Glucose-6-Phosphate Dehydrogenase Deficiency: An Etiology for Idiopathic Priapism?
Arthur L. Burnett, MD, Department of Urology, The John Hopkins Hospital, 600 North Wolfe Street/Marburg 407, Baltimore, MD 21287-2411 USA. Tel: 410-614-3986; Fax: 410-614-3695; E-mail: firstname.lastname@example.org
Introduction. Efforts to identify the health risk associations for priapism may reveal pathophysiologic mechanisms for the disorder and suggest a scientifically rational approach for correcting it.
Aim. We describe a clinical presentation of idiopathic recurrent priapism in a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency and consider a possible nitric oxide (NO)-dependent mechanistic basis from which the medical condition causes priapism.
Methods. The case report profiled a 35-year-old African-American man with G6PD deficiency who presented with a rapid progression of recurrent priapism episodes. He was outwardly healthy and did not have sickle cell disease or trait by hematologic screening. His management featured use of a long-term, continuous phosphodiesterase type 5 (PDE5) inhibitor therapeutic regimen.
Main Outcome Measures. Clinical history data and response to PDE5 inhibitor therapy.
Results. After a 3-month duration of PDE5 inhibitor therapy, priapism recurrences were sufficiently resolved and the patient discontinued therapy. At 18-month clinical follow-up, he experienced only minor priapism recurrences and retention of full erectile ability.
Conclusions. G6PD deficiency offers an explanation for idiopathic priapism. The medical condition generates a pathophysiologic milieu consistent with aberrant NO signaling and heightened oxidative stress in the penis. Burnett AL, and Bivalacqua TJ. Glucose-6-phosphate dehydrogenase deficiency: An etiology for idiopathic priapism? J Sex Med 2008;5:237–240.
Priapism, a clinical disorder of persistent penile erection unrelated to sexual excitement, has been associated with a host of intrinsic and extrinsic conditions. Common associations include certain disease states such as sickle cell disease and hematogenous malignancies, physical trauma such as spinal cord injury and pelvic injury, and pharmacologic complications from erectile dysfunction treatments to psychotropic medication use . Many investigators have sought to provide an etiologic organization of these risk associations. In an early attempt to do so, Frank Hinman Sr in 1914 categorized priapism as having principally mechanical (e.g., pelvic malignancy resulting in penile vascular obstruction) or nervous (e.g., syphilis, brain tumors) origins. However, it was recognized that some forms of priapism did not simply fit such classical divisions of the disorder. Because of this recognition together with the apparent lack of a discernible cause for their occurrences, these forms of priapism came to be identified as idiopathic. In 1960, Frank Hinman Jr acknowledged the significance of the idiopathic variety of the disorder, characterizing its natural history of repeated, short-lived events and its clinical complications including erectile function loss consequent to penile ischemia. Priapism assigned to this category is believed to be quite prevalent, and in reported clinical series, it represents as much as 50% of clinical presentations .
The endeavor to profile priapism according to etiologic categories is not just worthwhile for practical understanding. Presumably, it offers opportunities to apply appropriate disease-specific therapy. By identifying the health risk associations for priapism, one may gain insight into the pathophysiologic mechanisms responsible for the disorder and may derive a scientifically rational approach for correcting it. Recent consensus committee clinical practice guidelines for managing priapism essentially are in line with this view, demonstrated as much by recommendations to screen for sickle cell disease for clinically obscure presentations of this disorder [2,3]. Identification of this particular medical condition supposedly facilitates an optimal treatment plan.
In this report, we describe a clinical case of idiopathic priapism that offers new insight into its biological basis. We report on a patient presenting with the disorder who happened to have glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is a common enzyme defect, which is linked with hemolytic anemia [4,5]. Although it is highly prevalent, the medical condition is frequently subclinical and thus, its status is likely unsuspected in many afflicted individuals. Given these considerations, we conjectured that G6PD deficiency may account for many instances of idiopathic priapism. We additionally provide a scientific rationale supporting this association.
A 35-year-old unmarried African-American businessman presented emergently with a 5-hour episode of priapism with increasing penile pain, which was observed upon awakening from nighttime sleep. He had reported a long-standing history of recurrent priapism, which began approximately 8 years previously, at which time he developed a major priapism episode requiring a corporoglanular shunt (Winter shunt) procedure for its resolution. A subsequent medical workup confirmed the absence of sickle cell disease or trait. During the week prior to his current presentation, he had made four separate emergency room visits for recurrent priapism, for which he received corporal aspirations of blood and irrigations containing sympathomimetic agents resulting in successful penile detumescence each time. In addition to these local treatments, he had been administered oral regimens of terbutaline and pseudoephedrine, but these had failed to prevent priapism recurrences. Medical history revealed no other health concerns, with the exception of G6PD deficiency. Physical examination confirmed rigid, somewhat tender corporal bodies to palpation, and an intracorporal blood gas measurement was pH 6.57, pO2 10, pCO2 183. Systemic hemoglobin was 13.5 (normal range 13.9–16.3 g/dL). Urine toxicology was negative. After penile detumescence was achieved once again using local treatments; a new treatment plan was initiated consisting of penile self-injections with phenylephrine as needed for priapism recurrences of more than 2 hours along with sildenafil 25 mg orally in the morning time following patient counseling and consent procedures, as described previously . At clinical follow-up 3 weeks later, he had escalated the sildenafil dosage to 50 mg under medical supervision and had discontinued phenylephrine injections after using this treatment for only approximately a week's time for several recurrent priapism episodes. At that time, his priapism disorder had significantly lessened, and he noted only brief, infrequent episodes. Approximately 3 months later as it appeared his priapism disorder had resolved, he discontinued sildenafil. Eighteen months later, he reported experiencing only rare, minor priapism recurrences that had not required medical attention, and he had preserved full erectile ability.
Our case study well typifies idiopathic priapism. The disorder traditionally involves recurrent priapism episodes, which our patient experienced. A classic feature of the disorder is ischemia leading to penile pain, also manifest in our patient. In idiopathic priapism, recurrent, increasingly severe episodes may develop and evolve into a major priapism episode. Our patient, too, developed increasingly clinically urgent episodes. The cause of idiopathic priapism as implied is obscure, and individuals presenting with the disorder characteristically lack obvious medical condition associations. Likewise, our patient was outwardly healthy, and he had not required any sort of regular medical interventions. In exploring a possible association with sickle cell disease or trait, hematologic screening was carried out, which excluded these possibilities. Review of his health history revealed a prior diagnosis of G6PD deficiency. In light of this fact, we wondered whether G6PD deficiency could be implicated in the genesis of his priapism disorder.
G6PD deficiency is the most common of clinically significant enzyme defects, and estimates indicate that more than 400 million people worldwide are affected [4,5]. The genetic medical condition is seen primarily in African-American individuals in the United States, occurring in as much as 10% of males of this population. Clinical manifestations of the condition are associated with hemolytic anemia, which in severe form actually has a low incidence. Hemolysis resulting from G6PD deficiency is an acute, temporary intravascular event usually precipitated by infection or exposure to an oxidant drug (e.g., sulfonamides, nitrofurantoin, and primaquine). Beyond these acute contexts, G6PD deficiency adversely impacts vascular biologic health with likely long-term effects. The condition has recently been described to contribute to the pathophysiology of cardiovascular diseases and diabetes mellitus [7,8]. Having a key role in glucose metabolism, G6PD catalyzes the oxidation of glucose-6-phosphate while reducing nicotinamide-adenine-dinucleotide phosphate to NADPH. NADPH is required for the detoxification of free radicals and peroxidases within cells, and in erythrocytes, G6PD is particularly essential for their protection from oxidative stress. G6PD deficiency thus implies weakened antioxidant defenses, alterations in cellular redox homeostasis, and consequently nitric oxide (NO) depletion and endothelial cell injury in biologic tissues. Additionally, because the cellular generation of NADPH is lacking in this condition, the function of NO, which requires NADPH as a cofactor in its synthesis, is fundamentally reduced.
This understanding suggests that G6PD deficiency sufficiently generates a pathophysiologic milieu which in the penis predisposes the development of priapism. The suggestion follows descriptions of priapism resulting from aberrant signaling of the NO signal transduction pathway and modulatory effects of oxidative/nitrosative stress in the penis [9,10]. An emerging perspective on the role of NO in the penis is that it does not solely operate as a momentary regulator of penile erection; it is also a major factor in the vascular homeostasis of the organ . Accordingly, for recurrent priapism, disruptive vascular homeostatic actions of NO in the penis affect the expressions and activity levels of molecular players such as phosphodiesterase type 5 (PDE5) and RhoA/Rho-kinase, which are responsible for keeping the erection response “in check”. In support of this view, we have observed increased oxidative stress and altered NO delivery and signaling in the penis of the human sickle cell gene-transfected mouse, which models human sickle cell disease and exhibits a priapism phenotype (Bivalacqua et al., unpublished data). Conceivably, priapism associated with G6PD deficiency is linked with defective redox homeostasis in the penis affecting its local NO-based vascular biology. Scientific investigation at both preclinical and clinical levels may serve to evaluate this concept further.
The administration of the PDE5 inhibitor sildenafil according to a carefully prescribed, long-term, continuous dosing regimen in our patient evidently led to relief of his rapidly worsening priapism disorder. This well-tolerated therapeutic regimen has been described recently to alleviate recurrent priapism episodes in several patients with recurrent priapism while preserving their erectile capabilities . Our patient demonstrated recalcitrance to first-line therapy for acute major priapism episodes [1–3], and thus the alternative treatment plan consisting of “off-label” PDE5 inhibitor therapy was explored understanding that it would not preclude other more invasive interventions such as penile shunt surgery if necessary. In accordance with basic scientific findings that PDE5 levels can be up-regulated with chronic PDE5 inhibitor dosing in vivo , it is perceived that the therapy works by reversing down-regulated PDE5 levels and aberrant NO signaling in the penis of individuals with recurrent priapism, which then protects against priapism episodes. The observation that our patient responded to the therapy suggests that PDE5 dysregulation likely was his mechanism of priapism, and furthermore, reduced tonic NO signaling had led to this defect.
We acknowledge the limitations of this report representing one case study. However, this report prompts additional evaluations which may confirm and extend our preliminary findings. Perhaps individuals presenting with idiopathic priapism should be screened for G6PD deficiency to determine the frequency of this risk profile. This course of action may be most practical for males of African-American descent presenting with the disorder, particularly if hematologic screening has excluded the presence of sickle cell disease or trait. A caveat is that screening tests for G6PD deficiency may yield a normal result after a hemolytic event has resolved. Even so, in view of emerging concepts supporting a molecular mechanism for priapism and the apparent utility of a new therapeutic option based on this mechanism, recognition of this possible diagnosis may encourage a treatment plan that is rational and disease specific.
In summary, in describing a clinical presentation of idiopathic recurrent priapism in an individual with G6PD deficiency, we propose that this medical condition offers an explanation for the etiologically obscure erectile disorder. The proposal is supported by the pathological circumstances of G6PD deficiency which would scientifically predispose priapism occurrences in accordance with recently advanced precepts for a molecular mechanism underlying the disorder. The suggestion that G6PD deficiency may be a cause of idiopathic priapism is further supported by the fact that many seemingly healthy individuals carry the condition even though they are asymptomatic of its familiar clinical manifestations. The possibility of G6PD deficiency-associated priapism coincides with the notion that idiopathic priapism truly has scientific explanations. Indeed, the erectile disorder is not an entity without a cause but rather an entity requiring etiologic clarification.
Conflict of Interest: None declared.