Int Urol Nephrol (2014) 46:757–760 DOI 10.1007/s11255-013-0583-z

UROLOGY - CASE REPORT

Prostate cancer risk after anti-androgen treatment for priapism Tabitha Goetz • Arthur L. Burnett

Received: 13 September 2013 / Accepted: 3 October 2013 / Published online: 18 October 2013 Ó Springer Science+Business Media Dordrecht 2013

Abstract Background Patients with recurrent ischemic priapism have historically been treated with anti-androgen therapy due to the limited available evidence for more targeted therapies to treat the underlying pathophysiologic mechanisms of this condition. We report a case in which anti-androgen therapy caused significant adverse side effects and likely masked this patient’s elevated prostate-specific antigen (PSA) levels, which adversely impacted the timely diagnosis and treatment of his prostate cancer. Case report A 69-year-old man treated with antiandrogens for priapism initially developed unwanted anti-androgenic side effects such as gynecomastia, erectile dysfunction, and decreased libido. After decreasing his anti-androgen dosage and starting a specified regimen of phosphodiesterase type 5 inhibitor therapy, his serum PSA levels were found to be elevated. He was subsequently diagnosed with adenocarcinoma of the prostate and underwent a radical prostatectomy with the pathologic finding of high-grade, locally progressive disease. Conclusion Anti-androgen therapy carries significant complication risks, including the potential to alter the diagnosis and treatment of prostate cancer. Clinicians

T. Goetz  A. L. Burnett (&) Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, The Johns Hopkins Medical Institutions, 600 N. Wolfe St/Marburg 407, Baltimore, MD 21287-2411, USA e-mail: [email protected]

administering this therapy for priapism management should be aware of these possible risks. Keywords Priapism  Prostate cancer  Antiandrogens  Androgen deprivation  Castration  PDE5 inhibitor

Introduction Prostate cancer is the most commonly diagnosed cancer (29 % of all cases) and the second most common cause of male cancer deaths among American and European men [1]. This cancer is often asymptomatic in its early natural history, and therefore, its detection in modern times has relied greatly on serological prostate-specific antigen (PSA) testing as a standard diagnostic tool [2]. A variety of circumstances may influence the utility of PSA testing for prostate cancer diagnosis, from its inherent nonspecificity as a biomarker for prostate malignancy to assorted pharmacotherapies and substance exposures that alter PSA production and release from the prostate [3]. Agents with anti-androgenic properties notoriously cause a decrease in PSA concentration and possibly afford the untoward risk of masking the presence of prostate cancer or delaying its diagnosis [4, 5]. Anti-androgens have been used successfully to treat the recurrent ischemic priapism despite their common association with adverse quality-of-life effects such as erectile dysfunction and decreased libido [6]. This case highlights the significant risks involved with using anti-androgen therapy as a treatment option for priapism, not only because of its dramatic consequences on the patient’s quality of life but also because of its potential to promote the risks of prostate cancer.

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Case report A 69-year-old African American man was diagnosed with prostate cancer on a background history of recurrent ischemic priapism for the past 13 years. He had developed spontaneous ischemic priapism without any association with medical illness or medication use. His medical comorbidities included hypertension controlled with hydrochlorothiazide, diet-controlled diabetes mellitus, and chronic anemia. He also had a right hemicolectomy for a nonmalignant growth. He did not have sickle cell disease or blood dyscrasia and had never used trazodone or other medications commonly associated with priapism. Of note, he had no prior history of genital or pelvic trauma and no known family history of prostate cancer. Initially, the patient was started on daily oral bicalutamide, a nonsteroidal anti-androgen therapy, when his priapism episodes began occurring every other day and lasting 2–5 h. While receiving chronic anti-androgenic therapy, he developed bilateral gynecomastia, which required bilateral reduction mammoplasties. In addition, he experienced decreased libido, erectile dysfunction, and bilateral testicular atrophy. He elected to discontinue androgen deprivation but within 1 month had suffered several priapism recurrences and recommenced his bicalutamide therapy at a lower frequency of twice weekly and then once weekly. However, this adjustment was unsuccessful in controlling his priapism. The patient eventually was referred to our institution and initiated on an investigational pharmacotherapeutic regimen therapy consisting of daily oral lowdose sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which effectively and safely controlled his recurrent priapism and also recovered his erectile function [7]. It also allowed him to decrease his bicalutamide therapy to once every other week dosage, thereby mitigating unwanted anti-androgenic side effects. While using daily bicalutamide, to treat his priapism, his PSA level was found to be 1.2 ng/mL. A follow-up annual PSA reading while on bicalutamide therapy was found to be 2.3 ng/mL. Digital rectal examination had remained negative for any nodularity or induration throughout this therapy. After initiating sildenafil as a daily regimen and decreasing his bicalutamide dosage to once every other week, his next annual PSA measurement was found to be 4.99 ng/mL. Upon repeat PSA measurement 1 year thereafter, the value was found to be further elevated to 9.1 ng/ mL. A 12-core prostate biopsy procedure was carried out, after which he was diagnosed with adenocarcinoma of the prostate, Gleason score 3 ? 4=7, consistent with impalpable stage T1c disease. He subsequently underwent a successful radical prostatectomy. Histopathological analysis showed upgraded Gleason score 4 ? 3 = 7 adenocarcinoma of the prostate, with seminal vesicle invasion,

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consistent with locally progressive stage T3b, N0 disease. He elected clinical monitoring postoperatively rather than initiate adjuvant radiation or systemic hormonal ablation or chemotherapy.

Discussion Over approximately the last 20 years, advances in the early detection and treatment of prostate cancer have accounted significantly for the reduction in mortality rates associated with this disease. The PSA serological test has been figured prominently in this progress, and it is widely used to promote early detection of prostate cancer [2, 3]. Despite controversies surrounding the purpose of this test, such as its debated role for widespread population screening [8], the test has served well to monitor the risk of prostate cancer and guide intervention for this disease among several clinical indications for its use [2]. However, PSA levels can be artificially lowered by a host of clinical settings, including being overweight, use of medications such as finasteride, statins, thiazide diuretics, and nonsteroidal anti-inflammatories, and partial removal of the prostate such as transurethral prostatic resection, which may then yield a false sense of assurance that prostate cancer is absent [9–13]. In our patient, the PSA level was measurable only in the normal range (conventionally \ 4 ng/ml) with repeated checks, and only after discontinuing his anti-androgen therapy was it observed that his PSA test result was confounded. The substantial elevation in the PSA level in our patient after antiandrogen discontinuation and initiation of an alternative treatment for his priapism fortuitously prompted an assessment that rendered the diagnosis and subsequent treatment of prostate cancer. The notion that anti-androgens lower PSA levels hardly represents a new concept. Anti-androgen therapy is used commonly in the treatment of advanced prostate cancer, with knowledge that androgen withdrawal reduces prostate cancer progression, accompanied typically by the reduced PSA levels [14]. In this case, it was used as a treatment for priapism, a clinically under-recognized and therapeutically vexatious disorder of prolonged, nonwillful, and often painful penile erections without sexual purpose [15]. Our patient received hormonal therapy for the recurrent ischemic form of this disorder, applied as a preventative albeit mechanism-nonspecific intervention. Hormonal therapies, consisting of such options as anti-androgens, including bicalutamide, flutamide chlormadinone, ketaconazole, and 5alpha-reductase inhibitors (5ARI); estrogenic compounds, including diethylstilbestrol; and centrally acting GnRH agonists [16, 17], have been widely used in this arena under the rationale that they aim to control testosterone-

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dependent sleep-related penile erections which frequently precede priapism episodes [18]. Notwithstanding the seeming advantage of hormonal therapy for treating priapism, this option carries known potential adverse effects. It cannot be administered to prepubertal or adolescent males who have not reached sexual maturation or who desire to father children, because of the side effects of growth impairment and infertility [19]. Further concerns associated with prolonged hormonal treatment pertain to decreased bone density, gynecomastia, metabolic and cardiovascular disease risks, and sexual side effects, including decreased libido, erectile dysfunction, and inability to achieve orgasm or ejaculation [19]. Our patient sustained a host of complications from using anti-androgens, although the most symptomatic effects were apparently only recognized during the course of his anti-androgen therapy. The sequelae of using anti-androgen therapy in this case raise some interesting considerations. Indeed, he was discovered to have prostate cancer in a delayed fashion after the confounding suppressive effect of anti-androgen therapy on his disease was eliminated. However, is it also plausible that his use of anti-androgens may have played a role in the genesis and progression of his disease? Recent clinical trials of long-term 5ARI therapy as a possible prostate cancer chemoprevention have shown that although patients on such therapy have a reduced overall prostate cancer risk, they actually present with higher-grade prostate cancer [20]. The decrease in overall incidence of prostate cancer seen in patients on anti-androgen therapy is likely due to the fact that lower-grade, well-differentiated, early-stage tumors respond to anti-androgens, while higher-grade cancers with poorly differentiated dysfunctioning prostatic tissue do not [20]. Results from these trials also suggest worse progression-free survival in these patients on long-term anti-androgen therapy [21]. The finding in our patient of extensive, locally progressive, and high-grade disease prompts conjecture that the use of antiandrogen therapy in our patient contributed biochemically to his developing a high-profile-risk prostate cancer. A paradoxical agonist effect of anti-androgens on prostate cancer cells has been described [22]. This case also helps to demonstrate that the mechanism of priapism involves PDE5 dysregulation in the penis. Recent research using transgenic mouse models as well as new studies using penile tissue from humans suffering with priapism has shown that the pathophysiology of priapism involves function and regulation of the nitric oxide (NO), cyclic GMP (cGMP), protein kinase G (PKG), and PDE5 signaling cascades [23, 24]. Chronic baseline PDE5 downregulation in patients with priapism causes unrestrained erectile tissue relaxation following cGMP generation on neurostimulation [7]. Sildenafil, with a welldescribed mechanism of action as a PDE5 inhibitor,

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restores deficient production of PDE5 in the penis, normalizing cGMP levels and PKG, thereby restoring normal penile vascular function [24]. Early clinical trials have shown that daily PDE5 inhibitors are an effective preventative management strategy for recurrent ischemic priapism [7].

Conclusion While there are no definitive evidence-based medical prevention guidelines for the treatment of priapism, long-term anti-androgen therapy can be seen as potentially hazardous, as demonstrated in this case, not only because of its adverse symptomatic effects, but also because of its interference with elevated PSA level measurements as an indication of the possible presence of prostate cancer. Recent studies have elucidated plausible mechanisms as well as more targeted therapies for recurrent priapism such as continuous oral PDE5 inhibitor therapy. Conflict of interest interest.

The authors declare they have no conflict of

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Prostate cancer risk after anti-androgen treatment for priapism.

Patients with recurrent ischemic priapism have historically been treated with anti-androgen therapy due to the limited available evidence for more tar...
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