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AUA2021 State-of-the-Art Lecture: Stuttering Priapism Management: 2021 Update

By: Arthur L. Burnett, MD, MBA | Posted on: 06 Aug 2021

Priapism is a true erection disorder defined as prolonged penile erection occurring in the absence of sexual arousal or desire. The disorder impacts the physical and mental health of afflicted individuals. Its functional and structural complication risks for penile health are recognized, and common outcomes from priapism episodes include loss of erection ability as well as penile fibrosis with disfigurement. However, individuals with priapism also sustain hardships with regard to general well-being, work/employment and personal relationships. The disorder is a management dilemma for the clinical practitioner, and providing successful treatment whether to resolve an acute presentation of priapism or to control its recurrences remains a management challenge. Its common presentation is a recurrent ischemic form, also known as stuttering priapism, which often heralds a subsequent major priapism episode. Accordingly, stuttering priapism is further vexatious, and stokes the argument that medical preventive therapy for this disorder should be urgently pursued.

Recent progress in the molecular science of recurrent priapism has suggested that molecular therapeutics for this disorder are evolving. New treatments are being explored and developed in a rational way that targets the molecular scientific mechanisms of priapism. These stand to offer alternatives to historical medical and surgical treatments, such as sympathomimetics, androgen deprivation and penile shunts, that while possibly successful in curtailing the disorder have remained reactive, are temporary or fraught with potentially harmful or irreversible consequences. The overarching objective of treating priapism is to alleviate the disorder without adverse effects so that long-term erection ability and mental health are preserved.

The molecular basis of priapism references the neurovascular, hormonal and hematological systems involved in the penile erection process. At the corpora cavernosal tissue level, molecular signaling pathway derangements include downregulated nitric oxide/cGMP/phosphodiesterase type 5 signaling, elevated oxidative/nitrosative stress, vascular adhesion molecule defects, excessive adenosine and opiorphin signaling, dysregulated vasoconstrictive RhoA/ROCK signaling and testosterone deficiency.1 Central neurochemical mechanisms may also be in play but remain to be explored scientifically. Research in the field suggests a convergence mechanism for molecular derangements with respect to the local mechanisms of penile erection related to downregulated cGMP-dependent phosphodiesterase type 5 activity; this molecular factor accounts for unrestrained cavernosal tissue relaxation resulting in priapism. Targeting this convergence point may well offer a prime strategy for treating priapism. At the same time, further elucidating the roles of other pathways that may be associated with heterogenous causes of priapism could suggest specific interventions based on priapism etiology. Ongoing studies may be fruitful to develop such priapism therapeutic strategies.

With a focus on altered nitric oxide signaling in the penis as a mechanism for priapism, my research group has conducted studies over the past several years exploring the possible utility of regimented phosphodiesterase type 5 inhibitor therapy to medically manage recurrent priapism. This therapy consists of a daily low-dose phosphodiesterase type 5 inhibitor such as sildenafil at 25–50 mg dosages administered unassociated with sleep (morning dosing) or sexual activity, distinct from its prescription for erectile dysfunction. The rationale for regimented treatment is to modulate nitric oxide signaling that restores normative phosphodiesterase type 5 expression and activity in the penis of individuals with priapism and thereby protects against priapism.2 We have performed investigations in murine animal models of sickle cell disease-associated priapism showing this molecular effect of regimented treatment.3 We have also reported findings from our 15-year database of men with recurrent priapism who have used this treatment, showing its easy toleration and beneficial effects based on reduced emergency department visits for recurrent priapism management.4

The progress made in this field suggests that a practical clinical management scheme is feasible. Such a proposal advances treatment beyond diverse therapeutic agents described in the literature that have been touted based on limited scientific studies and small retrospective case series. We have recently proposed a currently best-evidenced clinical algorithm that suffices as a treatment framework, in combination with counseling and shared decision making.5 After the initial evaluation and stabilization of the patient with a priapism episode, this framework applies a tiered “preventive” medical management approach that balances efficacies against side effect risk profiles. The scheme endorses the general use of self-administered intracavernosal phenylephrine as needed because of its efficacy in causing detumescence as an alpha-adrenergic antagonistic agent, although this therapy correctly represents reactive rather than preventive intervention.

First-line prevention directs the correction of testosterone deficiency if found and treatment of underlying illnesses that may be contributory, such as sickle cell disease, in conjunction with the care of the patient’s primary health care providers. Hydroxyurea therapy as often used in patients having sickle cell disease may be beneficial in lessening priapism episodes. It has been associated with a low side effect profile, although concerns of its adverse effects on male fertility justify counseling and consideration of sperm cryopreservation.

Second-line prevention involves regimented phosphodiesterase type 5 inhibitors and 5-alpha reductase inhibitors, used as monotherapy or in combination. Because 5-alpha reductase inhibitors may induce sexual dysfunction, fatigue and gynecomastia, counseling is appropriate.

Third-line prevention offers digoxin, baclofen and peripheral androgen deprivation. Limited studies have suggested efficacies for digoxin and baclofen, and their roles may constitute fallback options. Side effect risks such as arrhythmias and weakness for digoxin and drowsiness for baclofen should be presented. Ketoconazole, a peripheral antiandrogen agent which suppresses androgen-dependent sleep-related erections that may precede priapism, carries the possibility of systemic side effects including sexual dysfunction, which warrants appropriate counseling.

In medically refractory or burdensome cases, central androgen ablation agents (eg gonadotropin-releasing hormone agonists) or penile prosthesis placement can be considered, which then have definitive therapeutic roles. However, these options are major or invasive, and accordingly are associated with possibly irreversible trade-off risks such as loss of natural sexual function.

This proposal reflects common aims to improve the quality of lives of individuals afflicted by priapism. Clinical management schemes will continue to be developed as new, rationally based treatments for this disorder come forward. It is hoped that further attention will be brought to modulating the course of priapism rather than simply treating its acute presentation.

  1. Musicki B and Burnett AL: Mechanisms underlying priapism in sickle cell disease: targeting and key innovations on the preclinical landscape. Expert Opin Ther Targets 2020; 24: 439.
  2. Burnett AL, Bivalacqua TJ, Champion HC et al: Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology 2006; 67: 1043.
  3. Bivalacqua TJ, Musicki B, Hsu LL et al: Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress. PLoS One 2013; 8: e68028.
  4. Hou LT and Burnett AL: Regimented phosphodiesterase type 5 inhibitor use reduces emergency department visits for recurrent ischemic priapism. J Urol 2021; 205: 545.
  5. Joice GA, Liu JL and Burnett AL: Medical treatment of recurrent ischaemic priapism: a review of current molecular therapeutics and a new clinical management paradigm. BJU Int 2021; 127: 498.

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