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Background: Patients with sickle cell disease (SCD) experience intravascular hemolysis, leading to elevated plasma heme levels. This phenomenon has been associated with increased priapism in men with SCD. The heme group can be metabolized by heme oxygenase (HO), generating carbon monoxide (CO), which is known to promote smooth muscle relaxation via soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP). However, the effects of heme on the relaxation responses of corpus cavernosum (CC) have not been investigated., Objectives: To evaluate the functional and biochemical effects of the heme group on mouse CC smooth muscle in vitro., Materials and Methods: Male C57BL/6 mice were used. CC tissues were mounted in organ baths. Measurement of cGMP in mice CC was evaluated., Results: The cumulative addition of heme concentrations promoted the relaxation of CC. HO inhibitor (1J, 100 μM) or sGC inhibitor (ODQ, 10 μM) blocked the relaxing effect of the heme group. Pre-incubation of CC with heme (100 μM) enhanced relaxation induced by acetylcholine, sodium nitroprusside, and nitrergic relaxation (electrical field stimulation), which was abolished by 1J or ODQ. The heme group increased the cGMP production in CC, which was abolished by 1J or ODQ. cGMP levels were significantly higher in CC treated with heme, and pre-incubation with compound 1J or ODQ abolished the effect of heme in raising cGMP levels., Discussion and Conclusion: The HO-CO-sGC-cGMP pathway appears to play a crucial role in promoting CC relaxation. Our study provides novel insight into the role of group heme in CC relaxation and its potential contribution to priapism in SCD. Heme may serve as a pharmacological target for new therapies to prevent priapism., (© 2024 American Society of Andrology and European Academy of Andrology.)

Background: Major ischemic priapism (IP) is defined as a persistent penile erection for >4 hours. IP may cause serious complications, especially if prompt resolution is not achieved. Therefore, selecting the most effective and usable shunt technique is crucial in IP cases that are refractory to medical therapy., Aim: To compare the effectiveness and complication risks of distal corporoglanular shunt procedures with and without the Burnett "snake" maneuver., Methods: We conducted a retrospective study of patients who presented with IP and underwent surgical treatment at our institution between 2005 and 2021. The patients were categorized into 2 groups: group 1 (n = 26) underwent distal shunt + Burnett snake maneuver, and group 2 (n = 56) underwent distal shunt-only. Clinical history, parameters of IP, details of medical and surgical treatments, and follow-up information were evaluated., Outcomes: Outcomes included differences in IP resolution and recurrence, functional erections, and complications between corporoglanular shunt procedures with and without the Burnett snake maneuver., Results: In group 1, 24 of 26 patients (92.3%) experienced priapism resolution with a single surgical intervention, while this outcome was observed in 30 of 56 patients (53.6%) in group 2 (P < .001). Notably, priapism recurrence was significantly lower in group 1, occurring in 1 of 24 patients (4.2%), as opposed to 8 of 30 patients (26.6%) in group 2 (P < .001). Of the patients with documented sexual function status at follow-up, functional erections (capable of penetration with or without phosphodiesterase 5 inhibitors) were noted in 6 of 14 patients (42.8%) in group 1 and 13 of 26 patients (50%) in group 2 (P = .66)., Clinical Implications: This study provides valuable insights regarding technical aspects of distal shunt procedures with and without the Burnett snake maneuver for treating major IP episodes. These results can help surgeons with clinical decision making for patients who present with IP., Strength and Limitations: Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, challenges in controlling confounding variables, and the lack of validated questionnaire scores for erectile function evaluation., Conclusion: Our study demonstrates that modifying distal shunt procedures using the Burnett snake maneuver significantly improves priapism resolution and effectively prevents further priapism episodes without introducing additional complications or erectile function loss, thereby distinguishing it from distal shunt-only procedures., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced nitric oxide (NO)-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased reactive oxygen species levels that inactive NO, and testosterone deficiency that leads to endothelial nitric oxide synthase downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. SIGNIFICANCE STATEMENT: This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, hydroxyurea, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Ischemic priapism is a common but underrecognized morbidity affecting about 33% of adult men with sickle cell disease (SCD). The onset of priapism occurs in the prepubertal period and tends to be recurrent with increasing age. Significantly, priapism is associated with an unrecognized high burden of mental duress and sexual dysfunctions. The diagnosis of priapism is clinical. Many episodes of priapism will resolve spontaneously, but when an episode lasts longer than 4 hours, the episode is considered a urologic emergency requiring quick intervention with either corporal aspiration or shunt surgery. Only 3 randomized clinical trials (stilbesterol, ephedrine or etilefrine, and sildenafil) have been conducted for secondary priapism prevention in SCD. All 3 trials were limited with small sample sizes, selection biases, and inconclusive results after completion. The current molecular understanding of the pathobiology of priapism suggests a relative nitric oxide (NO) deficiency secondary to chronic hemolysis in SCD and associated phosphodiesterase type 5 dysregulation. We posit an increase in NO levels will restore the normal homeostatic relationship between voluntary erection and detumescence. Currently, 2 randomized phase 2 trials (1 double-blind, placebo-controlled trial and 1 open-label, single-arm intervention) are being conducted for secondary priapism prevention in men at high risk for recurrent priapism (NCT03938454 and NCT05142254). We review the epidemiology and pathobiology of priapism, along with mechanistic therapeutic approaches for secondary prevention of priapism in SCD., (Copyright © 2022 by The American Society of Hematology.)

Patients with sickle cell disease and/or (rarely) trait are at increased risk for developing recurrent episodes of priapism, also known as stuttering priapism, and major ischemic priapism. Treatment of acute ischemic priapism is reactive; whereas ideal management consists of preventative approaches to ultimately promote the best improvement in patient's quality of life. Leg ulcers in patients with sickle cell disease (SCD) are quite common, with ∼20 % of patients with HBSS reporting either having an active or a past ucler. They can be confused with venous ulcers, with lower extremity hyperpigmentation confounding further the diagnosis. Several factors believed to contribute to the development of leg ulcers in patients with SCD are discussed in this article. Sickle cell liver disease (SCLD) occurs because of a wide variety of insults to the liver that happen during the lifetime of these patients. SCLD includes a range of complications of the hepatobiliary system and is increasing in prevalence with the aging adult sickle population. Liver nodular regenerative hyperplasia (NRH) is more common than realized and underappreciated as a diagnosis and requires liver biopsy with reticulin staining. Undiagnosed, the insidious damage from liver NRH can lead to noncirrhotic portal hypertension or cirrhosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We conducted one of the first prospective studies to test the hypothesis that the clinical history of priapism underestimates priapism incidence compared with a priapism pain diary. Eligibility criteria were men with sickle cell anemia (SCA) between 18 and 40 years of age who have had at least 3 episodes of priapism in the past 12 months. Seventy-one men with SCA completed the diary for at least 3 months. The first 3 months of the priapism diary were included in the analysis. A total of 298 priapism episodes were recorded, and 80% (57 of 71) of the participants had at least 1 priapism event. Priapism severity was reported in the range of moderate to the worst imaginable pain in 81.5% (263 of 298), and a total 57 participants (80%) had a median pain rating of 6 (interquartile range: 5-8) on a scale from 1 to 10. The monthly incidence rate of priapism per participant based on history versus self-report pain diary was 2.0 (95% confidence interval, 1.9-2.1) and 1.4 (95% confidence interval, 1.2-1.6), respectively (P < .001). For participants that had a prior priapism episode, 80% had another episode during the 3-month interval follow-up. The median time to that second episode was 27.5 days. Major priapism occurred in 9.9% of episodes and was associated with the sum of all prospective priapism events. Men with SCA and at least 3 priapism episodes in the past 12 months are at significant risk for recurrent priapism in the following 3 months., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1 J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD., (© 2022 Federation of American Societies for Experimental Biology.)

Background: Children and adult with sickle cell disease (SCD) display priapism associated with low nitric oxide (NO) bioavailability and oxidative stress in penis., Aim: This study aimed to evaluate the effects of hybrid compound RVT-FxMe, derived from resveratrol bearing a NO-donor subunit, on two murine model that display priapism phenotype, SCD transgenic mice and endothelial NO synthase gene-deficient (eNOS-/-) mice., Methods: Wild-type, SCD, and eNOS-/- mice were treated with RVT-FxMe (25 mg/kg/d, 2 weeks)., Outcomes: Hematological parameters, concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), as well as to electrical field stimulation (EFS), were obtained in mice corpus cavernosum strips., Results: Corpus cavernosum relaxations to SNP and EFS were increased in eNOS-/- group, which were normalized by RVT-FxMe treatment. SCD mice exhibited an excessive CC relaxant response induced by ACh, EFS and SNP RVT-FxMe treatment did not change the increased relaxant responses to ACh, EFS and SNP in corpus cavernosum from SCD group., Clinical Translation: Excess of plasma hemoglobin in SCD may interfere in pharmacological activity of NO donors compounds., Strength/limitations: While mechanistic data with promising potential is showed, the current study is not without limitations. RVT-FxMe effects in the mid- and long-term warrant complementary studies., Conclusion: Treatment with RVT-FxMe reversed the enhanced NO-cGMP-mediated CC relaxations in eNOS-/- mice, but not in SCD mice; it is likely that excess of plasma hemoglobin in SCD mice act to inactivate NO before it reaches soluble guanylyl cyclase, avoiding restoration of NO bioavailability in penis., Competing Interests: The authors have declared that no competing interests exist.

Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Musicki and Burnett.)

Despite priapism being one of the most frequent complications of sickle cell anemia (SCA) in male individuals, little has been reported about the impact of priapism in this population. The authors used a sequential independent mixed-methods design, which used both international multicenter focus group discussions (n=35) and a quantitative patient-reported outcome measure (n=131) to determine the impact of priapism on men with SCA in Nigeria and the United States. The authors analyzed data from focus groups using an iterative inductive-deductive approach. Comparison of the Priapism Impact Profile data was done using the Kruskal-Wallis H test. Our result showed that priapism, across cultures, is associated with shame and embarrassment. These emotions interfere with timely clinical and family communication about priapism symptoms and complications. Participants were dissatisfied with the quality of care at emergency facilities. The quality of life and physical wellness of men with SCA-related priapism were significantly different for the 3 groups: (1) priapism condition getting better, (2) priapism condition getting worse, and (3) priapism condition remain the same (P=0.002 and P=0.019, respectively). Psychological, sexual, and physical wellbeing are all adversely affected by priapism. Evidence-based methods are necessary for adequate medical, educational, and psychological treatment for recurrent priapism., Competing Interests: M.R.D. and his institution are the sponsors of 2 externally funded research investigator-initiated projects. Global Blood Therapeutics (GBT) will provide funding for the cost of the clinical studies. GBT will not be a cosponsor of either study. M.R.D. is not receiving any compensation for the conduct of these 2 investigator-initiated observational studies. Also, M.R.D. is a member of the GBT advisory board for a proposed randomized controlled trial for which he receives compensation. M.R.D. is the Chair of the steering committee for an industry-supported phase II trial (SPARTAN) to prevent priapism in men. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Priapism impairs quality of life and has a predilection for males with sickle cell disease (SCD). The Priapism Impact Profile (PIP) is a novel 12-item instrument designed to measure general health-related impact of priapism. The aim of the study was to evaluate the validity and reliability of the PIP in a Jamaican cohort of SCD patients experiencing priapism., Methods: One hundred SCD patients with a history of priapism were recruited from a sickle cell clinic in Kingston, Jamaica and administered the PIP questionnaire. Patients rated each item of the PIP for clarity and importance. Statistical testing was employed to evaluate the psychometric performance of the PIP. Content validation was assessed based on patient descriptive rating of the items based on clarity, and importance and criterion-oriented validity were assessed by evaluating the PIP's ability to distinguish between patient subgroups. Test-retest repeatability was assessed in 20 of the 100 patients., Results: Patients were stratified into active (54) and remission (46) priapism groups based on their experience of priapism within the past year. Patients in the active priapism group were younger (p = 0.011), had a shorter duration of disease (p = 0.023), and had more frequent priapism episodes (p = 0.036) than the remission group. PIP questionnaire scores differed significantly with respect to priapism activity (p < 0.001) and prevalence of erectile dysfunction (p < 0.05) but not by priapism severity (p = 0.62). The PIP questionnaire had good content validity, with questions rated as having medium or high clarity and importance by an average of 82.8% and 69.2% of patients, respectively., Conclusion: The PIP questionnaire was successfully validated in a Jamaican cohort of SCD patients and adequately discriminated patients with active priapism from those in remission. The instrument may be utilized in routine clinical management of patients with SCD-associated priapism. Further clinical investigations are warranted in other populations., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To examine the current molecular therapeutics in the medical treatment of recurrent ischemic priapism (RIP). To propose a stepwise clinical management paradigm for the treatment of RIP., Methods: We performed a literature search using the PubMed database for the terms 'recurrent ischemic priapism' and 'stuttering priapism' up until December 2020. We assessed pre-clinical and clinical studies regarding medical management of RIP and molecular pathophysiology. Case series and randomized trials were evaluated by study quality and patient outcomes to determine a potential clinical management scheme., Results: Recent research has fostered an improved understanding of the underlying molecular pathophysiology of RIP that has paved the way forward for developing new therapeutic agents. Medications targeting neurovascular, hormonal and haematological mechanisms associated with RIP show great promise towards remedying this condition. A host of therapeutic agents operating across different mechanistic directions may be implemented according to a clinical management scheme to potentially optimize RIP outcomes., Conclusion: RIP remains a medically neglected condition with current management focused on treating the acute condition rather than modulating the course of disease. Continued research into the molecular mechanisms of RIP and standardized clinical pathways can improve the quality of care for patients suffering from this condition., (© 2021 The Authors BJU International © 2021 BJU International.)

Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility., (© 2020 Wiley Periodicals LLC.)

Purpose: We evaluated the real-world effectiveness of regimented phosphodiesterase type 5 inhibitor dosing on recurrent ischemic priapism outcomes using emergency department visits as a proxy for therapeutic control of the disorder., Materials and Methods: We performed a retrospective chart review of patients with recurrent ischemic priapism who were started on regimented phosphodiesterase type 5 inhibitor therapy from May 2006 to January 2020. We compared the number of emergency department visits per month during a 6-month period before treatment, during treatment and after treatment discontinuation. We extracted and categorized priapism outcomes such as priapism frequency and duration., Results: Of 216 patients identified with all cause priapism 114 were diagnosed with recurrent ischemic priapism and 42 were initiated on regimented phosphodiesterase type 5 inhibitor therapy. Treatment effectiveness was analyzed for 24 evaluable patients. Priapism etiology was idiopathic in 12 patients (50%), sickle cell disease in 11 (46%) and drug-induced in 1 (4%). The median length of regimented phosphodiesterase type 5 inhibitor use was 3 months (IQR 2-7). Treatment decreased emergency department visits per month by 4.4-fold (p <0.001), priapism duration tiers (p <0.001) and priapism frequency tiers (p <0.001). Of 24 patients 22 (92%) reported improvement in priapism outcomes, 9 of whom reported resolution of recurrent ischemic priapism episodes. A subgroup analysis of 17 patients with recurrent ischemic priapism relapse after treatment discontinuation showed a significant increase in priapism duration (p <0.001) and frequency (p <0.001) but no significant change in emergency department visits per month (p=0.91)., Conclusions: Regimented phosphodiesterase type 5 inhibitor therapy was an impactful treatment in managing recurrent ischemic priapism according to objective and subjective parameters. This study provides further support for the use of regimented phosphodiesterase type 5 inhibitor dosing as a preventive strategy for recurrent ischemic priapism.

Recurrent ischemic priapism is a common complication of sickle cell disease (SCD). We assessed the burden, characteristics, and types of priapism, including sexual dysfunction, in a cohort of men with and those without SCD, to test the hypothesis that sexual dysfunction is more prevalent in men with SCD. In Kano, Nigeria, we conducted a comparative cross-sectional survey that included 500 and 250 men 18 to 40 years of age, with and without SCD, respectively. The survey used the Priapism Questionnaire and the International Index of Erectile Function for sexual function assessment. All eligible participants approached for the study gave informed consent and were enrolled. Stuttering and major priapism were defined based on the average duration of priapism experiences that lasted ≤4 and >4 hours, respectively. The prevalence of priapism was significantly higher in men with SCD than in those without it (32.6% vs 2%; P < .001). Stuttering priapism accounted for 73.6% of the priapism episodes in men with SCD. Nearly 50% of the participants with SCD-related priapism had never sought medical attention for this complication. The majority of the men with SCD-related priapism used exercise as a coping mechanism. Priapism affected the self-image of the men with SCD, causing sadness, embarrassment, and fear. The percentage of the men with SCD who had erectile dysfunction was more than twofold higher than that of those without SCD who had erectile dysfunction (P = .01). The men with SCD had a higher prevalence of priapism and sexual dysfunction than the men without SCD., (© 2020 by The American Society of Hematology.)

Introduction : Priapism is prolonged penile erection in the absence of sexual arousal or desire and is a devastating condition affecting millions of patients with sickle cell disease (SCD) globally. Available drug treatments for SCD-related priapism remain limited and have been primarily reactive rather than preventive. Hence, there is an unmet need for new drug targets and pharmacologic therapies. Areas covered : We examine the molecular mechanisms underlying SCD-associated priapism evaluated mostly in animal models. In mouse models of SCD, molecular defects of priapism operating at the cavernous tissue level include reduced tonic NO/cGMP signaling, elevated oxidative/nitrosative stress, vascular adhesion molecule derangements, excessive adenosine and opiorphin signaling, dysregulated vasoconstrictive RhoA/ROCK signaling, and testosterone deficiency. We discuss the consequences of downregulated cGMP-dependent phosphodiesterase type 5 (PDE5) activity in response to these molecular signaling derangements, as the main effector mechanism causing unrestrained cavernous tissue relaxation that results in priapism. Expert opinion : Basic science studies are crucial for understanding the underlying pathophysiology of SCD-associated priapism. Understanding the molecular mechanisms could unearth new therapeutic targets for this condition based on these mechanisms. Treatment options should aim to improve deranged erection physiology regulatory signaling to prevent priapism and potentially restore or preserve erectile function.

This literature review presents two unusual and mystifying disorders of penile erection: painful nocturnal erections, alternatively termed sleep-related painful erections, and idiopathic stuttering priapism, a variant of recurrent ischemic priapism in which no cause is discernible. The disorders are closely related although they are distinct clinically and pathologically. The main subject areas of discussion are recognition, clinical evaluation and management although current concepts surrounding their causes and mechanisms are also addressed. It is acknowledged that despite the perceived rarities of these disorders they are impactful in terms of their disease profiles and consequences. Future advances in their management will require continued development of evidence-based treatments., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Priapism is a disorder in which prolonged penile erection persists uncontrollably, potentially leading to tissue damage. Priapism commonly afflicts patient populations with severely low nitric oxide (NO) bioavailability. Because NO is a primary mediator of erection, the molecular mechanisms involved in priapism pathophysiology associated with low NO bioavailability are not well-understood. The objective of this study was to identify dysregulated molecular targets and signaling pathways in penile tissue of a mouse model of low NO bioavailability that have potential relevance to priapism. Neuronal plus endothelial NO synthase double knockout mice (NOS1/3 -/- ) were used as a model of low NO bioavailability. Priapic-like activity was demonstrated in the NOS1/3 -/- mice relative to wild-type (WT) mice by the measurement of prolonged erections following cessation of electrical stimulation of the cavernous nerve. Penile tissue was processed and analyzed by reverse-phase liquid chromatography tandem mass spectrometry. As a result, 1279 total proteins were identified and quantified by spectral counting, 46 of which were down-regulated and 110 of which were up-regulated in NOS1/3 -/- versus WT (P < 0.05). Ingenuity Pathway Analysis of differentially expressed proteins revealed increased protein kinase A and G-protein coupled receptor signaling in NOS1/3 -/- penises, which represent potential mechanisms contributing to priapism for secondary to low NO bioavailability.

Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild-type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone-responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α-smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser-92, eNOS at Ser-1177, neuronal (n) NOS at Ser-1412, and Akt at Ser-473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P-PDE5 (Ser-92), PDE5, P-eNOS (Ser-1177), and P-Akt (Ser-473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P-nNOS (Ser-1412), eNOS, nNOS, or α-smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis., (© 2017 American Society of Andrology and European Academy of Andrology.)

Patients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS -/ ) mice, focusing on the dysregulated NO-cGMP- phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS -/- mice were treated with compound 4C (100 μmol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS -/- mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS -/- mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91 phox , and 3-nitrotyrosine in penises from SCD and dNOS -/- mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Recent research suggests that priapism in sickle cell disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if subacute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the subacute setting., Aims: The aim of this study was to investigate the effects of subacute hemolysis (3-month exposure) on priapism and NO pathway regulation., Methods: Mice underwent bone marrow transplantation with either SCD (BM-SS) or wild-type (WT) bone marrow. BM-SS mice were treated with sildenafil 100 mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernous nerve stimulation following bone marrow transplantation to assess for priapism., Main Outcome Measures: ICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, protein kinase G (PKG), PDE5, and ROS activities., Results: BM-SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM-SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections per hour, P < 0.05). Penile tissues from BM-SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared with that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, P < 0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, P < 0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, P < 0.05) compared with non-PDE5I treated BM-SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, P < 0.05)., Conclusion: Short-term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, because of restored NO balance with decreased ROS generation and increased PDE5 activity., (© 2015 International Society for Sexual Medicine.)

Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic variant, is often associated with devastating complications, notably erectile dysfunction. Because priapism demonstrates high prevalence in patients with hematologic disorders, most commonly sickle cell disease (SCD), there is significant concern for its sequelae in this affected population. Thus, timely diagnosis and management are critical for the prevention or at least reduction of cavernosal tissue ischemia and potential damage consequent to each episode. Current guidelines and management strategies focus primarily on reactive treatments. However, an increasing understanding of the molecular pathophysiology of SCD-associated priapism has led to the identification of new potential therapeutic targets. Future agents are being developed and explored for use in the prevention of priapism., (© 2015 by The American Society of Hematology.)

Objective: To create and evaluate a psychometric instrument that measures the impact of experiencing priapism from the patient perspective., Methods: The research protocol consisted of several phases as follows: (1) generating items, (2) composing a patient questionnaire, (3) administering the questionnaire to patients with both active and remitted (≥1 year without priapism episodes) histories of priapism, (4) performing internal consistency and criterion-oriented validity analyses in correlation with clinical histories and erectile function assessment tools, and (5) ascertaining psychometric properties of the instrument., Results: The final instrument comprised a 12-item Priapism Impact Profile (PIP) questionnaire, representing the following 3 domains adversely impacted by priapism: quality of life (QoL), sexual function (SF), and physical wellness (PW), with higher scores indicating inferior experience in respective domains. Internal consistency reliability coefficients for the total PIP score and the 3 domain scores were >0.75. Fifty-four patients (mean age, 31.7 ± 11.4 years) completed the questionnaire. Patients with active priapism (n = 42) had higher total, QoL, SF, and PW scores than those with priapism remission (n = 8; P <.05, P <.05, P = .09, and P <.01, respectively). Patients with a history of recurrent priapism episodes >2 hours in duration had higher total, QoL, SF, and PW scores than those with "very minor" priapism recurrences (≤2 hours in duration; P <.01, P <.01, P <.05, and P <.001, respectively). Patients with "mild-to-moderate" to "severe" erectile dysfunction had higher total, QoL, SF, and PW scores than those with no or "mild" erectile dysfunction (P <.05, P = .14, P <.01, and P = .25, respectively)., Conclusion: The PIP questionnaire is a novel psychometric instrument that offers a means to quantify the adverse health impact of the patient's experience with priapism., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Risk factors associated with erectile dysfunction (ED) that results from recurrent ischemic priapism (RIP) in sickle cell disease (SCD) are incompletely defined., Aim: This study aims to determine and compare ED risk factors associated with SCD and non-SCD-related "minor" RIP, defined as having ≥2 episodes of ischemic priapism within the past 6 months, with the majority (>75%) of episodes lasting <5 hours., Methods: We performed a retrospective study of RIP in SCD and non-SCD patients presenting from June 2004 to March 2014 using the International Index of Erectile Function (IIEF), IIEF-5, and priapism-specific questionnaires., Main Outcome Measures: Prevalence rates and risk factor correlations for ED associated with RIP., Results: The study was comprised of 59 patients (40 SCD [mean age 28.2 ± 8.9 years] and 19 non-SCD [15 idiopathic and four drug-related etiologies] [mean age 32.6 ± 11.7 years]). Nineteen of 40 (47.5%) SCD patients vs. four of 19 (21.1%) non-SCD patients (39% overall) had ED (IIEF <26 or IIEF-5 <22) (P = 0.052). SCD patients had a longer mean time-length with RIP than non-SCD patients (P = 0.004). Thirty of 40 (75%) SCD patients vs. 10 of 19 (52.6%) non-SCD patients (P = 0.14) had "very minor" RIP (episodes regularly lasting ≤2 hours). Twenty-eight of 40 (70%) SCD patients vs. 14 of 19 (73.7%) non-SCD patients had weekly or more frequent episodes (P = 1). Of all patients with very minor RIP, ED was found among 14 of 30 (46.7%) SCD patients vs. none of 10 (0%) non-SCD patients (P = 0.008). Using logistic regression analysis, the odds ratio for developing ED was 4.7 for SCD patients, when controlling for RIP variables (95% confidence interval: 1.1-21.0)., Conclusions: ED is associated with RIP, occurring in nearly 40% of affected individuals overall. SCD patients are more likely to experience ED in the setting of "very minor" RIP episodes and are five times more likely to develop ED compared with non-SCD patients., (© 2015 International Society for Sexual Medicine.)

Priapism is an erectile disorder involving uncontrolled, prolonged penile erection without sexual purpose, which can lead to erectile dysfunction. Ischemic priapism, the most common of the variants, occurs with high prevalence in patients with sickle cell disease. Despite the potentially devastating complications of this condition, management of recurrent priapism episodes historically has commonly involved reactive treatments rather than preventative strategies. Recently, increasing elucidation of the complex molecular mechanisms underlying this disorder, principally involving dysregulation of nitric oxide signaling, has allowed for greater insights and exploration into potential therapeutic targets. In this review, we discuss the multiple molecular regulatory pathways implicated in the pathophysiology of priapism. We also identify the roles and mechanisms of molecular effectors in providing the basis for potential future therapies.

Purpose: The purpose of this study was to determine the association of testosterone deficiency and priapism in adult men with sickle cell disease (SCD)., Methods: A cross-sectional study of 50 adult men with SCD (hemoglobin SS) was performed. All patients had early morning blood taken for total and free testosterone, FSH, LH, prolactin, lipid levels, LDH and hematological indices. Patients completed an interviewer-administered questionnaire regarding priapism frequency, duration and treatment. Testosterone deficiency was defined as a serum total testosterone<12 nmol/L (346 ng/dL)., Results: The mean age of the study population was 34.2±8.9 years. Priapism was noted in 24 (48%) patients and was most frequently seen in men between ages 18-25 years. Testosterone deficiency was observed in 11 of the 50 (22%) patients, particularly in 6 of 24 (25%) patients with histories of priapism. There was no difference in mean total testosterone levels in patients with and without a history of priapism (16.7±4.9 nmol/L and 15.4±5.9 nmol/L, respectively) (p=0.43). Similarly, there was no difference in serum LH and FSH levels based on history of priapism., Conclusion: Testosterone deficiency is prevalent in patients with SCD; however, we did not identify an association based on a history of priapism. Larger, prospectively gathered data are needed to define the priapism profile of SCD patients with testosterone deficiency.

Prolonged ischemic priapism in patients with sickling hemoglobinopathies is a urologic emergency requiring immediate intervention to avoid irreversible anoxic penile injury, corporal fibrosis, and erectile dysfunction. Therapeutic options, however, are limited and often ineffective. Here, we report recovery of erectile function with hydroxyurea therapy in an adolescent with hemoglobin SS following a prolonged episode of priapism and subsequent severe erectile dysfunction. This case suggests a potential role of hydroxyurea in reversing end organ damage in patients with hemoglobin SS and also supports basic science work indicating involvement of the NO-dependent pathway in the pathogenesis of sickle cell disease-associated priapism.

Background: Successful preventive therapy for ischemic priapism, a disorder of penile erection with major physical and psychologic consequences, is limited. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of sildenafil by a systematic dosing protocol to prevent recurrent ischemic priapism associated with sickle cell disease., Methods: Thirteen patients with sickle cell disease reporting priapism recurrences at least twice weekly were randomized to receive sildenafil 50 mg or placebo daily, unassociated with sleep or sexual activity, for 8 weeks, followed by open-label use of this sildenafil regimen for an additional 8 weeks., Results: Priapism frequency reduction by 50% did not differ between sildenafil and placebo groups by intention-to-treat or per protocol analyses (P = 1.0). However, during open-label assessment, 5 of 8 patients (62.5%) by intention-to-treat analysis and 2 of 3 patients (66.7%) by per protocol analysis met this primary efficacy outcome. No significant differences were found between study groups in rates of adverse effects, although major priapism episodes were decreased 4-fold in patients monitored "on-treatment.", Conclusions: Sildenafil use by systematic dosing may offer a strategy to prevent recurrent ischemic priapism in patients with sickle cell disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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 anti-androgens 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 administering this therapy for priapism management should be aware of these possible risks.

Introduction: Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear., Aims: We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis., Methods: SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot., Main Outcome Measures: Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse., Results: Continuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters., Conclusion: Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD., (© 2013 International Society for Sexual Medicine.)

We evaluated the therapeutic potential of a sustained nitric oxide (NO)-releasing compound to correct the molecular hallmarks and pathophysiology of priapism, an important but poorly characterized erectile disorder. 1,5-Bis-(dihexyl-N-nitrosoamino)-2,4-dinitrobenzene (C6') and an inactive form of the compound [1,5-bis-(dihexylamino)-2,4-dinitrobenzene (C6)] were tested in neuronal cell cultures and penile lysates for NO release (Griess assay) and biological activity (cGMP production). The effect of local depot C6' or C6 was evaluated in mice with a priapic phenotype due to double neuronal and endothelial NO synthase deletion (dNOS(-/-)) or human sickle hemoglobin transgenic expression (Sickle). Changes in NO signaling molecules and reactive oxygen species (ROS) surrogates were assessed by Western blot. The physiological response after C6' treatment was assessed using an established model of electrically stimulated penile erection. C6' generated NO, increased cGMP, and dose dependently increased NO metabolites. C6' treatment reversed abnormalities in key penile erection signaling molecules, including phosphodiesterase type 5, phosphorylated endothelial nitric oxide synthase, and phosphorylated vasodilator-stimulated phosphoprotein. In Sickle mice, C6' also attenuated the increased ROS markers gp91(phox), 4-hydroxynonenal, and 3-nitrotyrosine. Finally, C6' corrected the excessive priapic erection response of dNOS(-/-) mice. Exogenous sustained NO release from C6' corrects pathological erectile signaling in mouse models of priapism and suggests novel approaches to human therapy.

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

Hypogonadism, which is highly prevalent in men with sickle cell disease (SCD), affects quality of life and causes great morbidity. The safety of testosterone replacement therapy (TRT) in SCD in relation to priapism episodes is relatively unknown. Our aim was to monitor the safety of TRT in a cohort of seven hypogonadal men with SCD. Testosterone undecanoate (Nebido) 1 g was administered intramuscularly to adult men with homozygous SCD (Hb SS) having hypogonadism [serum total testosterone ≤12.0 nmol/L (346 ng/dL), reference range 12.5-38.1 nmol/L (360-1098 ng/dL)] for 12 months. Serum total testosterone, haemoglobin, haematocrit, renal and liver function tests, glucose and PSA measurements were done at baseline and 12-month follow-up. Trough serum total testosterone, haemoglobin and haematocrit were measured three monthly. Priapism events and adverse drug events were assessed every 3 months. International Index of Erectile Function (IIEF), Androgen Deficiency in the Ageing Male (ADAM) and World Health Organization Quality of Life (WHOQOL) questionnaires were administered at baseline, 6 and 12 months. Seven men with a mean age of 34.4 years were treated. Median total testosterone increased from 10.6 to 11.2 nmol/L (p = 0.46). Median serum lactate dehydrogenase levels decreased from 1445 to 1143.5 IU/L (p < 0.05), while all other laboratory indices remained stable. Injection site pain was the most frequently reported adverse event, with no increases in painful crises, hypersensitivity or oedema. After TRT, there was no significant increase in priapism frequency. Median questionnaire scores were increased for the IIEF (46-68, p = 0.018), reduced for ADAM (5.0-2.0, p = 0.016) and unchanged for WHOQOL (98-103, p = 0.086). TRT using testosterone undecanoate with eugonadal intent for hypogonadism appears to be safe in men with SCD. This treatment does not appear to promote priapism occurrences and rather it possibly improves sexual function. Future prospective evaluations in larger groups of hypogonadal men with SCD are necessary to confirm these findings., (© 2013 American Society of Andrology and European Academy of Andrology.)

Introduction: Although testosterone replacement therapy (TRT) is the preferred treatment for hypogonadism, information for patients using testosterone includes too frequent or prolonged erections as a potential side effect., Aim: To assess the frequency and risk of priapism or related adverse events (AEs) in hypogonadal men treated with a 1% testosterone gel., Methods: Safety and tolerability data for AndroGel 1% were assessed, including three randomized, controlled clinical trials in varying populations of hypogonadal or near hypogonadal men. Study 1 was a Phase 3 trial of AndroGel 1% 5 g, 7.5 g, or 10 g once daily for 6 months (N = 227). Study 2 was a Phase 2 trial of AndroGel 1% 7.5 g once daily titrated as needed vs. placebo for 26 weeks in men with type 2 diabetes (N = 180). Study 3 was a Phase 4 trial of AndroGel 1% 5 g once daily vs. placebo for 12 weeks in men previously unresponsive to sildenafil 100 mg monotherapy and receiving concomitant sildenafil 100 mg (N = 75). Postmarketing AndroGel pharmacovigilance reporting data from 2001 to 2011 was searched for events coded as priapism., Main Outcome Measures: The incidence of priapism and/or related symptoms reported as urogenital or reproductive system AEs., Results: In the 283 men exposed to AndroGel 1% over the three trials, mean exposure ranged from 84 days to 149 days. No AEs described as priapism or related symptoms were reported in the three trials. In the postmarketing data, representing 40 million units sold, eight cases described as priapism were reported. Of the six cases with accompanying data, all were judged as possibly related to AndroGel., Conclusions: Safety data from the clinical trials for AndroGel 1% did not report any cases of priapism, and its incidence in the postmarketing pharmacovigilance data is extremely low, indicating a minimal risk of inducing priapism., (© 2013 Abbott Laboratories. Journal of Sexual Medicine © 2013 International Society for Sexual Medicine.)

Priapism due to sickle cell disease is a common but less well characterized complication of the disorder. It represents a "medical emergency" with the key determinant of outcome being the duration of penile ischaemia and time to detumescence of <4 h associated with a successful treatment outcome. Management can be outpatient-based and consists of pre-emptive strategies for early stuttering attacks based on prior health education of the association between the 2 disorders, non pharmacological management, outpatient penile aspiration and irrigation with or without instillation of alpha and beta adrenergic agonists for acute episodes and secondary prophylaxis to prevent the high rates of recurrences. The evidence to recommend medical prophylaxis is sparse but based on a consensus of experts and small phase 2 or III clinical trials. A clearer understanding of the molecular mechanism(s) involving normal and dysregulated erectile physiology, scavenger haemolysis and nitric oxide pathway paves way for the use of phosphodiesterase type 5 inhibitors in medical prophylaxis of stuttering attacks. These agents will need to be studied in multi-centre randomized phase III trials before they become standard of care. A multidisciplinary team approach is required to enhance "sexual wellness" and prevent erectile dysfunction in this sexually vulnerable group., (© 2013 Blackwell Publishing Ltd.)

Purpose: We provide long-term followup on a modification of the Al-Ghorab distal penile corporoglanular shunt surgery for the treatment of ischemic priapism., Materials and Methods: We conducted a retrospective review of patients surgically treated for ischemic priapism at The Johns Hopkins Hospital from January 2008 to April 2012 with the Burnett "Snake" maneuver of the Al-Ghorab shunt. Electronic medical records were reviewed to collect demographic information and telephone followup was performed to verify treatment outcomes. Patients completed the SHIM (Sexual Health Inventory for Men) to assess current erectile function., Results: A total of 10 patients were analyzed (age range 31 to 59 years). Mean followup was 6.7 months (range 0.5 to 17). Priapism etiologies were idiopathic (3), trazodone (2), trazodone and cocaine (3), intracavernous injection of trimix (1) and spinal cord injury (1). There were 6 patients who had previously undergone unsuccessful surgical attempts at priapism decompression and mean priapism duration was 75 hours (range 24 to 288). Of the 10 men 8 achieved successful resolution of priapism with no recurrence. There were 2 men with recurrent priapism refractory to all management who were definitively treated with insertion of an inflatable penile prosthesis. Of 9 men 6 had normal erectile function preoperatively, of whom 2 achieved at least partial erectile function postoperatively. Complications were sustained by 2 men, including wound infection with skin necrosis in 1, and an intraoperative urethral injury in the other with subsequent urethrocutaneous fistula formation and wound infection with skin necrosis., Conclusions: The modified Al-Ghorab corporoglanular shunt using the Burnett snake maneuver is successful in resolving ischemic priapism, particularly in cases refractory to first line management, and in preventing further episodes of priapism., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Priapism is a vasculopathy that occurs in approximately 40% of patients with sickle cell disease. Mouse models suggest that dysregulated nitric oxide synthase and RhoA/ROCK signaling as well as increased oxidative stress may contribute to the mechanisms of sickle cell disease associated priapism. We examined changes in the protein expression of nitric oxide synthase and ROCK signaling pathways, and a source of oxidative stress, NADPH oxidase, in penile erectile tissue from patients with a priapism history etiologically related and unrelated to sickle cell disease., Materials and Methods: Human penile erectile tissue was obtained from 5 patients with sickle cell disease associated priapism and from 6 with priapism of other etiologies during nonemergent penile prosthesis surgery for erectile dysfunction or priapism management and urethroplasty. Tissue was also obtained from 5 control patients without a priapism history during penectomy for penile cancer. Samples were collected, immediately placed in cold buffer and then frozen in liquid nitrogen. The expression of phosphodiesterase 5, endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, RhoA, ROCK1, ROCK2, p47(phox), p67(phox), gp91(phox) and β-actin were determined by Western blot analysis. Nitric oxide was measured using the Griess reaction., Results: In the sickle cell disease group phosphodiesterase 5 (p <0.05), endothelial nitric oxide synthase (p <0.01) and RhoA (p <0.01) expression was significantly decreased, while gp91(phox) expression (p <0.05) was significantly increased compared to control values. In the nonsickle cell disease group endothelial nitric oxide synthase, ROCK1 and p47(phox) expression (each p <0.05) was significantly decreased compared to control values. Total nitric oxide levels were not significantly different between the study groups., Conclusions: Mechanisms of sickle cell disease associated priapism in the human penis may involve dysfunctional nitric oxide synthase and ROCK signaling, and increased oxidative stress associated with NADPH oxidase mediated signaling., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: To provide standard operating procedures for the diagnosis and management of priapism., Methods: Review of the literature., Main Outcome Measures: Reduction of priapism and preservation of erectile function., Results: Priapism is a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation. Priapism requires prompt evaluation and usually requires emergency management. There are two types of priapism: (i) ischemic (veno-occlusive or low flow), which is found in 95% of cases, and (ii) nonischemic (arterial or high flow). Stuttering (intermittent) priapism is a recurrent form of ischemic priapism. To initiate appropriate management, the physician must determine whether the priapism is ischemic or nonischemic. Necessary diagnostic steps are an accurate history, physical examination, and cavernous blood gas analysis and/or color duplex ultrasonography of the corpora cavernosa. Management of ischemic priapism should achieve resolution as promptly as possible. Initial treatment is therapeutic aspiration with or without irrigation of the corpora. If this fails, intracavernous injection of sympathomimetic drugs is the next step. Surgical shunts should be performed if nonsurgical treatment has failed. The initial management of nonischemic priapism should be observation. Selective arterial embolization is recommended for the management of nonischemic priapism in patients who request treatment. The goal of management for a patient with recurrent (stuttering) priapism is prevention of future episodes., Conclusion: Management of priapism has become increasingly successful as scientific understanding of the pathophysiology and molecular biology of priapism improves. The key to further success in the treatment of priapism is basic research of this uncommon but potentially devastating condition., (© 2012 International Society for Sexual Medicine.)

Priapism is defined as a persistent, painful erection that continues beyond, or is unrelated to, sexual stimulation. It may be categorized as either ischemic (low/absent flow) or nonischemic (high flow). Stuttering priapism is a variant of the ischemic type that is characterized by repetitive, transient, painful, self-limiting episodes of priapism. It is associated with various hematological disorders, including sickle cell disease and pharmacological treatments. The consequences of ineffective treatment of priapism are erectile dysfunction and impaired quality of life due to chronic pain and physical disfigurement. Many of the existing medical therapeutic options for treatment of stuttering priapism are nonmechanistic and associated with significant adverse effects. However, the scientific knowledge of stuttering priapism has transitioned in the past few years, from a condition that is poorly understood to one that has borne a burst of evolving molecular science. In this review, the pathophysiology of priapism is discussed, with particular emphasis on new molecular effectors and mechanisms. Novel treatment methods, as well as potential future agents, based on the emerging molecular evidence are discussed.

Introduction: Ischemic priapism is a true male sexual dysfunction, consisting of uncontrollable, prolonged, and often painful erections of the penis. A commonly observed outcome, as a result of erectile tissue damage and fibrosis in this setting, is the complete loss of natural erectile ability. Males with sickle cell disease (SCD) are commonly affected. Given the adverse health consequences of this condition coupled with its specific population extent, health policy considerations are warranted., Aim: This article aimed to study circumstances surrounding priapism associated with SCD for the purpose of pushing forward health policy objectives that improve sexual health-related outcomes., Methods: Medline searches through July 2010 were conducted using the following terms: priapism, sickle cell disease, epidemiology, public health, health economics, and health policy., Main Outcome Measure: Expert opinion was based on review of the medical literature related to this subject matter., Results: The literature search affirmed that SCD-associated priapism threatens sexual health and also exerts a greatly negative impact on the physical and mental health of affected individuals. Various socioeconomic, behavioral, and cultural factors in the SCD population bearing negatively on sexual health outcomes were delineated. Deficiencies in several aspects of medical services for patients with SCD including scientific research funding support, which evoke an element of ethnic healthcare disparities, were further delineated., Conclusions: SCD-associated priapism is a medical condition of societal health significance, which can and should be addressed through comprehensive healthcare programmatic efforts. These efforts comprise advancement of educational and clinical training programs, support of interdisciplinary healthcare delivery services, diffusion of clinical advances, enactment of guidelines for effective clinical management, and resource allocation for enabling scientific advancements., (© 2011 International Society for Sexual Medicine.)

Introduction: Priapism is defined as an erectile disorder, in which erection persists uncontrollably without sexual purpose. The precise mechanisms involved in the development of sickle cell disease-associated priapism are ill defined., Aim: To summarize the recent developments that increase our understanding of the molecular mechanisms of priapism., Methods: This article reviews the literature (Medline search 2000-2010) that relates the key molecular signaling pathways that contribute to the development of priapism associated with sickle-cell disease. It focuses on basic science investigations using multiple animal models., Main Outcome Measures: The reader will be informed of the most current research regarding the role of endothelial nitric oxide synthase, phosphodiesterase type 5 (PDE5), adenosine, RhoA/Rho-kinase (ROCK), and opiorphins in the pathophysiology of priapism., Results: New concepts in the field of priapism research suggest that priapism often results from altered vascular homeostatic actions in the penis and is associated with deficient erection control mechanisms on a molecular level. A leading proposal in this regard is the notion of aberrant signaling of the endothelium-derived nitric oxide and PDE5 signal transduction pathway in the penis. Additionally, dysfunctional regulatory control of signal transduction systems which interact with this pathway such as adenosine and RhoA/Rho-kinase may contribute to the development of priapism. Recent investigations of opiorphins also demonstrate a role in regulating corporal smooth muscle tone and thereby dysregulation of erection physiology in priapism. These advances have paved the way for understanding this disorder as having a molecular pathogenesis., Conclusions: As the science underlying priapism further emerges, increasingly effective therapeutics for sickle cell disease-associated priapism is certain to follow., (© 2011 International Society for Sexual Medicine.)

Introduction: Surgery is a mainstay in the management of ischemic priapism. The surgical armamentarium for this condition has recently been expanded with the introduction of several innovative procedures., Aim: To review surgical procedures offered in the treatment of ischemic priapism and present a rational framework for their use., Methods: Medline searches through July 2010 were conducted using the terms priapism, surgery, shunt, and prosthesis., Main Outcome Measure: Expert opinion was based on review of the medical literature related to this subject matter., Results: A host of surgical procedures exist to address the genital complications of both acute presentations of ischemic priapism and its non-acute pathologic sequelae, which include penile deformities and erectile dysfunction. For the former, the intervention is used principally in an emergent context with the intention to relieve the acute pathologic effects of the condition and preserve erectile function. For the latter, the intervention is aimed generally toward restoring anatomic normalcy and the functional ability to perform sexual intercourse. A rational framework for surgical management, based on the circumstances of the clinical presentation, is described., Conclusions: The surgical management for ischemic priapism has evolved with the application of a host of surgical procedures. These procedures address acute and non-acute genital complications of the condition and are intended to retain or restore sexual ability effectively and safely. They can be applied using a rational clinical management framework., (© 2011 International Society for Sexual Medicine.)

The objective of this report is to discuss the potential for normal hormone regulation and application of chronic phosphodiesterase type 5 inhibition for the management of recurrent ischemic priapism. A 64-year-old man presented with refractory priapism treated with antiandrogen therapy. He was transitioned to and well controlled on a regimen of daily phosphodiesterase type 5 inhibitor and every other week antiandrogen therapy. Our treatment of recurrent priapism implicates androgens and both biochemical and neurovascular control mechanisms in the penis.

Advances have recently been made in both medical and surgical management of priapism, and these offer improvements in the level of care afforded such patients. Further developments can be expected based on ongoing progress, particularly in the area of molecular science, which is the primary source for driving novel therapeutic approaches. Continued action to address the health care administrative concerns of those most commonly affected by priapism, specifically individuals with sickle cell disease, is also appropriate. All successes in these arenas ensure that afflicted individuals avoid the health burdens of priapism and preserve sexual function., (2011 Elsevier Inc. All rights reserved.)

Priapism is a true urological emergency that is typified by a persistent and painful erection. High-risk groups include patients with hematological or coagulative disorders; for example, those with sickle cell disease, leukemia or glucose-6-phosphate dehydrogenase deficiency. The diagnosis for priapism must be made urgently using patient history, physical examination and blood gas findings on corporal aspiration. Emergency treatment is needed to avoid erectile dysfunction. However, in high-risk groups, prophylaxis must be encouraged. A number of prophylactic measures are emerging based on progress in the understanding of the pathophysiology of priapism in these particular patients. In this Review, priapism as it relates to hematological disorders is discussed, focusing on treatment and prophylaxis.

Objectives: The Ras homolog gene family, member A (RhoA) and its main downstream effector, Rho-kinase (ROCK) are important in maintaining the penis in the flaccid state. The pathophysiology of sickle cell disease-associated priapism is not well defined. We hypothesized that the RhoA/ROCK vasoconstrictive pathways might be involved in the development of priapism. Therefore, the objective of the present study was to evaluate the molecular changes in RhoA and ROCK in an established transgenic sickle cell mouse model of priapism., Methods: Two groups of mice were used: wild type (WT; C57BL/6) mice and transgenic sickle cell mice. We evaluated RhoA guanosine triphosphatase and total ROCK activities, as well as ROCK1 and ROCK2 protein expression, in WT and sickle mice penises. We also evaluated the in vivo erectile responses to cavernous nerve stimulation and the frequency and duration of spontaneous erections before and after cavernous nerve stimulation., Results: Sickle mice demonstrated significantly (P <.05) enhanced erectile responses to cavernous nerve stimulation and frequency of spontaneous erections both before and after cavernous nerve stimulation compared with the WT mice. The sickle mice penises had a significant decline in RhoA guanosine triphosphatase (P <.01) and total ROCK activities (P <.05) compared with the WT mice. A significant (P <.05) reduction in ROCK2 protein expression in sickle mice penises compared with WT mice protein expression. No change in ROCK1 protein expression was observed in either cohort of mice penises., Conclusions: These data suggest that sickle cell disease associated-priapism might be contributed by a lack of RhoA/ROCK-mediated vasoconstriction and highlight a novel molecular mechanism in the pathophysiology of priapism., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: Priapism is a poorly understood disease process with little information on the etiology and pathophysiology of this erectile disorder. One group of patients with a high prevalence of priapism is men with sickle-cell disease., Aim: Establish an in vivo transgenic sickle-cell mouse model to study the pathophysiology of sickle-cell disease-associated priapism., Methods: Transgenic sickle-cell disease mice, expressing human sickle hemoglobin, were utilized. Three groups of mice were used: (i) wild type (WT), (ii) sickle-cell heterozygotes (Hemi), and (ii) sickle-cell homozygotes (Sickle). Two age groups of each cohort of mice were utilized: young adult (4-6 months) and aged (18-22 months)., Main Outcome Measures: Histological (trichrome stain to measure ratio of collagen to smooth muscle), penile hydroxyproline content (collagen content), and transmission electron microscopic analysis of WT, Hemi, and Sickle mice penes, as well as in vivo erectile responses [change in intracavernous pressure (ICP)] to cavernous nerve stimulation (CNS), were determined. The frequency of erectile responses (erections/hour) pre- and poststimulation was also measured in each of the experimental groups., Results: Sickle mice had increased (P < 0.05) collagen to smooth muscle ratio and hydroxyproline content in the penis when compared with WT and Hemi mice penes. Transmission electron microscopy demonstrated thickened smooth muscle cell bundles, disruption of the endothelial lining of the corporal sinusoids, and increased (P < 0.05) caveolae number. Sickle mice had significantly (P < 0.05) higher ICP to CNS and increased (P < 0.05) frequency of erections pre- and post-CNS when compared with WT and Hemi mice erectile responses. Sickle mice did develop ED (change in ICP in response to CNS) with increasing age., Conclusion: The morphometric changes of the penis and exaggerated in vivo erectile responses support the use of this transgenic sickle-cell disease animal model to study the pathophysiological mechanisms involved in sickle-cell disease-associated priapism.

Introduction: A scientific explanation remains elusive for many presentations of recurrent ischemic priapism., Aim: The aim of this article was to evaluate the possible clinical association between idiopathic priapism and anxiety disorders., Methods: Twenty-one patients without identifiable, presumed etiologies for their priapism disorders presented consecutively to a single practitioner's clinical practice and underwent clinical history evaluation and management over a 2(1/2)-year interval., Main Outcome Measures: The main outcome is the documentation of patient demographics and clinical profiles relating to medical history and priapism presentations., Results: Anxiety disorders including generalized anxiety, attention-deficit hyperactivity disorder, and obsessive-compulsive disorder were self-reported in 10 patients., Conclusions: The possible association between idiopathic priapism and anxiety disorders lends support for a central neurobiologic pathophysiology for the erectile disorder. Further neuropsychiatric studies of this clinical population is required to confirm the hypothesis.