The Case Report of Priapus and a Modern Approach to an Ancient Affliction

The Case Report of Priapus and a Modern Approach to an Ancient Affliction Ömer Barıs¸ Yücel, MD, Emre Salabas¸, MD, Bahadır Ermeç, MD, and Ates¸ Kadıo glu, MD

ABSTRACT

Introduction: Priapism, taking its name from God Priapus, is total or partial erection lasting longer than 4 hours independent of sexual stimulus and can result in erectile dysfunction. There are three subtypes of priapism. Aim: To review the three subtypes of priapism, their pathophysiology, current treatment options, and complications. Methods: The literature including priapism guidelines, review articles, and current trial studies was reviewed and the priapism type of God Priapus was investigated according to the mythology. Main Outcome Measures: All three types of priapism were reviewed for etiology, diagnosis, and management. Medical and surgical treatment options were reviewed in relation to the current literature. Special emphasis concerned current treatment strategies and controversial surgical topics. Results: Ischemic priapism is the most common type, constituting 95% of all cases, and is an emergency. First-line treatments are blood aspiration and intracavernosal sympathomimetic drug injections. If these fail, then surgical shunt operations are recommended. A T-shunt combined with corporal tunneling is the currently popular option. Immediate penile prosthesis implantation is recommended for patients who present 48 to 72 hours after the onset of a priapism episode. High-flow priapism is caused by irregular arterial cavernosal blood flow, which usually occurs after a blunt perineal trauma. Antiandrogens and selective arterial embolization are the treatment options. Stuttering priapism is repetitive, self-limiting ischemic priapism and frequent in patients with sickle cell anemia. Ketoconazole is safe, cheap, and effective and appears to be a logical and suitable current treatment option to prevent further episodes, which is the primary treatment goal of stuttering priapism. Conclusion: Priapism is a relatively common condition but not well known by clinicians. The lack and delay of treatment result in irreversible complications such as erectile dysfunction. Each type of priapism should be diagnosed and treated correctly with caution. Sex Med Rev 2016;-:1e9. Copyright
2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Key Words: Priapism; Erectile Dysfunction; Treatment

INTRODUCTION In Greek mythology, Priapus (Ancient Greek, Prίapo2) was a minor rustic fertility god who was the protector of livestock, fruit plants, gardens, and male genitalia. The garden gnome in modern folklore might have originated from the description of Priapus. His permanently erect phallus was the only weapon for this lustful gnome. The mythology of Priapus originates in Lampsacus (currently Lapseki; Dardenelles, Çanakkale, Turkey). He was described as Received April 12, 2016. Accepted August 17, 2016. Department of Urology, Faculty of Medicine, Istanbul University, Istanbul, Turkey Copyright ª 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.sxmr.2016.08.003

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the son of Aphrodite and possibly Hermes, Zeus, or even Dionysus; his parents change concurrently with the origins of this mythic hero. Hera cursed him with ugliness, perversity, and impotence when he was in the womb of the beautiful Aphrodite owing to her jealousy, which was because of her rivalry against Aphrodite in the beauty contest of Paris or the infidelity of Zeus with Aphrodite. Priapus was born with a huge belly, huge feet, hands, nose, tongue, and a gigantic, continuously erect phallus.1 The etymologic explanations of priapism and priapic are “persistent erection of the penis” and “phallic,” so the origin of the current medical term priapism is likely based on this character. The legend of Priapus, starting from Lampsacus in Anatolia, traveling in time and distance to the Italian region of Rome and then to the Christian lands of Europe, might be exaggerated and implausible but probably is based on a real man. This legendary 1

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man in all probability became a paradoxical symbol of impotence and potency and erection. However, what type priapism did Priapus have? He had a macropenis that was rumored to be erect at all times. What if we could travel back in time to the lands of ancient Anatolia for diagnosis and treatment of the unfortunate Priapus? However, before disclosing the mysterious nature of Priapus’ disease, we should ascertain the current understanding of priapism and advances in its treatment.2,3 Priapism is defined as a full or partial erection lasting longer than 4 hours after sexual stimulation and orgasm or is unrelated to sexual stimulation.5 Although the condition is a rare male genital emergency, with an incidence rate of 1.5 to 5.34 per 100,000 person-years, the irreversible nature of untreated priapism requires urgent identification and treatment.4e6 Burnett et al7 prepared a novel questionnaire for patients with priapism (Priapism Impact Profile Questionnaire) and demonstrated that the condition has a negative impact on patients’ sexual life, physical wellness, and quality of life. These effects worsen in patients with episodes longer than 2 hours, active priapism episodes, and all degrees of erectile dysfunction (ED). Priapism is categorized into three subgroups: ischemic priapism (veno-occlusive, low flow), stuttering priapism (intermittent), and non-ischemic priapism (high flow, arterial).

DID PRIAPUS HAVE ISCHEMIC PRIAPISM? If Priapus had ischemic priapism (veno-occlusive, low flow), he would present with a persistent erection accompanied by rigid and painful corpora cavernosa and decreased cavernous arterial inflow on penile Doppler imaging. Hypoxia, hypercarbia, and acidosis would be the metabolic signs from his blood gas analysis. Prolonged hypoxia and hypercarbia are the major causes of irreversible changes in the corporal smooth muscle (CSM), as shown in animal studies.8 Histologic examination of the corporal tissue shows interstitial edema by 12 hours and destruction of endothelium and platelet adherence at 24 hours. At 48 hours, muscle cell necrosis and fibroblast-like cells can be observed and thrombi can be found in the sinusoidal cavities.9 This histologic necrotic progress has been confirmed by intra-shunt biopsy examinations, with the initiation of extensive necrosis (>50% tissue necrosis) at 12 hours and complete extensive necrosis as an end result at the end of 48 hours.10

ETIOLOGY If Priapus had ischemic priapism, then what might be its etiology? Although ischemic priapism constitutes 95% of all priapism cases and most are idiopathic, various etiologies have been identified with advancing technology: drug-induced or hematologic (sickle cell disease [SCD], glucose-6-phosphate dehydrogenase, hereditary spherocytosis, thalassemia and other hemoglobinopathies are usually seen), thrombophilia states (protein C and other forms of thrombophilia, lupus), hyperviscosity (hyperleukocytosis, polycythemia), and central nervous system disorders. Additional

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factors such as hormones (gonadotropin-releasing hormone, testosterone), recreational substances (cocaine, marijuana), infectious diseases (scorpion and spider bite, malaria), metabolic diseases (amyloidosis, Fabry disease, gout), anxiety disorders (general anxiety disorder, obsessive-compulsive disorder, panic disorder), and anesthesia (general or regional) have been reported causes of priapism.11,12 Intracavernosal injection (ICI) for diagnosis and treatment results in priapism in 5.3% and 0.4% of patients, respectively.14 Although the incidence of reported priapism ranges from 0.25% to 36%, papaverine and phentolamine and/or alprostadil ICI programs, usage of a bi-mix or tri-mix injection regime, and careful postinjection follow-up seem to limit the incidence rate to 0.5%.4,13,15,16 The prevalence of the sickle cell anemia trait is 0.5% in Turkey, the home of Priapus.17 The lifetime probability of a man with SCD developing priapism is 27% to 42%, although a lifetime expectancy rate of priapism episodes of 89% was reported in one study.18e20 In addition, the prevalences of SCD in adult and pediatric priapism cases were 23% and 63%, respectively.21 Although 34% of children with SCD had priapism episodes, the ischemic and stuttering types constituted 21% and 79% of these episodes, respectively.22 Is it a coincidence that the legend of Priapus originates from the land where there is a high incidence rate of SCD, a major cause of priapism? Priapus had probably an SCD. Another question is how SCD would cause priapism in Priapus. An early explanation of SCD and priapism was the sludging of deformed erythrocytes in the cavernosal sinusoids, thereby inhibiting venous outflow, and further erythrocyte deformity caused by cavernosal hypoxia, acidosis, and paralysis of CSMs.23 The pathophysiology of this disease recently has been explored, with the postulation that vascular occlusion and tissue ischemia combined with chronic hemolysis of erythrocytes result in the conversion of active nitric oxide (NO) into nitrate, the oxidized inert state of NO, and methemoglobin and of arginine, a NO synthesis substrate, into ornithine and free oxygen radicals. Overall, these effects result in decreased NO bioavailability, that is, hemolysis-associated endothelial dysfunction.24,25 How would we diagnose the dwarf god in a modern clinic? In addition to routine anamnesis, physical examination, laboratory and radiologic tests, assessment of hematologic abnormalities, plasma toxicology, and blood gas analyses would be performed. His physical examination would show rigid cavernosal bodies that would be painful during palpation. A blood count would be required for his SCD diagnosis. Hypoxia (pO2 < 30 mm Hg), hypercapnia (pCO2 > 60 mm Hg), and acidosis (pH < 7.25) in corporal blood gas analysis are typical for ischemic priapism. Penile Doppler ultrasonography is a complementary test of blood gas analysis and can diagnose 70% of all cases.26e28 Magnetic resonance imaging (MRI) can depict necrosis in the CSM with 100% sensitivity for preoperative assessment in patients who plan to undergo shunt or penile prosthesis implantation (PPI).29,30 Sex Med Rev 2016;-:1e9

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Priapus and a Modern Approach to an Ancient Affliction

CONSERVATIVE TREATMENT FOR PRIAPUS Ejaculation, ice packs, cold baths, and cold water enemas might have been fundamental in the ancient era of Priapus but they have been replaced by modern medicine. In the only prospective trial investigating 369 patients who had quadri-mix ICI for penile Doppler imaging, 52 patients (14.4%) had a prolonged erection and detumescence was achieved only with physical exercise in 21 patients (39.6%) after 30 minutes. Of the remaining 32 patients, salbutamol reversed the erection in 18 (34%) after 60 minutes and 26% required aspiration and/or phenylephrine injection. However, this study lacked a control group and its findings were not sufficient to change the current perspective.31 The recommended first-line treatment of ischemic priapism is decompression of the corpora cavernosa by corporal aspiration followed by ICI of a sympathomimetic agent. Before aspiration, antibiotic prophylaxis and local penile shaft block can be offered.32 The resolution rates are 36% and 43% to 81% for aspiration and aspiration plus phenylephrine injection, respectively.4 Phenylephrine, a potent a-adrenergic agonist, is recommended because of its low b-receptor selectivity and low cardiovascular side effects.15 The dosage of phenylephrine treatment is 100 to 500 mg/mL applied with 1-mL doses with 3- to 5-minute intervals to maximum of 1 mg. Serial monitoring of blood pressure and pulse should accompany the injection because of side effects such as headache, dizziness, hypertension, cardiac arrhythmia, and even subarachnoid hemorrhage. High-dose phenylephrine has no benefit in the management of ischemic priapism. The effectiveness of current medical treatment of ischemic priapism depends on reversing the negative contractile effects of hypoxia, acidosis, and glucopenia on cavernosal smooth muscle by draining the ischemic blood and stimulating the CSM with a sympathomimetic agent. The classic treatments of SCD, such as analgesics, hydration, oxygen, bicarbonate, and blood transfusion, also should be considered when SCD accompanies priapism. In an in vitro animal model,33 putative agents such as N-acetylcysteine, BayK 8644, glutathione, digoxin, calcium, and L-NG-nitro-arginine methyl ester failed to reverse the ischemic changes of smooth muscle. The damaging effects of oxidative agents released during reperfusion of the corporal tissue could not be prevented by antioxidants in this study.34 Hydroxyurea therapy for SCD was shown to be effective at reversing the organ damage (ED) in sporadic adult priapism cases and supported the NO-dependent pathway in the pathogenesis of SCD-induced priapism.35

enclosed blood in cavernosal sinusoids to the glans (distal shunts) or the corpus spongiosum or veins (proximal shuns). They are recommended when medical treatments have failed for 1 hour or when medical treatments are contraindicated (malignant or uncontrolled hypertension, use of monoamine oxidase inhibitors). A literaturesupported discussion with the patient about the potential ED caused by priapism is essential to prepare the patient for surgery and prevent medicolegal issues. Distal shunts are preferred over proximal shunts as initial surgical treatment because of similar success and lower complication rates, but the procedure chosen is determined by the surgeons’ preference and experience. Complications such as ED, infection, urethro-cavernous fistulas, cavernositis, and urethral strictures can have drastic effects on patients.4,32 The 2010 International Consultation on Sexual Medicine Priapism Guidelines made the following recommendations4: 1. Distal shunts a. Percutaneous distal shunts: Winter, Ebbehoj, T-shunt b. Open distal shunts: Al-Ghorab, Burnett 2. Proximal shunts: Quackles, Sacher 3. Vein anastomoses: Grayhack, Barry37 The concept of shunting and management of low-flow priapism changed with the introduction of the T-shunt procedure to the literature. The T-shunt is a modification of the Ebbehoj procedure with a number 10 blade fully penetrating the cavernosum and staying 4 mm and rotating 90
away from the urethra under local or general anesthesia. If detumescence does not occur within 10 to 15 minutes (or 48 hours after ischemic priapism), the procedure is repeated for the other side. If the detumescence still does not occur, corporal tunneling with a 20- to 24-Fr urethral dilator or corporal snake maneuver with 7/8 Hegar dilators is performed. For priapism longer than 48 to 72 hours’ duration, bilateral T-shunts followed by corporal tunneling should be performed.38 The T-shunt technique combines proximal and distal shunting and it drains the sludged blood from the cavernosa superiorly with its wide area of incision.39 Some researchers have recommended perioperative anticoagulation for the prevention of premature shunt obstruction; the regimen includes subcutaneous heparin 5,000 units, aspirin 325 mg orally preoperatively, and aspirin 81 mg/d for 2 weeks.40

Timing of Shunting

European Association of Urology guidelines define the resolution of priapism as maintaining the flaccid state for longer than 24 hours and the recurrence of priapism as repetitive erections after this period.36

The success of treatment is resolution of priapism and preservation of erectile function, which depend on the duration of priapism. When the duration of priapism is shorter than 24 hours, potency can be preserved in 92% of men. For priapism episodes longer than 48 hours, the procedure is less reliable and can result in ED from smooth muscle necrosis.10 According to current guidelines, shunting for episodes longer than 72 hours is not recommended and the 48- to 72-hour time span is a surgeon’s preference.

SHUNTING

WHEN TO IMPLANT A PENILE PROSTHESIS

Surgical intervention starts with shunt operations. The mechanism of shunt surgery is the establishment of a pathway for

Patients with priapism, when irreversible and protracted, can be offered early prosthesis implantation to preserve erectile

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function and penile size.16 Immediate PPI might be suggested because of high ED rates of priapism episodes longer than 48 to 72 hours, but the possible complications of infection, mechanical malfunction, urethra injury, and device malfunction should be discussed with the patient. This operation is a solution for penile shortening after priapism, technical challenges in the insertion of the prosthesis into the fibrotic tissue, and a relenting priapism episode. Infection, mechanical failure, erosion, and revision surgery rates are lower when the surgery is performed within first 6 weeks (early surgery). Establishing CSM necrosis with MRI or intraoperative biopsy examination is recommended. In a study of 68 patients, 64 malleable and 4 inflatable implants were implanted within a median of 7 days from the onset of priapism. Overall satisfaction and infection rates were 96% and 6%, respectively. Twenty-seven patients underwent delayed implantation, and 80% of all patients required a second corporotomy and downsized cylinders because of dense fibrosis. Patient satisfaction decreased to 60% because of shortened penile length. Seven patients (26%) required revision surgery because of infection, erosion, or mechanical failure.41,42 The need for sharp dissection of fibrotic tissue and even excision has been reported from other studies including one with 17 patients with priapism who underwent surgery after 6 to 18 months.43 The concern for distal erosion was investigated in a study of 15 patients with priapism who underwent early PPI. A malleable prosthesis was fixed to the tunica albuginea at the site of the corporotomies by non-absorbable sutures and no infection or migration was observed at 15-month follow-up.16,44 PPI is recommended for patients who are at high risk of new priapism episodes or have ED after resolved priapism caused by shunt treatment or long-lasting priapism. Owing to fibrosis and penile shortening after priapism episodes, the surgery could be challenging and a narrow prosthesis might be used.

Malleable or Inflatable Prosthesis The concern for infection and potential erosion of the prosthesis after a shunt procedure steer the choice toward a malleable prosthesis. In addition, a downsized cylinder might be implanted owing to dilatation difficulty of the fibrotic tissue. In a study from London, 64 of 68 patients received a successful malleable penile prosthesis. In the subsequent study of 10 patients who had an inflatable prosthesis upgrade 3 months later, the satisfaction rate increased from 80% to 90%. In addition, prosthesis cylinder length increased by a mean of 1.6 cm in patients with prior shunting (n ¼ 5) and 1 cm (1e3) in the remaining patients (n ¼ 5) after this secondary surgery. Its noteworthy that 21 patients refused the PPI upgrade because they were satisfied with the malleable prosthesis.41,42 In another study of 14 early PPIs (mean ¼ 82 hours), infection, urethral erosion, and distal extrusion rates each were 7%. This group also advocated for the early usage of the malleable penile prosthesis with long corporotomies and downsized length to prevent distal extrusion. In addition, a substantial benefit to

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the medical cost was achieved by preventing repetitious hospitalization, aspiration, and shunting.15,45 Priapus’ priapism could not be ischemic, because ED or fibrotic penis would not suit his divinity.

DID PRIAPUS HAVE NON-ISCHEMIC PRIAPISM? Non-ischemic (high-flow, arterial priapism) is a persistent erection caused by unregulated cavernous arterial inflow and is seen in fewer than 5% of all priapism cases. Despite corporal tumescence, the penis is neither rigid nor painful. It is usually associated with a blunt penile trauma within the previous 2 to 3 weeks leading to injury of the cavernous artery and a high-flow fistula between the cavernosal artery and the lacunar areas in the sinusoidal space. In addition to perineal blunt trauma, other arterial injuries such as arterial aneurysm, arteriovenous fistula, and iatrogenic needle injury can cause high-flow priapism.4,32,46 Uncontrolled penile tumescence occurs from unregulated blood flow directly from the cavernosal artery instead of the helicine artery. Full rigidity can occur under sexual stimulation, but then the penis returns to its previous state. High-flow priapism also has been observed in patient with SCD but no injury. Therefore, there might be an unidentified association between hematologic disorders and hyperemic status.47 High-flow priapism might be observed in penile metastasis, spinal cord injury, and after Nesbit plication, internal urethrotomy or shunt operations, and ICIs.47e53 Perineal trauma in anamnesis and a painless semirigid erection during physical examination are typical. Cavernosal blood gas values do not show hypoxia, hypercapnia, or acidosis. Penile Doppler ultrasonography should be performed to show increased cavernosal blood flow when high-flow priapism is suspected. Although pudendal angiography can show arterial injury and fistula, it is preferred when embolization is planned, because of its invasiveness.4 MRI is not used for the diagnosis of arterial priapism.36 Emergency treatment is not required, because there is no penile ischemia and erectile function is preserved even after several episodes of non-ischemic priapism. However, in vitro studies have shown that long exposure to oxygen induces fibrosis in CMSs and can cause ED.54 Observation, perineal pressure application, and ice compression are conservative treatment options and spontaneous resolution of the priapism and closure of the fistula can occur in two of three cases. Especially in children, first-line management should be clinical surveillance.4 Zacharakis et al55 recommended close clinical follow-up with reimaging using penile Doppler imaging or penile MRI. For distal smooth muscle fibrosis or the development of distal flaccidity, superselective embolization is recommended to prevent long-term ED. Monthly leuprolide injections and adjunct treatments of bicalutamide and ketoconazole (KTZ) were successful in six of seven patients. The reported side effects were loss of libido, hot Sex Med Rev 2016;-:1e9

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flushes, fatigue, and ED, but no residual ED after treatment withdrawal was reported.56 Low-dose KTZ (200 mg/d) lowers testosterone levels to a point below which nocturnal penile erections are inhibited. Because continuous engorgement of the penis and thus the cavernosal artery is inhibited, thrombosis can occur in the fistula tract. When the fistula closes, high-flow priapism is prevented.57 Selective arterial embolization with permanent or nonpermanent materials is another treatment option and has a success rate of 89%, a recurrence rate of 40%, and an ED rate of 5% to 39%. Penile gangrene, gluteal ischemia, cavernositis, and perineal abscess formation are other possible complications.36,58,59 Permanent (eg, coils, acrylic glue, ethanol) and non-permanent (eg, autologous blood clot, absorbable gels) materials can be used to close the fistula, but non-permanent materials cause lysis over time and are associated with a lower incidence of subsequent ED.60 In a study of superselective autologous blood embolization (n ¼ 11), the reported success rate was 100%, the recurrence rate was 27%, and the ED rate was 0%.59 Penile Doppler ultrasonography should be performed 1 to 2 weeks after embolization; for recurrence, the procedure could be repeated. Selective surgical ligation of the fistula should be the last treatment option.36 A novel technique of percutaneous direct puncture embolization of a post-traumatic cavernosal arteriovenous fistula using N-butylcyanoacrylate was reported and erectile function was preserved at 1-year follow-up. This technique was proposed as a second-line alternative when primary embolization failed.20 Priapus’ priapism could not be non-ischemic because he could not have been divine without a fully rigid penis.

DID PRIAPUS HAVE STUTTERING PRIAPISM? Hinman61 was the first to recognize the pattern of “acute transitory attacks” as distinct from persistent, or rapid, recurrence of a single episode of priapism. Emond et al18 named this phenomena stuttering priapism from their observations of patients with SCD. Stuttering (recurrent, intermittent) priapism is a unique type of priapism in which patients have recurrent painful and prolonged erections that are short-lived and self-limiting in contrast to ischemic priapism. These episodes usually last shorter than 4 hours and typically occur more often after puberty. This type of priapism is generally associated with SCD and the pathologic mechanism and new treatments of stuttering priapism are being investigated. In earlier studies, the lifetime probability of developing priapism as a result of SCD was reported to be 29% to 42%.18,62 Nelson and Winter21 and Winter63 stated SCD was the cause of priapism in 29% of adult patients and 63% of pediatric patients. Adeyoju et al19 reported 35% of patients with SCD had a prior priapism episode and 72% of these attacks were stuttering. Even in the stuttering group, SCD had a profound effect on ED rate and episode duration. In a study of Sex Med Rev 2016;-:1e9

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59 patients with stuttering priapism, the ED rate was 47.5% for those with SCD vs 21.1% for those without SCD. The mean duration of stuttering priapism in SCD was statistically longer. The ED odds ratio for SCD was 4.7 in logistic regression analysis.64 The first pathophysiologic explanation of priapism was reported by Hinman61 who described it as the inhibition of venous outflow as a result of deformed erythrocytes blocking the cavernosal sinusoids of the penis. Subsequently, it was postulated that the hypoxia and acidosis induced by blood stasis in the corpora further advanced the erythrocyte deformity, thus causing a negative cycle. Cavernosal smooth muscles were paralyzed by hypoxia and acidosis and could not contract to achieve detumescence.65 The contractile disability of the CSM is explained by the decreased response to a-adrenergic stimulation, which is the end result of apoptosis, fibrosis, and necrosis. Impairment of adrenoreceptors of the corpora and disruption of the neurologically and endothelially mediated mechanisms maintaining detumescence also have been suggested as possible causes of priapism.66 Knowledge on the mechanism of priapism has been advanced by in vitro and in vivo animal models. Penile injury from reactive oxygen species, indicated by lipid peroxidation and hemo-oxygenase expression, occur during hypoxic priapism episodes.67,68 Transforming growth factor-b, a cytokine for tissue repair, is upregulated in hypoxic conditions and could be involved in fibrosis after priapism episodes.69 Endothelial cells in the penis are a source for adenosine and NO (vasodilation factors) and RhoA/Rho-kinase (vasoconstrictive factor). Mutant mice without endothelial NO synthase (eNOS/), an animal model that mimics endothelial NO production deficiency, lack the basal NO production induced by endothelial cells and cyclic guanosine monophosphate (cGMP) levels decrease in the absence of NO stimulation. Phosphodiesterase type 5 (PDE-5) is normally under positive feedback control of cGMP by transcription of the PDE-5 promoter gene and allosteric binding of cGMP and protein kinase G to PDE-5. The promoter site for PDE-5 was reported to be responsive cGMP in animal models. In eNOS/ mice, penile PDE-5 levels decrease as a result of decreased cGMP.70 When neuronal NO synthase levels increase during sexual stimulation or nocturnal erections, there is an extreme cGMP augmentation without a controlling mechanism because of insufficient levels of PDE-5. Higher cGMP levels in addition to the absent vasoconstrictive effect of the RhoA/Rho-kinase system leads to uncontrolled vasodilation of CMSs (ie, priapism). This entire cascade of events is called PDE-5 dysregulation and is the foundation of daily PDE-5 inhibitor treatment for stuttering priapism.71,72 The eNOS knockout mice mimic patients with SCD and stuttering priapism. PDE-5 expression is significantly decreased in corpora smooth muscle cells cultivated in hypoxic conditions. After the initial episode of priapism, a type of compartment syndrome occurs with hypoxic blood in the corpora, in addition to destruction of the vascular endothelium, thus decreasing

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endothelial NO activity, basal cGMP level, and the PDE-5 enzyme. These mechanisms, endothelial NO release deficiency and PDE-5 dysregulation, might explain the greater probability of ischemic priapism in patients with SCD or stuttering priapism.

vomiting (50%), skin rash, fatigue, gynecomastia, nail dystrophy, QT prolongation, and hepatotoxicity (<1%) are expected side effects and liver function tests should be performed during therapy. KTZ is an inexpensive, safe, and effective treatment option for stuttering priapism.

The treatment of an acute episode is similar to that for ischemic priapism and the primary goal of managing stuttering priapism is the prevention of further episodes.

CONCLUSION

In a study of recurrent priapism, seven patients were treated with daily PDE-5 inhibitors and the frequency of priapism decreased in six patients. Three patients with idiopathic priapism did not have subsequent episodes after 3 to 8 months of sildenafil 50 mg treatment. Although the other three patients with SCD responded to treatment, the priapism recurred after the discontinuation of 24 months of therapy. The nonresponder returned to his prior flutamide treatment despite its severe side effects.73,74 In a recent double-blinded, randomized, placebo-controlled study, sildenafil usage failed to reach statistical significance during the blinded phase but an episode prevention rate up to 67% was achieved in the open phase of this study.75 Other treatment options for stuttering priapism are oral and injectable a-adrenergic agonists; terbutaline and digoxin; the SCD drug hydroxycarbamide; drugs affecting the androgenic system such as estrogens, gonadotropin-releasing hormone analogs, and antiandrogens; and neurotransmission modifier drugs such as baclofen and gabapentin. Daily oral etilefrine treatment has 72% and 50% success rates in decreasing and completely resolving priapism episodes, respectively.76 In another study, the success rate of etilefrine in adults was only 50% despite complete remission of priapism in children treated with etilefrine.77 Phenylephrine, metaraminol, ephedrine, and pseudoephedrine are other sympathomimetic drugs studied for the treatment of stuttering priapism. Etilefrine and ephedrine had similar but statistically insignificant effects on recurrent priapism.78 The role of hormonal therapy in stuttering priapism is androgen suppression by targeting pituitary glands (gonadotropin-releasing hormone agonists), blocking androgen receptors (antiandrogens), and decreasing adrenal and testicular synthesis (KTZ). KTZ is an oral antifungal medication and high-dose KTZ (400 mg three times daily combined with prednisone 5 mg) is used for hormone-refractory prostate cancer treatment. Low-dose KTZ treatment (200 mg three times daily combined with prednisone 5 mg for 2 weeks and then 200 mg nightly without prednisone) suppresses testosterone levels and nocturnal erections and is recommended for the medical treatment of stuttering priapism. In two studies, KTZ was successful in resolving priapic episodes without any sexual side effects in 100% of patients, and 78.6% of patients had partial or complete resolution of symptoms persisting after the therapy was discontinued.79 Nausea,

It is speculated that Priapus had a huge penis. A “macropenis” could be defined as more than 2.5 SD above the mean (0.14% of the male population). According to the findings of a recent systematic review, the stretched length of a macropenis should be longer than 18 cm.80 Priapus most likely had stuttering priapism accompanying sickle cell anemia, a disease common in his birthplace (0.5%). Although frequent recurrent episodes must have been painful for him, they would have allowed him to keep his erectile function intact. With his rigid mega-penis, Priapus only could have had stuttering priapism and he probably would have benefited from the modern and still developing treatment modalities. The prevalence of dwarfism is approximately 750 per million people.81 As stated earlier, the prevalence of sickle cell anemia in Anatolia is 0.5%. The lifetime probability of having priapism is approximately 30% for patients with sickle cell anemia. Therefore, the probability of a god such as Priapus with stuttering priapism and a macropenis in Anatolia is approximately 16 per 100 million. Corresponding Author: Ates¸ Kadıoglu, MD, Urology Department, Andrology Division, Faculty of Medicine, Istanbul University, Çapa, Istanbul, Turkey; E-mail: kadiogluates@ ttmail.com Conflicts of Interest: The authors report no conflicts of interest. Funding: None.

STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Ömer Barıs¸ Yücel; Emre Salabas¸; Bahadır Ermeç; Ates¸ Kadıo glu (b) Acquisition of Data Ömer Barıs¸ Yücel; Emre Salabas¸; Bahadır Ermeç (c) Analysis and Interpretation of Data Ömer Barıs¸ Yücel; Emre Salabas¸; Ates¸ Kadıo glu Category 2 (a) Drafting the Article Ömer Barıs¸ Yücel; Emre Salabas¸; Bahadır Ermeç; Ates¸ Kadıo glu (b) Revising It for Intellectual Content Ömer Barıs¸ Yücel; Emre Salabas¸; Ates¸ Kadıo glu Category 3 (a) Final Approval of the Completed Article Ömer Barıs¸ Yücel; Emre Salabas¸; Bahadır Ermeç; Ates¸ Kadıo glu

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