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Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism
ADULT UROLOGY
LONG-TERM ORAL PHOSPHODIESTERASE 5 INHIBITOR THERAPY ALLEVIATES RECURRENT PRIAPISM ARTHUR L. BURNETT, TRINITY J. BIVALACQUA, HUNTER C. CHAMPION,
AND
BILJANA MUSICKI
ABSTRACT Objectives. Recurrent ischemic priapism describes a disorder of repeated episodes of prolonged penile erection that frequently leads to devastating complications of erectile tissue damage and erectile dysfunction. A mechanistic role for dysregulated phosphodiesterase 5 (PDE5) in the deranged smooth muscle response of the corpus cavernosum of the penis offers new understanding about the pathogenesis of the disorder and suggests that PDE5 may serve as a molecular target for its treatment and prevention. We explored the use of PDE5 inhibitors to treat recurrent priapism, based on the hypothesis that the erection regulatory function of PDE5 would be regularized by this treatment and protect against further episodes. Methods. We administered PDE5 inhibitors using a long-term therapeutic regimen to 3 men with sickle cell disease-associated priapism recurrences and 1 man with idiopathic priapism recurrences. Results. Long-term PDE5 inhibitor treatment alleviated priapism recurrences. Conclusions. These observations support the hypothesis that PDE5 dysregulation exerts a pathogenic role for priapism associated with hematologic dyscrasias, as well as idiopathic priapism. Although these preliminary findings suggest that continuous, long-term PDE5 inhibitor therapy may be useful as a preventative strategy for priapism, additional evaluation in the form of a controlled clinical trial is needed. UROLOGY 67: 1043–1048, 2006. © 2006 Elsevier Inc.
P
riapism is an obscure erectile disorder in which prolonged penile erection occurs uncontrollably and often painfully without sexual purpose. It is distinguished from the more familiarly known erectile disorder, erectile dysfunction, which is characterized by the loss of erectile ability and commonly associated with such major comorbidities as cardiovascular disease and diabetes mellitus, as well as older age. However, priapism is an equally important clinical entity that is also associated with complications of erectile dysfunction, and it occurs with substantial frequency in certain populations. It most recognizably afflicts men with sickle cell disease in whom the prevalence rate of priapism exceeds 40%,1–3 and the rate of erectile dysfunction as a sequela from priapism approximates 30%.3
A. L. Burnett is a speaker for Pfizer, Lilly/ICOS, Bayer/GlaxoSmithKline, and Schering. From the Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland Reprint requests: Arthur L. Burnett, M.D., Department of Urology, Johns Hopkins Hospital, 600 North Wolfe Street, Marburg 407, Baltimore, MD 21287-2411. E-mail: [email protected] Submitted: September 9, 2005, accepted (with revisions): November 22, 2005 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
Priapism is poorly recognized as an important clinical condition. The disorder is fundamentally misunderstood from a pathophysiologic standpoint, and thus effective treatments having a mechanism-specific basis are lacking. For many men experiencing priapism, adverse consequences occur despite the use of available clinical management practices for it. Unresolved major episodes of priapism commonly produce ischemic effects within the penis equivalent to a compartment syndrome of an extremity. The end-stage pathologic features consist of erectile tissue necrosis and genital organ fibrosis, which impedes normal erectile tissue hemodynamic responses. Such complications are even more lamentable considering that they could be preventable. The natural history of priapism commonly involves recurrent short-lived episodes, which frequently herald a subsequent major episode; thus, preventive action taken early in its course may be advantageous. Diverse clinical treatments are currently used for ischemic priapism, including presentations associated with hematologic dyscrasias such as sickle cell disease. Nonsurgical treatments include analgesia, intravenous hydration, oral and intracavernous alpha-adrenergic agonists, gonadotropin-re0090-4295/06/$32.00 doi:10.1016/j.urology.2005.11.045 1043
leasing hormone analogs, antiandrogens, baclofen, and digoxin.4,5 Additional treatments used particularly for patients with sickle cell disease having priapism include red blood cell transfusion, partial exchange transfusion to lower hemoglobin S, and hydroxyurea.4 – 6 Surgical management, commonly instituted for medically refractory episodes, primarily consists of local treatment such as aspiration and irrigation of the corpora cavernosa and, if these are unsuccessful, penile shunt procedures that vent blood from the corpora cavernosa to the corpus spongiosum.4,5 In general, these treatments are devised to produce immediate penile detumescence or oppose presumable pathogenic factors. However, they remain reactive management approaches, frequently failing to achieve these objectives or avert complications of the disorder. The classic tenets of the pathophysiology of ischemic priapism have supported increased intracavernous blood viscosity and venous outflow obstruction of the corpora cavernosa, the main corporal bodies of the penis, as likely major mechanisms.7,8 This belief has long been accepted to explain the association between hematologic dyscrasias, particularly sickle cell disease, and priapism. However, recent clinical observations, including the finding that priapism occurs in hematologic disease states in the absence of corporal veno-occlusion,9,10 have raised questions as to whether the venous congestion hypothesis is too simplistic. Several investigators have conjectured that dysregulatory molecular mechanisms of penile erection may be involved in the pathogenesis of priapism.11–14 Although the underlying pathogenic mechanisms of priapism remain elusive, current basic science progress in the field suggests that priapism in various instances may result from disturbances in the regulatory control of the main molecular pathway mediating penile erection, the nitric oxide-signaling pathway.15,16 This dysregulation specifically involves the reduced expression in the penis of phosphodiesterase-5 (PDE5), which hydrolyzes the pathway’s second messenger molecule cyclic guanosine monophosphate (cGMP).16 This discovery supports the proposal that PDE5 represents a feasible molecular target for developing scientifically cogent, new priapism treatments. We describe new insights into the disease process of priapism and the rationale for PDE5 inhibitor therapy specifically to serve in the management of this disorder. The promise of this therapy is preliminarily demonstrated by its success in treating several patients with recurrent ischemic priapism. MATERIAL AND METHODS In each of the following cases, the management options currently available for recurrent priapism4,5 were initially ap1044
plied unsuccessfully. In acknowledgment of the possibility that these men would progress to have major complications from priapism, the option of using PDE5 inhibitor therapy as an off-label treatment was discussed and used with individual patient consent. An initial treatment approach consisted of the short-acting PDE5 inhibitor sildenafil citrate at a 25-mg oral daily dosage in the morning under conditions of complete penile flaccidity, with subsequent medication adjustments as needed.
RESULTS CASE 1 A 24-year-old man with hemoglobin SS disease had had recurrent priapism for 3 years, worsening during a 6-month interval from sporadic events to an almost daily frequency. Episodes were commonly 3 hours in duration, occurring with nighttime sleep or persisting after sexual activity. Ice packs applied to the penis and analgesic use was of increasingly limited benefit. He started taking sildenafil. His priapism frequency lessened within 1 week, and he experienced only three or four shortlived episodes monthly during the next 3 months. Worried that the continuous use of the medication would eventually impair his natural erections, he discontinued sildenafil. Priapism recurrences returned at the rate of a few episodes weekly, although they were again reduced to rare events within 1 to 2 weeks after resuming the medication. He was subsequently switched to a long-acting PDE5 inhibitor, tadalafil, at a 5-mg oral dosage, taken 3 times weekly, also in the morning. He retained erectile ability and remained sexually active 14 months later. CASE 2 A 37-year-old man with hemoglobin SC disease had had recurrent priapism for 9 months, progressing from sporadic events to episodes recurring three times weekly. A single brief episode had been noted several years earlier. The episodes were commonly 3 hours in duration, occurring with nighttime sleep, although longer episodes on three occasions required penile aspiration and irrigation, despite exchange blood transfusions, intravenous hydration, systemic oxygenation, and analgesic use. A trial of oral baclofen was ineffective in preventing the recurrent episodes. He started taking sildenafil. He had a reduction in his priapism frequency within 2 weeks. With the exception of one subsequent 6-hour priapism episode occurring after an evening use of the medication that required penile aspiration and irrigation, he reported only rare, minor priapism recurrences. He was subsequently switched to tadalafil at a 5-mg oral dosage, taken three times weekly, also in the morning. He retained erectile ability and remained sexually active 9 months later. UROLOGY 67 (5), 2006
CASE 3 A 22-year-old man with hemoglobin SC disease had recurrent priapism for 4 months that had begun as a few episodes monthly, 2 hours in duration, in association with nighttime sleep. Two major episodes several hours in duration occurred, requiring emergency medical treatment. Despite regular and exchange blood transfusions, along with additional hematologic support, penile aspiration and irrigation were required for priapism resolution. A trial of oral terbutaline did not prevent recurrent episodes, and another major episode necessitated penile aspiration and irrigation. He started taking sildenafil. He reported only one minor recurrent priapism episode, and retained erectile ability useful for sexual activity 7 months later. CASE 4 A 22-year-old man with no major health problems had recurrent priapism for 8 months, progressing from a few episodes monthly to daily recurrences up to 5 hours in duration. The episodes were commonly associated with nighttime sleep. A hematologic workup was negative. Oral terbutaline, oral pseudoephedrine hydrochloride, and “nitrate poppers” were ineffective in correcting the problem. A prolonged episode required penile aspiration and irrigation for resolution. He started taking sildenafil, in combination with intracavernosal phenylephrine self-injections for use in the event of an episode of longer than 4 hours. During the next 2 months, the episodes were reduced to six to eight times monthly. Phenylephrine treatment was required three times. He was switched to sildenafil at a 50-mg oral morning dosage, with only occasional recurrent episodes. He retained erectile ability and remained sexually active 5 months later. COMMENT Recent basic science investigation has determined that a mechanism of priapism involves PDE5 downregulation in the penis, resulting from altered signaling of the nitric oxide signaling pathway.15,16 Accordingly, during occasions of neurologically mediated sexual stimulation or sleep-related erectile phenomena, cGMP is generated and exerts an unchecked action because of PDE5 deficiency. Consistent with the physiologic function of cGMP to induce the smooth muscle relaxation in the penis required for penile erection,17,18 the excessive amount of cyclic nucleotide accounts for the prolonged erectile tissue relaxation that manifests as priapism. It is importantly recognized that PDE5 operates under a complex system of regulatory control in smooth muscle cells, in a manner that involves reUROLOGY 67 (5), 2006
ciprocal actions of downstream components of the nitric oxide signaling pathway. These components include cGMP and its effector, cGMP-dependent protein kinase (PKG). Beyond acting as the substrate for degradation within the catalytic domain of PDE5, cGMP influences the activation of the enzyme. The cyclic nucleotide also binds to PDE5 at its allosteric (noncatalytic) domain, or regulatory domain, inducing the enzyme to undergo a conformational change.19,20 This conformational change exposes a phosphorylation site in the regulatory domain of the enzyme, which is phosphorylated by PKG, thereby further enhancing the catalytic activity of PDE5.21,22 However, the conformational change also increases the number of affinity binding sites for the cyclic nucleotide.23 The increased binding of cGMP to PDE5 reduces its availability for activation of PKG. These molecular events, taken together, contribute to feedback inhibition of smooth muscle relaxation. They indicate the existence of a precise regulatory system of “checks and balances,” which controls cGMP signaling. In contrast, the feedback control exerted by cGMP is entirely altered after administration of specific inhibitors of PDE5 catalysis. Although PDE5 inhibitors interact at the catalytic site of PDE5 directly inhibiting cGMP degradation, they stimulate cGMP binding to the allosteric sites of the enzyme without competing directly with the cyclic nucleotide for binding at the allosteric sites.24 In the context of PDE5 catalytic domain binding, these agents block cGMP-elicited negative feedback mechanisms responsible for additional cGMP degradation. They cause cGMP sequestration at the PDE5 regulatory domain, which facilitates the structural binding of PDE5 inhibitors at the enzyme’s catalytic domain. By promoting cGMP-induced allosteric binding of PDE5 and hence its conformational changes, PDE5 inhibitors gain greater access to the catalytic sites of the enzyme and further block its activity.25 Such positive feedback for PDE5 inhibition, exploiting the chemical binding and conformational properties of PDE5, reveals the mechanism by which PDE5 inhibitors used in the treatment of erectile dysfunction achieve maximal erectogenesis. Specifically, although cGMP is generated by nitric oxide signaling in the penis during sexual stimulation, PDE5 inhibitors prevent its degradation directly by blocking the catalytic function of PDE5 and also by blocking negative feedback control mechanisms responsible for additional cGMP degradation. Another positive feedback control mechanism to sustain cGMP signaling is provided by accumulated cGMP binding to allosteric cGMPbinding sites of PKG, thereby protecting the cyclic nucleotide from PDE5 hydrolysis.25 1045
In potentiating endogenous increases in cGMP, PDE5 inhibitors may also exert additional effects influencing PDE5 expression and PDE5 gene regulation. In an analysis of the genetic elements that control the expression of PDE5 isoforms, Lin and associates26 confirmed that three PDE5A isoform mRNAs exist in human penile cavernosum and differ at the 5= end based on their generation from the splicing of three alternative first exons.26 The investigators also showed that these isoforms are preceded by cyclic nucleotide-inducible promoters, as well as adjacent enhancers, which confer additive cyclic nucleotide-inducible responsiveness to the basal promoter.26 In promoter activity assays, the administration of cGMP or cyclic adenosine monophosphate increased PDE5A promoter activity.26 The inducibility of PDE5A promoters by cyclic nucleotides suggests that increased cGMP levels resulting from the use of PDE5 inhibitors may increase the expression of PDE5. Sildenafil administration to rat cavernous smooth muscle cells in vitro leads to PDE5 protein upregulation and such treatment of monkey fibroblast cell line COS-7 cells transfected with plasmid constructs carrying PDE5A promoters in vitro elevates PDE5A promoter activity.27 It is acknowledged that the concentration of sildenafil required in these experiments to produce the effects was high (25 M), which has led to questions regarding the clinical relevance of the findings. However, given the low or absent concentrations of cGMP in the cell culture systems used in these studies, the possibility remains that with sufficient availability of the PDE5 substrate as expected in vivo, PDE5 upregulation could occur at much lower concentrations of the PDE5 inhibitor. In line with the PDE5 downregulatory hypothesis for recurrent priapism, hypoxic conditions that mimic penile ischemia occurring during priapism cause PDE5 downregulation in cultured cavernous smooth muscle cells.27 To evaluate the possibility of PDE5 upregulation in vivo, Musicki and associates28 studied the effects of sildenafil administration to rats at therapeutic dosing levels on both PDE5 protein expression and activity in penes and erection physiology. In young adult rats treated with sildenafil for 3 weeks with a dosing schedule equivalent to a man taking sildenafil citrate at the standard maximal 100 mg dose daily for 2 years, PDE5 expression in penes was elevated to a similar extent as shown in previous in vitro studies.26 The findings suggested that longterm PDE5 inhibitor therapy in vivo causes prolonged accumulation of cGMP that acts sufficiently on the promoter region of PDE5 to induce its upregulation. However, such treatment does not alter PDE5 catalytic activity in penes or result in therapeutic resistance, because the animals preserved 1046
functional erectile responses to PDE5 inhibitor treatment.28 These series of investigations provided direct support for the use of PDE5 inhibitors to treat priapism clinically. The suggestion does seem counterintuitive and opposes earlier cautions against such use in patients who have conditions predisposing them to priapism such as sickle cell disease.29 However, we hypothesized that continuous, long-term, low-dose PDE5 inhibitor treatment may achieve a normative (although reversible) resetting of PDE5 expression in penile tissue, which would control the excessive cGMP signaling associated with priapism. We further hypothesized that the treatment would not necessarily impair voluntary sexually stimulated erections, because a sufficient intrapenile release of cGMP would occur in these situations to temporarily overcome the normalized PDE5 regulation. In essence, we postulated that PDE5 inhibitor treatment in patients with recurrent ischemic priapism would restore a normal balance of regulatory factors involved in the erectile response. In addition to the biologic coherence supporting its application, the clinical results showed consistency, dose specificity, and a temporal relationship. Efficacy was shown for long-term, low-dose PDE5 inhibitor therapy in each of these cases. For the fourth index case in which priapism had developed to an apparently more severe extent, dose elevation was necessary to achieve alleviation of the disorder. The temporal sequence in our first index case was quite dramatic. In that case, after cessation of therapy, priapism recurred; reinstitution of therapy again alleviated his priapism. The salubrious effects have been durable because the resolution of the priapism has continued for these patients at extended intervals of follow-up. In all 4 cases, erectile capability sufficient for sexual activity was preserved. Several practical matters deserve brief discussion. Our treatment approach began initially with morning treatment using a short-acting PDE5 inhibitor such as sildenafil, which has a 4-hour halflife and an expected elimination of more than 80% within 12 hours after administration.29 Our intent was to reduce the risk that the drug would be present to any sufficient extent in the body during nighttime sleep and thereby promote the conversion of a sleep-related erection into a priapism episode. The major priapism episode occurred in our second index case during sildenafil use and may have resulted from its inadvised use. The patient admitted taking the medication preceding this event in the evening with sexual stimulation. However, we found that conveniently useful, long-acting PDE5 inhibitors could readily be used over time, judging their safety to have been met after UROLOGY 67 (5), 2006
intrapenile PDE5 expression levels conceivably had normalized. We also used a sympathomimetic agent as needed by intracavernosal delivery in our fourth index case. That patient’s recurrences were so severe that this treatment was temporarily necessary for erectolysis while awaiting the effects of our therapeutic strategy. This observation revealed the delayed therapeutic role of PDE5 inhibitor therapy for priapism and suggests that a direct PDE5 activator or agonist targeting PDE5-binding sites would be advantageous for early control of recurrent priapism. In a data search, we learned of a previously published letter describing the surprisingly complete resolution of major painful priapism episodes in 3 patients with sickle cell disease after single, acute oral administration of the PDE5 inhibitor sildenafil citrate at a 50-mg dose.30 Also in that report, the repeated use of the medication as an “on-demand” intervention at the onset of subsequent painful erections in these patients successfully alleviated the pain and curtailed the development of any further major episodes. The investigators speculated that the medication caused selective vasodilation in the corpus cavernosum, possibly promoting the egress of anoxic, sickled red cells from the organ. Our experience with the presentations of priapism suggests that PDE5 inhibitor therapy is unlikely to have efficacy in the face of a major priapism episode, for which conventional local treatments are routinely necessary to produce immediate penile detumescence. CONCLUSIONS These findings suggest that PDE5 offers a molecular target for the therapeutic management of priapism. PDE5 inhibitor therapy used as a long-term preventative strategy to control the disorder may offer a clinical advance because therapies for priapism remain mostly reactive or otherwise fail to preserve normal erectile function. Whether PDE5 inhibitor therapy is useful to treat recurrent priapism in other contexts such as that associated with neurogenic conditions awaits additional study. Further evaluation in the form of a controlled clinical trial is required. REFERENCES 1. Emond AM, Holman R, Hayes RJ, et al: Priapism and impotence in homozygous sickle cell disease. Arch Intern Med 140: 1434 –1437, 1980. 2. Fowler JE Jr, Koshy M, Strub M, et al: Priapism associated with the sickle cell hemoglobinopathies: prevalence, natural history and sequelae. J Urol 145: 65– 68, 1991. 3. Adeyoju AB, Olujohungbe AB, Morris J, et al: Priapism in sickle-cell disease: incidence, risk factors and complications—an international multicentre study. BJU Int 90: 898 – 902, 2002. UROLOGY 67 (5), 2006
4. Berger R, Billups K, Brock G, et al: Report of the American Foundation for Urologic Disease (AFUD) Thought Leader Panel for evaluation and treatment of priapism. Int J Impot Res 13(suppl 5): S39 –S43, 2001. 5. Montague DK, Jarow J, Broderick GA, et al: American Urological Association guideline on the management of priapism. J Urol 170: 1318 –1324, 2003. 6. Al Jam’a AH, and Al Dabbous IA: Hydroxyurea in the treatment of sickle cell associated priapism. J Urol 159: 1642, 1998. 7. Hinman F Jr: Priapism; reason for failure of therapy. J Urol 83: 420 – 428, 1960. 8. Winter CC, and McDowell G: Experience with 105 patients with priapism: update review of all aspects. J Urol 140: 980 –983, 1988. 9. Ramos CE, Park JS, Ritchey ML, et al: High flow priapism associated with sickle cell disease. J Urol 153: 1619 – 1621, 1995. 10. Foda MM, Mahmood K, Rasuli P, et al: High-flow priapism associated with Fabry’s disease in a child: a case report and review of the literature. Urology 48: 949 –952, 1996. 11. Lue TF, Hellstrom WJ, McAninch JW, et al: Priapism: a refined approach to diagnosis and treatment. J Urol 136: 104 – 108, 1986. 12. Levine JF, Saenz de Tejada I, Payton TR, et al: Recurrent prolonged erections and priapism as a sequela of priapism: pathophysiology and management. J Urol 145: 764 –767, 1991. 13. Melman A, and Serels S: Priapism. Int J Impot Res 12(suppl 4): S133–S139, 2000. 14. Burnett AL: Pathophysiology of priapism: dysregulatory erection physiology thesis. J Urol 170: 26 –34, 2003. 15. Burnett AL, Chang AG, Crone JK, et al: Noncholinergic penile erection in mice lacking the gene for endothelial nitric oxide synthase. J Androl 23: 92–97, 2002. 16. Champion HC, Bivalacqua TJ, Takimoto E, et al: Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA 102: 1661– 1666, 2005. 17. Burnett AL: Novel nitric oxide signaling mechanisms regulate the erectile response. Int J Impot Res 16(suppl 1): S15–S19, 2004. 18. Andersson KE: Pharmacology of penile erection. Pharmacol Rev 53: 417– 450, 2001. 19. Francis SH, Bessay EP, Kotera J, et al: Phosphorylation of isolated human phosphodiesterase-5 regulatory domain induces an apparent conformational change and increases cGMP binding affinity. J Biol Chem 277: 47581– 47587, 2002. 20. Okada D, and Asakawa S: Allosteric activation of cGMPspecific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002. 21. Corbin JD, Turko IV, Beasley A, et al: Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 267: 2760 –2767, 2000. 22. Rybalkin SD, Rybalkina IG, Feil R, et al: Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem 277: 3310 –3317, 2002. 23. Gopal VK, Francis SH, and Corbin JD: Allosteric sites of phosphodiesterase-5 (PDE5): a potential role in negative feedback regulation of cCMP signaling in corpus cavernosum. Eur J Biochem 268: 3304 –3312, 2001. 24. Turko IV, Ballard SA, Francis SH, et al: Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (type 5) by sildenafil and related compounds. Mol Pharmacol 56: 124 –130, 1999. 1047
25. Kotera J, Francis SH, Grimes KA, et al: Allosteric sites of phosphodiesterase-5 sequester cyclic GMP. Front Biosci 9: 378 –386, 2004. 26. Lin CS, Chow S, Lau A, et al: Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. Int J Impot Res 14: 15–24, 2002. 27. Lin G, Xin ZC, Lue TF, et al: Up and down-regulation of phosphodiesterase-5 as related to tachyphylaxis and priapism. J Urol 170: S15–S18, 2003.
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28. Musicki B, Champion HC, Becker RE, et al: Erection capability is potentiated by long-term sildenafil treatment: role of blood flow-induced endothelial nitric-oxide synthase phosphorylation. Mol Pharmacol 68: 226 –232, 2005. 29. Product Information: Viagra®, Sildenafil Citrate. New York, Pfizer Laboratories, 1998. 30. Bialecki ES, and Bridges KR: Sildenafil relieves priapism in patients with sickle cell disease. Am J Med 113: 252, 2002.
UROLOGY 67 (5), 2006
LONG-TERM ORAL PHOSPHODIESTERASE 5 INHIBITOR THERAPY ALLEVIATES RECURRENT PRIAPISM ARTHUR L. BURNETT, TRINITY J. BIVALACQUA, HUNTER C. CHAMPION,
AND
BILJANA MUSICKI
ABSTRACT Objectives. Recurrent ischemic priapism describes a disorder of repeated episodes of prolonged penile erection that frequently leads to devastating complications of erectile tissue damage and erectile dysfunction. A mechanistic role for dysregulated phosphodiesterase 5 (PDE5) in the deranged smooth muscle response of the corpus cavernosum of the penis offers new understanding about the pathogenesis of the disorder and suggests that PDE5 may serve as a molecular target for its treatment and prevention. We explored the use of PDE5 inhibitors to treat recurrent priapism, based on the hypothesis that the erection regulatory function of PDE5 would be regularized by this treatment and protect against further episodes. Methods. We administered PDE5 inhibitors using a long-term therapeutic regimen to 3 men with sickle cell disease-associated priapism recurrences and 1 man with idiopathic priapism recurrences. Results. Long-term PDE5 inhibitor treatment alleviated priapism recurrences. Conclusions. These observations support the hypothesis that PDE5 dysregulation exerts a pathogenic role for priapism associated with hematologic dyscrasias, as well as idiopathic priapism. Although these preliminary findings suggest that continuous, long-term PDE5 inhibitor therapy may be useful as a preventative strategy for priapism, additional evaluation in the form of a controlled clinical trial is needed. UROLOGY 67: 1043–1048, 2006. © 2006 Elsevier Inc.
P
riapism is an obscure erectile disorder in which prolonged penile erection occurs uncontrollably and often painfully without sexual purpose. It is distinguished from the more familiarly known erectile disorder, erectile dysfunction, which is characterized by the loss of erectile ability and commonly associated with such major comorbidities as cardiovascular disease and diabetes mellitus, as well as older age. However, priapism is an equally important clinical entity that is also associated with complications of erectile dysfunction, and it occurs with substantial frequency in certain populations. It most recognizably afflicts men with sickle cell disease in whom the prevalence rate of priapism exceeds 40%,1–3 and the rate of erectile dysfunction as a sequela from priapism approximates 30%.3
A. L. Burnett is a speaker for Pfizer, Lilly/ICOS, Bayer/GlaxoSmithKline, and Schering. From the Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland Reprint requests: Arthur L. Burnett, M.D., Department of Urology, Johns Hopkins Hospital, 600 North Wolfe Street, Marburg 407, Baltimore, MD 21287-2411. E-mail: [email protected] Submitted: September 9, 2005, accepted (with revisions): November 22, 2005 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED
Priapism is poorly recognized as an important clinical condition. The disorder is fundamentally misunderstood from a pathophysiologic standpoint, and thus effective treatments having a mechanism-specific basis are lacking. For many men experiencing priapism, adverse consequences occur despite the use of available clinical management practices for it. Unresolved major episodes of priapism commonly produce ischemic effects within the penis equivalent to a compartment syndrome of an extremity. The end-stage pathologic features consist of erectile tissue necrosis and genital organ fibrosis, which impedes normal erectile tissue hemodynamic responses. Such complications are even more lamentable considering that they could be preventable. The natural history of priapism commonly involves recurrent short-lived episodes, which frequently herald a subsequent major episode; thus, preventive action taken early in its course may be advantageous. Diverse clinical treatments are currently used for ischemic priapism, including presentations associated with hematologic dyscrasias such as sickle cell disease. Nonsurgical treatments include analgesia, intravenous hydration, oral and intracavernous alpha-adrenergic agonists, gonadotropin-re0090-4295/06/$32.00 doi:10.1016/j.urology.2005.11.045 1043
leasing hormone analogs, antiandrogens, baclofen, and digoxin.4,5 Additional treatments used particularly for patients with sickle cell disease having priapism include red blood cell transfusion, partial exchange transfusion to lower hemoglobin S, and hydroxyurea.4 – 6 Surgical management, commonly instituted for medically refractory episodes, primarily consists of local treatment such as aspiration and irrigation of the corpora cavernosa and, if these are unsuccessful, penile shunt procedures that vent blood from the corpora cavernosa to the corpus spongiosum.4,5 In general, these treatments are devised to produce immediate penile detumescence or oppose presumable pathogenic factors. However, they remain reactive management approaches, frequently failing to achieve these objectives or avert complications of the disorder. The classic tenets of the pathophysiology of ischemic priapism have supported increased intracavernous blood viscosity and venous outflow obstruction of the corpora cavernosa, the main corporal bodies of the penis, as likely major mechanisms.7,8 This belief has long been accepted to explain the association between hematologic dyscrasias, particularly sickle cell disease, and priapism. However, recent clinical observations, including the finding that priapism occurs in hematologic disease states in the absence of corporal veno-occlusion,9,10 have raised questions as to whether the venous congestion hypothesis is too simplistic. Several investigators have conjectured that dysregulatory molecular mechanisms of penile erection may be involved in the pathogenesis of priapism.11–14 Although the underlying pathogenic mechanisms of priapism remain elusive, current basic science progress in the field suggests that priapism in various instances may result from disturbances in the regulatory control of the main molecular pathway mediating penile erection, the nitric oxide-signaling pathway.15,16 This dysregulation specifically involves the reduced expression in the penis of phosphodiesterase-5 (PDE5), which hydrolyzes the pathway’s second messenger molecule cyclic guanosine monophosphate (cGMP).16 This discovery supports the proposal that PDE5 represents a feasible molecular target for developing scientifically cogent, new priapism treatments. We describe new insights into the disease process of priapism and the rationale for PDE5 inhibitor therapy specifically to serve in the management of this disorder. The promise of this therapy is preliminarily demonstrated by its success in treating several patients with recurrent ischemic priapism. MATERIAL AND METHODS In each of the following cases, the management options currently available for recurrent priapism4,5 were initially ap1044
plied unsuccessfully. In acknowledgment of the possibility that these men would progress to have major complications from priapism, the option of using PDE5 inhibitor therapy as an off-label treatment was discussed and used with individual patient consent. An initial treatment approach consisted of the short-acting PDE5 inhibitor sildenafil citrate at a 25-mg oral daily dosage in the morning under conditions of complete penile flaccidity, with subsequent medication adjustments as needed.
RESULTS CASE 1 A 24-year-old man with hemoglobin SS disease had had recurrent priapism for 3 years, worsening during a 6-month interval from sporadic events to an almost daily frequency. Episodes were commonly 3 hours in duration, occurring with nighttime sleep or persisting after sexual activity. Ice packs applied to the penis and analgesic use was of increasingly limited benefit. He started taking sildenafil. His priapism frequency lessened within 1 week, and he experienced only three or four shortlived episodes monthly during the next 3 months. Worried that the continuous use of the medication would eventually impair his natural erections, he discontinued sildenafil. Priapism recurrences returned at the rate of a few episodes weekly, although they were again reduced to rare events within 1 to 2 weeks after resuming the medication. He was subsequently switched to a long-acting PDE5 inhibitor, tadalafil, at a 5-mg oral dosage, taken 3 times weekly, also in the morning. He retained erectile ability and remained sexually active 14 months later. CASE 2 A 37-year-old man with hemoglobin SC disease had had recurrent priapism for 9 months, progressing from sporadic events to episodes recurring three times weekly. A single brief episode had been noted several years earlier. The episodes were commonly 3 hours in duration, occurring with nighttime sleep, although longer episodes on three occasions required penile aspiration and irrigation, despite exchange blood transfusions, intravenous hydration, systemic oxygenation, and analgesic use. A trial of oral baclofen was ineffective in preventing the recurrent episodes. He started taking sildenafil. He had a reduction in his priapism frequency within 2 weeks. With the exception of one subsequent 6-hour priapism episode occurring after an evening use of the medication that required penile aspiration and irrigation, he reported only rare, minor priapism recurrences. He was subsequently switched to tadalafil at a 5-mg oral dosage, taken three times weekly, also in the morning. He retained erectile ability and remained sexually active 9 months later. UROLOGY 67 (5), 2006
CASE 3 A 22-year-old man with hemoglobin SC disease had recurrent priapism for 4 months that had begun as a few episodes monthly, 2 hours in duration, in association with nighttime sleep. Two major episodes several hours in duration occurred, requiring emergency medical treatment. Despite regular and exchange blood transfusions, along with additional hematologic support, penile aspiration and irrigation were required for priapism resolution. A trial of oral terbutaline did not prevent recurrent episodes, and another major episode necessitated penile aspiration and irrigation. He started taking sildenafil. He reported only one minor recurrent priapism episode, and retained erectile ability useful for sexual activity 7 months later. CASE 4 A 22-year-old man with no major health problems had recurrent priapism for 8 months, progressing from a few episodes monthly to daily recurrences up to 5 hours in duration. The episodes were commonly associated with nighttime sleep. A hematologic workup was negative. Oral terbutaline, oral pseudoephedrine hydrochloride, and “nitrate poppers” were ineffective in correcting the problem. A prolonged episode required penile aspiration and irrigation for resolution. He started taking sildenafil, in combination with intracavernosal phenylephrine self-injections for use in the event of an episode of longer than 4 hours. During the next 2 months, the episodes were reduced to six to eight times monthly. Phenylephrine treatment was required three times. He was switched to sildenafil at a 50-mg oral morning dosage, with only occasional recurrent episodes. He retained erectile ability and remained sexually active 5 months later. COMMENT Recent basic science investigation has determined that a mechanism of priapism involves PDE5 downregulation in the penis, resulting from altered signaling of the nitric oxide signaling pathway.15,16 Accordingly, during occasions of neurologically mediated sexual stimulation or sleep-related erectile phenomena, cGMP is generated and exerts an unchecked action because of PDE5 deficiency. Consistent with the physiologic function of cGMP to induce the smooth muscle relaxation in the penis required for penile erection,17,18 the excessive amount of cyclic nucleotide accounts for the prolonged erectile tissue relaxation that manifests as priapism. It is importantly recognized that PDE5 operates under a complex system of regulatory control in smooth muscle cells, in a manner that involves reUROLOGY 67 (5), 2006
ciprocal actions of downstream components of the nitric oxide signaling pathway. These components include cGMP and its effector, cGMP-dependent protein kinase (PKG). Beyond acting as the substrate for degradation within the catalytic domain of PDE5, cGMP influences the activation of the enzyme. The cyclic nucleotide also binds to PDE5 at its allosteric (noncatalytic) domain, or regulatory domain, inducing the enzyme to undergo a conformational change.19,20 This conformational change exposes a phosphorylation site in the regulatory domain of the enzyme, which is phosphorylated by PKG, thereby further enhancing the catalytic activity of PDE5.21,22 However, the conformational change also increases the number of affinity binding sites for the cyclic nucleotide.23 The increased binding of cGMP to PDE5 reduces its availability for activation of PKG. These molecular events, taken together, contribute to feedback inhibition of smooth muscle relaxation. They indicate the existence of a precise regulatory system of “checks and balances,” which controls cGMP signaling. In contrast, the feedback control exerted by cGMP is entirely altered after administration of specific inhibitors of PDE5 catalysis. Although PDE5 inhibitors interact at the catalytic site of PDE5 directly inhibiting cGMP degradation, they stimulate cGMP binding to the allosteric sites of the enzyme without competing directly with the cyclic nucleotide for binding at the allosteric sites.24 In the context of PDE5 catalytic domain binding, these agents block cGMP-elicited negative feedback mechanisms responsible for additional cGMP degradation. They cause cGMP sequestration at the PDE5 regulatory domain, which facilitates the structural binding of PDE5 inhibitors at the enzyme’s catalytic domain. By promoting cGMP-induced allosteric binding of PDE5 and hence its conformational changes, PDE5 inhibitors gain greater access to the catalytic sites of the enzyme and further block its activity.25 Such positive feedback for PDE5 inhibition, exploiting the chemical binding and conformational properties of PDE5, reveals the mechanism by which PDE5 inhibitors used in the treatment of erectile dysfunction achieve maximal erectogenesis. Specifically, although cGMP is generated by nitric oxide signaling in the penis during sexual stimulation, PDE5 inhibitors prevent its degradation directly by blocking the catalytic function of PDE5 and also by blocking negative feedback control mechanisms responsible for additional cGMP degradation. Another positive feedback control mechanism to sustain cGMP signaling is provided by accumulated cGMP binding to allosteric cGMPbinding sites of PKG, thereby protecting the cyclic nucleotide from PDE5 hydrolysis.25 1045
In potentiating endogenous increases in cGMP, PDE5 inhibitors may also exert additional effects influencing PDE5 expression and PDE5 gene regulation. In an analysis of the genetic elements that control the expression of PDE5 isoforms, Lin and associates26 confirmed that three PDE5A isoform mRNAs exist in human penile cavernosum and differ at the 5= end based on their generation from the splicing of three alternative first exons.26 The investigators also showed that these isoforms are preceded by cyclic nucleotide-inducible promoters, as well as adjacent enhancers, which confer additive cyclic nucleotide-inducible responsiveness to the basal promoter.26 In promoter activity assays, the administration of cGMP or cyclic adenosine monophosphate increased PDE5A promoter activity.26 The inducibility of PDE5A promoters by cyclic nucleotides suggests that increased cGMP levels resulting from the use of PDE5 inhibitors may increase the expression of PDE5. Sildenafil administration to rat cavernous smooth muscle cells in vitro leads to PDE5 protein upregulation and such treatment of monkey fibroblast cell line COS-7 cells transfected with plasmid constructs carrying PDE5A promoters in vitro elevates PDE5A promoter activity.27 It is acknowledged that the concentration of sildenafil required in these experiments to produce the effects was high (25 M), which has led to questions regarding the clinical relevance of the findings. However, given the low or absent concentrations of cGMP in the cell culture systems used in these studies, the possibility remains that with sufficient availability of the PDE5 substrate as expected in vivo, PDE5 upregulation could occur at much lower concentrations of the PDE5 inhibitor. In line with the PDE5 downregulatory hypothesis for recurrent priapism, hypoxic conditions that mimic penile ischemia occurring during priapism cause PDE5 downregulation in cultured cavernous smooth muscle cells.27 To evaluate the possibility of PDE5 upregulation in vivo, Musicki and associates28 studied the effects of sildenafil administration to rats at therapeutic dosing levels on both PDE5 protein expression and activity in penes and erection physiology. In young adult rats treated with sildenafil for 3 weeks with a dosing schedule equivalent to a man taking sildenafil citrate at the standard maximal 100 mg dose daily for 2 years, PDE5 expression in penes was elevated to a similar extent as shown in previous in vitro studies.26 The findings suggested that longterm PDE5 inhibitor therapy in vivo causes prolonged accumulation of cGMP that acts sufficiently on the promoter region of PDE5 to induce its upregulation. However, such treatment does not alter PDE5 catalytic activity in penes or result in therapeutic resistance, because the animals preserved 1046
functional erectile responses to PDE5 inhibitor treatment.28 These series of investigations provided direct support for the use of PDE5 inhibitors to treat priapism clinically. The suggestion does seem counterintuitive and opposes earlier cautions against such use in patients who have conditions predisposing them to priapism such as sickle cell disease.29 However, we hypothesized that continuous, long-term, low-dose PDE5 inhibitor treatment may achieve a normative (although reversible) resetting of PDE5 expression in penile tissue, which would control the excessive cGMP signaling associated with priapism. We further hypothesized that the treatment would not necessarily impair voluntary sexually stimulated erections, because a sufficient intrapenile release of cGMP would occur in these situations to temporarily overcome the normalized PDE5 regulation. In essence, we postulated that PDE5 inhibitor treatment in patients with recurrent ischemic priapism would restore a normal balance of regulatory factors involved in the erectile response. In addition to the biologic coherence supporting its application, the clinical results showed consistency, dose specificity, and a temporal relationship. Efficacy was shown for long-term, low-dose PDE5 inhibitor therapy in each of these cases. For the fourth index case in which priapism had developed to an apparently more severe extent, dose elevation was necessary to achieve alleviation of the disorder. The temporal sequence in our first index case was quite dramatic. In that case, after cessation of therapy, priapism recurred; reinstitution of therapy again alleviated his priapism. The salubrious effects have been durable because the resolution of the priapism has continued for these patients at extended intervals of follow-up. In all 4 cases, erectile capability sufficient for sexual activity was preserved. Several practical matters deserve brief discussion. Our treatment approach began initially with morning treatment using a short-acting PDE5 inhibitor such as sildenafil, which has a 4-hour halflife and an expected elimination of more than 80% within 12 hours after administration.29 Our intent was to reduce the risk that the drug would be present to any sufficient extent in the body during nighttime sleep and thereby promote the conversion of a sleep-related erection into a priapism episode. The major priapism episode occurred in our second index case during sildenafil use and may have resulted from its inadvised use. The patient admitted taking the medication preceding this event in the evening with sexual stimulation. However, we found that conveniently useful, long-acting PDE5 inhibitors could readily be used over time, judging their safety to have been met after UROLOGY 67 (5), 2006
intrapenile PDE5 expression levels conceivably had normalized. We also used a sympathomimetic agent as needed by intracavernosal delivery in our fourth index case. That patient’s recurrences were so severe that this treatment was temporarily necessary for erectolysis while awaiting the effects of our therapeutic strategy. This observation revealed the delayed therapeutic role of PDE5 inhibitor therapy for priapism and suggests that a direct PDE5 activator or agonist targeting PDE5-binding sites would be advantageous for early control of recurrent priapism. In a data search, we learned of a previously published letter describing the surprisingly complete resolution of major painful priapism episodes in 3 patients with sickle cell disease after single, acute oral administration of the PDE5 inhibitor sildenafil citrate at a 50-mg dose.30 Also in that report, the repeated use of the medication as an “on-demand” intervention at the onset of subsequent painful erections in these patients successfully alleviated the pain and curtailed the development of any further major episodes. The investigators speculated that the medication caused selective vasodilation in the corpus cavernosum, possibly promoting the egress of anoxic, sickled red cells from the organ. Our experience with the presentations of priapism suggests that PDE5 inhibitor therapy is unlikely to have efficacy in the face of a major priapism episode, for which conventional local treatments are routinely necessary to produce immediate penile detumescence. CONCLUSIONS These findings suggest that PDE5 offers a molecular target for the therapeutic management of priapism. PDE5 inhibitor therapy used as a long-term preventative strategy to control the disorder may offer a clinical advance because therapies for priapism remain mostly reactive or otherwise fail to preserve normal erectile function. Whether PDE5 inhibitor therapy is useful to treat recurrent priapism in other contexts such as that associated with neurogenic conditions awaits additional study. Further evaluation in the form of a controlled clinical trial is required. REFERENCES 1. Emond AM, Holman R, Hayes RJ, et al: Priapism and impotence in homozygous sickle cell disease. Arch Intern Med 140: 1434 –1437, 1980. 2. Fowler JE Jr, Koshy M, Strub M, et al: Priapism associated with the sickle cell hemoglobinopathies: prevalence, natural history and sequelae. J Urol 145: 65– 68, 1991. 3. Adeyoju AB, Olujohungbe AB, Morris J, et al: Priapism in sickle-cell disease: incidence, risk factors and complications—an international multicentre study. BJU Int 90: 898 – 902, 2002. UROLOGY 67 (5), 2006
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25. Kotera J, Francis SH, Grimes KA, et al: Allosteric sites of phosphodiesterase-5 sequester cyclic GMP. Front Biosci 9: 378 –386, 2004. 26. Lin CS, Chow S, Lau A, et al: Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. Int J Impot Res 14: 15–24, 2002. 27. Lin G, Xin ZC, Lue TF, et al: Up and down-regulation of phosphodiesterase-5 as related to tachyphylaxis and priapism. J Urol 170: S15–S18, 2003.
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28. Musicki B, Champion HC, Becker RE, et al: Erection capability is potentiated by long-term sildenafil treatment: role of blood flow-induced endothelial nitric-oxide synthase phosphorylation. Mol Pharmacol 68: 226 –232, 2005. 29. Product Information: Viagra®, Sildenafil Citrate. New York, Pfizer Laboratories, 1998. 30. Bialecki ES, and Bridges KR: Sildenafil relieves priapism in patients with sickle cell disease. Am J Med 113: 252, 2002.
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