient experienced an increase in testosterone from 361 to SRE ⫽ sleep related erections
432 ng/dl after initiation of therapy, and 3 recurrent ischemic priapism episodes T ⫽ testosterone
requiring emergency corporal irrigation. After dose titration testosterone was 184 tid ⫽ 3 times daily
ng/dl and the patient has had no subsequent episodes. Mean International Index
of Erectile Function-5 score was 24.8 points. There were no recurrent ischemic Submitted for publication January 30, 2009.
priapism episodes after withdrawal of ketoconazole and prednisone, and no * Correspondence: Rush University Medical
reported symptoms of hypogonadism. Center, 1725 W. Harrison St., Chicago, Illinois
60612 (telephone: 312-563-5000; FAX: 312-563-
Conclusions: Ketoconazole and prednisone therapy was well tolerated in these 8 5007; e-mail: drlevine@hotmail.com).
patients with recurrent ischemic priapism, and with testosterone monitoring and † Financial interest and/or other relationship
dose titration it was successful in preventing recurrent episodes while preserving with Pfizer, Coloplast Corp., FastSize Medical,
Lilly and Auxilium.
sexual function.

Key Words: priapism, penile erection, ketoconazole

RECURRENT ischemic priapism or stut- ischemic priapic episodes. In addition,

tering priapism is defined as recurrent
episodes of prolonged painful penile
erections devoid of sexual stimulation
or desire often resulting in progressive
corporal fibrosis and sexual dysfunc-
tion. RIP episodes are characteristi-
cally associated with painful and com-
pletely rigid corpora cavernosa which
distinguish them clinically from non-
RIP episodes are associated with aci-
dotic and hypoxemic cavernous blood
as measured by a pH and pO2 less than
the normal values found in mixed ve-
nous blood of 7.35 and 40 mm Hg, re-
spectively. Duplex ultrasonography
of the penile arteries will reveal no
flow or decreased velocity of flow
during a RIP episode as opposed to

0022-5347/09/1824-1401/0 Vol. 182, 1401-1406, October 2009

THE JOURNAL OF UROLOGY® Printed in U.S.A.
www.jurology.com 1401
Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2009.06.040
1402 KETOCONAZOLE AND PREDNISONE TO PREVENT RECURRENT ISCHEMIC PRIAPISM
increased velocity and flow in the nonischemic
priapic penis.
The exact mechanism of RIP, a relatively rare
condition, is unknown. However, there are many
pathophysiological hypotheses including medication
related blockade of vascular tone, red blood cell
sludging and dysregulation of NOS and PDE5.1 Glu-
cose 6-phosphate dehydrogenase deficiency has re-
cently been implicated as a contributing factor to
RIP via hemolytic anemia and resultant oxidative
stress in the penis.2 Many preventive systemic ther-
apies have been described including oral baclofen,
digoxin, terbutaline, sympathomimetics and more
recently PDE5 inhibitors. However, the clinical
course of this disorder for many patients includes mul-
tiple emergency department visits and surgical shunt
procedures, and may necessitate penile prosthesis
implantation for irreversible corporal fibrosis and
resultant ED.
An alternative hypothesis entails a relationship
between SRE and priapic episodes. Nocturnal erec-
tions occur during REM sleep and are devoid of
tactile or visual erotic stimuli. Multiple animal mod-
els have been used to demonstrate the androgen
dependence of SRE. In a ferret model the medial
preoptic area of the forebrain has been proven to
contain androgen sensitive neurons which control
the release of gonadotropin-releasing hormone and
regulate copulatory behavior.3 Interestingly in the
rat forebrain lesions of the lateral preoptic area have
been shown to disrupt REM sleep architecture and
SRE without effect on awake state erections.4 Per-
haps dysregulation of this central mechanism has a
role in RIP. Peripherally SRE are theorized to be
triggered by androgen dependent release of nitric
oxide by cavernous nerves.5
Human studies have also supported the andro-
gen dependence of SRE. Increases in T have a
temporal relationship with REM sleep episodes as
evidenced by studying men with disrupted sleep
patterns.6 Furthermore, study has demonstrated
a mean threshold serum T of 200 ng/dl below
which nocturnal erections do not occur.7 Con-
versely T supplementation has been shown to in-
crease frequency, duration and magnitude of SRE
Table 1. Patient characteristics
Pt No. Etiology Duration of Episodes (yrs) Prior Episodes
1 SCA 5 Multiple
2 Idiopathic 1 2
3 SCA 1 3
4 Idiopathic 3 30
5 Idiopathic 2 2
6 Idiopathic 1 20
7 Idiopathic 0.5 5 None
8 Idiopathic 1 4
in hypogonadal men.8 In addition, there is a well
described syndrome of painful nocturnal erections
which may be due to transient corporal ischemia
much like RIP.9,10
Antiandrogen therapies such as luteinizing hor-
mone-releasing hormone agonists, estrogens, andro-
gen receptor blockers and 5␣-reductase inhibitors
have been used to prevent RIP episodes with mixed
success.11–14 Concerns with these agents include po-
tential sexual side effects, inhibition of bone devel-
opment and gynecomastia in a relatively young pa-
tient population. An ideal antiandrogen therapy
would suppress nocturnal erections but not pro-
duce castrate T levels, thereby permitting sexu-
ally stimulated erections and fewer hypogonadal
symptoms.
Ketoconazole is an inhibitor of androgen synthe-
sis in the testicle and adrenal gland, and has been
used extensively as a secondary hormonal agent for
prostate cancer. The primary mechanism of action
in humans is inhibition of 17,20 lyase in the adrenal
cortex. However, it has also been shown to inhibit
the conversion of lanosterol to cholesterol in the
adrenal endoplasmic reticulum, and to inhibit lu-
teinizing hormone stimulated and basal T synthesis
in testicular Leydig cells.15 It has a rapid onset of 2
hours and a peak serum concentration of 4 to 8
hours. Serum T has been shown to return to baseline
in approximately 24 hours after withdrawal of treat-
ment.16 The adrenolytic effect of ketoconazole prompts
the use of glucocorticoids such as prednisone in many
protocols to avoid adrenal insufficiency. We titrated
KP to reduce serum T to a lower but not castrate range
to prevent SRE and RIP episodes but preserve sexual
function in a group of 8 patients.
MATERIALS AND METHODS
Eight patients with RIP were treated with KP during a
4-year period in this prospective noncontrolled study
(table 1). The patients ranged in age from 21 to 49 years.
Two patients had SCA and 6 had idiopathic RIP. Priapism
episodes were defined as painful penile erections greater
than 4 hours in duration causing the patient to seek
emergency treatment or in some cases to use self-treat-
ment strategies including oral and injectable medications.
Failed/Discontinued Preventive Treatment Initial T (ng/dl)
None 669
None 354
None 327
Pseudoephedrine, terbutaline
Bicalutamide 425
Pseudoephedrine, terbutaline 361
859
None 280
 KETOCONAZOLE AND PREDNISONE TO PREVENT RECURRENT ISCHEMIC PRIAPISM
Most patients were referred to our center with RIP for
preventive management. They had RIP episodes for 0.5 to
5 years before treatment. A complete laboratory evalua-
tion was performed including corporal venous blood gas
when possible, complete blood count, coagulation profile,
hepatic function panel and hemoglobin electrophoresis
when indicated. Total T (Immunoassay, Quest Diagnos-
tics, Wood Dale, Illinois) was measured on initial presen-
tation, and therapy with 200 mg ketoconazole orally twice
daily and 5 mg prednisone orally 4 times daily was initi-
ated. Each patient was counseled regarding the risks and
potential benefits of the off-label use of the medication
regimen.
The patients were seen monthly for 6 months. On the
second visit T was rechecked and KP dosing was titrated
as needed to T of approximately 200 ng/dl or to a level
resulting in suppression of RIP episodes, whichever re-
sulted in a higher total T. At each followup visit patients
were physically examined for testicular size, penile fibro-
sis and gynecomastia, and they were interviewed for signs
and symptoms of hypogonadism as well as priapic epi-
sodes treated elsewhere. The IIEF-5 questionnaire was
administered after ketoconazole dose titration for patients
on therapy or after therapy was completed to evaluate for
ED. After 6 months therapy was empirically withdrawn
and patients were followed as needed for recurrent priapic
episodes.
RESULTS
Pertinent results are displayed in table 2. All pa-
tients had RIP as evidenced by corporal blood gas
and physical examination parameters. Of our 8 pa-
tients 3 had evidence of mild penile fibrosis on initial
physical examination. Mean followup was approxi-
mately 1.5 years (range 0.25 to 3). All patients tol-
erated KP therapy with no adverse effects resulting
in discontinuation. Mean pretreatment and post-
treatment T was 468 and 275 ng/dl, respectively
(normal range 241 to 827). There were no reported
symptoms of hypogonadism or gynecomastia. Six
patients completed the 6-month treatment protocol.
Patient 3 did not respond to corporal injection and
irrigation, and required a bilateral Al-Ghorab shunt.
He was started on KP therapy postoperatively and
had a precipitous decrease in T to 33 ng/dl after
Table 2. Results
Initial T Final Dose K Final Dose P Final T
Pt No. (ng/dl) (mg) (mg/qd) (ng/dl)
1 669 400 tid 2.5
2 354 400 bid 2.5
3 327 100 bid 5 33
4 200 tid 5 353
5 425 200 bid 5 179
6 361 200 tid 5 184
7 859 200 tid 5 520
8 280 200 tid 5 140
Mean 468 275.2
1403
initiation of treatment. Evaluation revealed a prolacti-
noma. Treatment was discontinued, T rebounded to
the normal range and sexual function was pre-
served. Patient 1 was not compliant with the KP
protocol (patient preference not related to medica-
tion side effects) and opted for an inflatable penile
prosthesis as he continued to have RIP episodes.
Patient 6 experienced an increase in T from 361 to
432 ng/dl after initiation of therapy and had 3 RIP
episodes requiring emergency corporal irrigation.
After dose titration T was 184 ng/dl and he has had
no subsequent episodes.
Patients were screened for ED during office visits
and none of the patients complained of any sexual
dysfunction at the onset of KP therapy. An IIEF-5
score was obtained for 4 patients, 1 still on KP
therapy at a stable dose and 3 who had been off
therapy for 3, 12 and 24 months. The IIEF-5 score of
each patient demonstrated preservation of erectile
function as shown in table 2.
After termination of the 6-month KP treatment
program only patient 2 had any recurrent priapic
episodes. These were managed by patient adminis-
tered phenylephrine injection. Of note, this patient
was treated before our standard practice of serum T
monitoring and KP dose titration. As shown in table
3 the cost of KP therapy is approximately $160 per
month, which is less expensive than other forms of
antiandrogen therapy.
DISCUSSION
Published studies to date on prevention of RIP have
been retrospective case reports and various strate-
gies have shown success. However, no definitive
standard of care exists. This is the largest series of
RIP patients to date studied prospectively. High
dose ketoconazole was recently found to be ineffec-
tive in the prevention of postoperative erections in a
double-blinded, randomized, placebo controlled trial.
However, serum T (and, therefore, compliance or
adequate T suppression) and presence of sexual
stimuli were not evaluated.17 As virtually all of the
episodes in our study were associated temporally
Mos
Mos Treatment Followup IIEF-5 Score Outcome
Not applicable 24 Opted for prosthesis
6 24 25 2 Episodes in 2 yrs, relieved by self-injected phenylephrine
2 4 25 Started KP after bilat Al-Ghorab shunt, no episodes
6 36 No episodes
6 24 No episodes
6 12 25 No episodes
6 24 No episodes
6 3 24 No episodes
18.8 24.8
1404 KETOCONAZOLE AND PREDNISONE TO PREVENT RECURRENT ISCHEMIC PRIAPISM
Table 3. Antiandrogen medication cost
Drug Dose (mg) Quantity (1 mo)
Ketoconazole 200 bid 60 Tablets
Prednisone 5 qd 30 Tablets
Flutamide 250 tid 180 Tablets
Bicalutamide 50 qd 30 Tablets
Leuprolide acetate 7.5/Mo 1 Injection
* Retail price at Rush University Medical Center outpatient pharmacy october
2008.
with SRE, our goal with this group was specifically
to eliminate them while permitting sexually stimu-
lated erections. In addition, titration of dose to a
threshold serum T allows assessment of compliance
with therapy.
Fertility, sexual side effects and other sequelae of
low T including osteopenia, sarcopenia, gynecomas-
tia, hot flushes and fatigue are important consider-
ations in a young patient population. Minimizing
the dose and duration of antiandrogen therapy is
desirable to avoid these effects. It is unknown if
durable changes in the androgen dependent mecha-
nisms involved with nocturnal erections can be pro-
duced with less than 6 months of therapy.
Although ketoconazole does have a rapid effect on
decreasing T it is unknown if this therapy would be
efficacious in an acute priapism episode. We do
check serum T in patients presenting with a first
acute priapism but rule out other etiologies with a
complete laboratory evaluation. Further studies
would be necessary to determine the efficacy of de-
creasing T in the acute setting but at this time we
advocate proceeding with aspiration and vasocon-
strictor injections as a treatment strategy.
Champion et al made an important contribution to
our understanding of the mechanisms of priapism by
demonstrating that mice deficient in endothelial NOS
and neuronal NOS are prone to priapic events. In
addition, these animals have exaggerated production
of cyclic guanosine monophosphate and PDE5a pro-
teins in response to neuronal and biochemical stimu-
lation indicating dysregulation of pathways down-
stream of NOS.18 Although specific studies have not
been performed, we can speculate that RIP is associ-
ated with dysregulation of these pathways. Suppress-
ing T directly or nocturnal erections for 6 months may
allow regulation of these pathways such that uninhib-
ited penile vasodilation does not occur as has been
suggested as a mechanism following a course of
chronic PDE5 inhibitor therapy for RIP.19
We did not perform IIEF-5 before initiating the
treatment protocol because none of the 8 patients
had sexual dysfunction on history taking. Interest-
ingly patients 3 and 8 had a T of 327 and 280 ng/dl,
respectively, which is near hypogonadal levels.
These patients each had a normal IIEF-5 score, pa-
tient 3 while on therapy and patient 8 immediately
Cost* after 6 months of therapy. The lack of ED may be
due to the relatively young cohort (mean age 34
$150.71
years). Future protocol adjustments should include
$8.65
$389.49 pretreatment IIEF-5 scores, especially in men with
$578.60 complaints of sexual dysfunction, to monitor changes
$830.77 in this important outcome.
Ketoconazole has been combined with glucocorti-
coid replacement when used in high dose and low dose
forms for advanced prostate cancer but not when used
as an antimycotic.20,21 However, ketoconazole has
been shown to inhibit the human glucocorticoid recep-
tor and there have been cases of adrenal insufficiency
attributed to low dose ketoconazole.22,23 Therefore, we
added prednisone to our treatment protocol. If this
step is omitted a high level of suspicion should be paid
to signs or symptoms of adrenal insufficiency, ie hypo-
tension, electrolyte abnormalities or weakness. This
did not occur on our protocol and at a low dose of 5 mg
prednisone a dosing taper is not necessary. Since all
men in our protocol received prednisone it is unknown
if it had a contributory antipriapic effect, although we
believe this is unlikely at this dose.
Future directions of this study include modify-
ing the dosing schedule along with nocturnal pe-
nile tumescence monitoring to correlate nocturnal
erectile activity with recurrent priapic episodes.
We did perform nocturnal penile tumescence mon-
itoring on patient 8 which demonstrated low am-
plitude tumescence and rigidity episodes at inter-
vals between 1 and 2 hours consistent with normal
REM sleep intervals (see figure). The tumescence
activity unit measurements of tip and base were 0
for the entire night. The rigidity activity unit mea-
surements were 12.5 for the tip and 8.5 for the
base. Based on the criteria of Levine and Carroll
this places the patient in approximately the 10th
percentile for tip rigidity activity unit and 5th
percentile for base rigidity activity unit.24 The
peak tip rigidity remained below 60% to 70%, another
threshold for normal nocturnal erections.25,26 There-
fore, by established criteria this patient had sup-
pression of nocturnal erections. Ketoconazole has
been shown to result in a nadir of serum T after 2
to 8 hours of ingestion. If RIP is associated with
nocturnal erections it is possible that once nightly
dosing (or dosing before sleep) may result in the
same effect as twice daily or 3 times daily dosing,
thereby reducing cost and potential side effects.
Patient 8 has been transitioned to nightly dosing
without recurrence after 2 months of followup.
A limitation of this study is the lack of random-
ization to a control group. Low disease prevalence
and lack of a gold standard therapy for prevention
are barriers to this study design. Extension of the
protocol to a multicenter study with a placebo group
 KETOCONAZOLE AND PREDNISONE TO PREVENT RECURRENT ISCHEMIC PRIAPISM
RigiScan® nocturnal penile tumescence monitoring for patient 8 performed while on 200 mg ketoconazole 3 times daily. No sexual
dysfunction was noted.
and prednisone alone group would help to isolate the
effect of KP.
CONCLUSIONS
KP therapy is cost-effective and was well tolerated in
these 8 patients with RIP. With dose titration and T
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