Original Research

International Journal of Impotence Research (2004) 16, 346–349. doi:10.1038/sj.ijir.3901160 Published online 19 February 2004

Use of oral ketoconazole to prevent postoperative erections following penile surgery

K C Evans1, A C Peterson1, H E Ruiz1 and R A Costabile1

1Urology Service, Madigan Army Medical Center, Tacoma, Washington, USA

Correspondence: AC Peterson, MD, Urology, Department of Urology, Madigan Army Medical Center, 9040A Fitzsimmons Ave., Tacoma, WA 98431, USA. E-mail: andrewcp@u.washington.edu

Disclaimers: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46

Received 17 December 2002; Revised 26 July 2003; Accepted 6 October 2003; Published online 19 February 2004.

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Abstract

Analgesics and topical agents ineffectively inhibit painful erections after penile and urethral surgery. Oral ketoconazole reversibly inhibits testosterone production and has been used empirically at our institution to decrease postoperative erections. We performed a retrospective review of 38 patients who had undergone penile and urethral reconstructive surgery. In all, 31 patients received 400 mg of ketoconazole three times daily for 10–14 days postoperatively (the study group) and seven patients did not receive ketoconazole (the control group). The incidence of postoperative erections, pain, side effects, surgical outcomes and patient satisfaction in each group were compared. Of the control group, 71% reported erections in the immediate postoperative period, and all these patients reported the erections were painful. Only 23% of the patient taking ketoconazole reported postoperative erections, and only 16% reported the erections were painful. We conclude that ketoconazole effectively prevents painful postoperative erections with minimal side effects.

Keywords:

ketoconazole, penile erection, penis surgery, urethra surgery

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Introduction

Spontaneous and nocturnal erections are a common complaint of patients after penile and urethral reconstructive surgery. Current methods available to prevent painful postoperative erections are inadequate. Amyl nitrate, narcotics, refrigerant sprays, and dorsal nerve blocks are usually initiated after the erection has begun, frequently provide incomplete relief, and their effects are short lived. We sought a treatment that could safely, effectively, and reversibly inhibit erections.

In 1995, Stock and Kaplan published their success using ketoconazole to prevent postoperative erections in eight patients.1 Ketoconazole inhibits the production of testosterone, and has been used by urologists to treat refractory bone pain and impending neurologic injury in patients with advanced metastatic prostate cancer. Ketoconazole is an imidazole derivative and a common antifungal. In the fungus, ketoconazole inhibits 14-demethylation and blocks the conversion of lanosterol to ergosterol.2 In humans, ketoconazole inhibits gonadal and adrenal steroid synthesis to varying degrees at several enzymatic steps. Research in humans reveals that ketoconazole preferentially inhibits 17,20 desmolase, an enzyme necessary for the production of testosterone near the final step of its synthesis.3, 4, 5 This preference allows the selective inhibition of testosterone production, while cortisol and mineralocorticoid synthesis remain relatively unaffected.6 Ketoconazole is orally administered, has a rapid onset, and its inhibition of testosterone synthesis is completely reversible. Peak serum levels of ketoconazole are reached 2–4 h after the administration of ketoconazole.3, 7 Serum testosterone levels decline significantly 2 h after 600 mg of ketoconazole was administered to healthy male volunteers.2 In healthy male volunteers administered 400 or 600 mg doses of ketoconazole, serum testosterone reaches nadir at 4–8 h, and begin to rebound 8 h after administration.2 Testosterone levels return to normal within 24 h after cessation of ketoconazole therapy.6

The antisteriodogenic side effects of ketoconazole have been exploited for the treatment of other medical conditions to include precious puberty, hirsutism, treatment-resistant depression, and Cushing's disease. Long term and high dose use of ketoconazole for these and other medical conditions have established that ketoconazole is a safe medication. Based on its established safety and antiandrogenic side effects, ketoconazole has been used empirically at our institution to prevent postoperative erections. The objective of our study was to evaluate retrospectively the efficacy of ketoconazole to inhibit painful postoperative erections after penile and urethral reconstructive surgery. Our secondary end points were to evaluate the incidence of overall postoperative pain, surgical outcomes, side effects of ketoconazole, and the patient's overall satisfaction.

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Materials and methods

A retrospective chart review was performed on all patients who had undergone penile or urethral surgery at our institution over the previous 3 y. We identified patients through surgical logs, ambulatory surgery records, and clinic records. When necessary, telephone interviews were conducted to complete the data.

We studied males, aged 13 y and older, who had undergone penile or urethral surgery at our institution during the preceding 3 y. Patients who had been prescribed ketoconazole in the immediate postoperative period were designated the study group. Patients who did not receive ketoconazole were designated the control group. Patients were categorized as experiencing or not experiencing erections during the immediate postoperative period (designated as the first 2 weeks after the operation, or the length of time during which the patient took ketoconazole). Patients experiencing nocturnal, spontaneous, or diminished erections and/or erections caused by stimulation were categorized as experiencing erections. Patients experiencing erections that were painful enough to cause them to take, or want to take, pain medication were further categorized as experiencing painful erections. The Fisher's exact test and the unpaired t-test were used to calculate statistical significance. All patients contacted by telephone agreed to participate in the analysis. Patients with inadequate data were excluded from the analysis.

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Results

In all, 49 candidates were identified through our surgical logs. Of the candidates identified, 38 patients had complete data and were included in this analysis. The patients ranged from 13 to 72 y in age. Of the 38 patients, 31 had received ketoconazole in the immediate postoperative period and were designated as the study group. Seven of the 38 patients had not received ketoconazole and were designated as the control group. The mean and median age of the study patients was 38.1 and 29 y, respectively. The mean and median age of the control patients was 39.6 and 33 y. The difference in the ages between the study and control groups was not statistically significant (P=0.8, unpaired t-test).

Of the 38 patients included in the study, 28 had undergone urethroplasty, eight had undergone corporal plication, and two had undergone circumcision or circumcision revision. The distribution of the operative procedures is comparable between the study and control groups, and is summarized in Table 1.


Four of the seven control patients (57%) reported significant overall postoperative pain. Of the 31 study patients, 19 (61%) reported significant overall postoperative pain. The difference in the incidence of postoperative pain between the study and control groups was not statistically significant.

Five of the seven control patients (71%) reported postoperative erections. Seven of 31 study patients (23%) reported postoperative erections while taking ketoconazole. The difference between the incidence of erections in the study and control groups was statistically significant (P-value=0.02, Fisher's exact test). Furthermore, only five of the seven patients taking ketoconazole who experienced erections reported their erections were painful (16% of the study group). In contrast, all five of the control patients who experienced erections reported their erections were painful (71% of the control group and 100% of the control group that reported erections). These results are represented in Figure 1. The difference between the incidence of painful erections in the control and study groups was statistically significant (P-value=0.008, Fisher's exact test). Of note, three of the patients in the study group who experienced erections volunteered that their erections were diminished in strength while taking ketoconazole. The difference in the mean and median age of the men experiencing erections in the study and control groups was not statistically significant (P=0.14, unpaired t-test).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Incidence of postoperative erections.

Full figure and legend (17K)

All seven of the control patients had excellent surgical outcomes documented in their medical records, and all seven reported they were satisfied with their surgeries. Of the 31 study patients, 30 had excellent surgical outcomes documented in their medical records and one study patient had a postoperative urethral diverticulum after an urethroplasty for stricture disease. Of the 31 study patients, 28 reported they were satisfied with their surgeries and three patients were dissatisfied. One patient was dissatisfied by the progression of his Peyronie's disease after a successful corporal plication, one patient was dissatisfied because he experienced testalgia after a successful urethroplasty, and one patient was dissatisfied by continued symptoms of urge incontinence after a successful urethroplasty for stricture disease.

Seven of the 31 study patients (22%) reported side effects from the ketoconazole. Three of the study patients (9%) reported nausea and one patient each reported 'feet swelling', pruritus, frequent urination, and headache.

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Discussion

An erection is a complex physiological and psychological phenomenon that is modulated through the central nervous system. Animal studies have identified several areas in the brain, to include the medial preoptic area (MPOA), the paraventicular nucleus, and the limbic system, which are important to male sexual activity. Stimulation of the MPOA in male rodents facilitates sexual activity, while destructive lesions in the MPOA severely inhibit copulation.8, 9, 10 Animal studies also reveal a high concentration of testosterone receptors in the neurons of the MPOA. It is theorized that the MPOA integrates the sensory and hormonal signals that initiate male sexual activity. In theory, alterations in the hormonal levels, specifically a decrease in testosterone, could influence the initiation of centrally mediated erections.

Our patients were empirically administered ketoconazole in the immediate postoperative period after penile and urethral reconstructive surgery at a dose of 400 mg three times daily for 10–14 days. A retrospective analysis of these patients demonstrated that ketoconazole effectively inhibited erections and decreased the incidence of painful erections. Surgical outcomes and patient satisfaction were comparable. The incidence and type of side effects at our dosing schedule were comparable with 400 mg daily dosing and were lower than the incidence of side effects with high dose (greater than or equal to800 mg/day) daily dosing (22 vs up to 50%).7

This pilot study is an analysis of patients treated empirically with ketoconazole to inhibit postoperative erections. This study is limited by its retrospective nature, small sample size, and lack of a placebo control. We are currently performing a placebo-controlled, double-blinded study to assess prospectively the ability of ketoconazole to inhibit erections after penile and urethral reconstructive surgery.

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Conclusion

Ketoconazole effectively inhibits postoperative erections after urethral and penile reconstructive surgery, and should be considered a useful adjunct for the prevention of painful erections in the immediate postoperative period. The side effects from ketoconazole therapy were minor and infrequent in our retrospective analysis.

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References

  1. Stock JA, Kaplan GW. Ketoconazole for prevention of postoperative penile erections. Urology 1995; 45: 308–309. | Article | PubMed |
  2. Pont A et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med 1982; 142: 2137–2140. | Article | PubMed |
  3. Santen RJ et al. Site of action of low dose ketoconazole on androgen biosynthesis in men. J Clin Endocrinol Metab 1983; 57: 732–736. | PubMed |
  4. Sikka SC, Swerdloff RS, Rajfer J. In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology 1985; 116: 1920–1925. | PubMed |
  5. Trachtenberg J, Zadra J. Steriod synthesis inhibition by ketoconazole: sites of action. Clin Invest Med 1988; 11: 1–5. | PubMed |
  6. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317: 812–818. | PubMed | ISI | ChemPort |
  7. Sugar A et al. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother 1987; 31: 1874–1878. | PubMed |
  8. Yahr P, Gregory JE. The medial and lateral cell groups of the sexual dimorphic area of the gerbil hypothalamus are essential for male sex behavior and act via separate pathways. Brain Res 1993; 631: 287–296. | Article | PubMed |
  9. Wood RI, Williams SJ. Steroidal control of male hamster sexual behavior in ME and MPOA. Physiol Behav 2001; 72: 727–733. | Article | PubMed |
  10. Edwards DA, Einhorn LC. Pre-optic and midbrain control of sexual motivation. Physiol Behav 1986; 37: 329–335. | Article | PubMed |
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