© 2007 International Society for Sexual Medicine Classic Citations Priapism: Reasons for Failure by Frank Hinman Jr Sidney Glina, MD,* Arthur L. Burnett, MD,† Edgardo Becher, MD,‡ Gerald Brock,§ and Wayne Hellstrom, MD¶ *Department of Urology, Instituto H. Ellis, São Paulo, Brazil; †Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital and The Johns Hopkins University School of Medicine, Baltimore, MD, USA; ‡Division of Urology, University of Buenos Aires, Argentina; §Division of Urology, University of Western Ontario, Canada; ¶Department of Urology, Tulane University, New Orleans, LA, USA I n his article from 1960, Frank Hinman Jr [1] through the description of seven cases of idiopathic priapism gave the features of this disease. All seven patients had had previous transient episodes of priapism and prolonged sexual excitement before the final episode; erection of the corpora cavernosa sparing of corpus spongiosum; presence of dark thick blood, without clots, inside the corpora and refilling with bright blood after aspiration; limited subsidence after aspiration and eventual nonrefilling after it; and partial or complete erectile dysfunction after the episode. Patients’ ages were between 31 and 53 years, and six of seven had been treated with repeated aspirations or incisions until the erection went away. One patient had received a ganglionic blocking agent on the ninth day of priapism. The author suggested that priapism was caused by an overfunction of the normal erectile mechanism, sometimes reversible. For him, the disorder was related to vascular stasis, increase of carbon dioxide of the blood, and blood viscosity. He also found on biopsies that cavernous spaces had become edematous and thickened after days of erection that progressed to fibrosis. This would be one of the reasons why none of seven patients regained a normal erection; although four had a partial proximal erection. After discussing the current theories of erection mechanism in the 1950s, the author defined priapism “as persistent erection without sexual excitation.” He also proposed a classification of the disorder: neurogenic, mechanical, and idiopathic. Finally, he proposed a “working hypothesis” for the physiopathology of priapism: erection was prolonged by psychic or local excitatory factors, resulting in venous stasis, rise in blood viscosity, which produced relative venous occlusion at the J Sex Med 2007;4:1539–1543 site of the junction of cavernous spaces and collecting veins, edema of the trabeculae, which reduced further venous outflow, eventually occlusion of the arterioles, and finally fibrosis and disruption of the arteriovenous supply mechanism preventing normal erections. Hinman evaluated available treatment options, and declared that none was really effective because they could neither restore venous drainage nor eliminate the progressive damage to the erectile tissue. He suggested sedation, analgesia, local hypothermia, and aspiration as treatment. The last suggestion did not promise a perfect result for the patient. Sidney Glina, MD Editor, Classic Citations The article by Frank Hinman Jr, on the subject of priapism, is a classic article in the discipline of sexual medicine [1]. In it, Hinman undertook an illuminative, critical analysis of the clinicopathological features of priapism, a historically misconceived and mysterious clinical disorder, laying the groundwork for its improved treatment. His main interest was idiopathic priapism, an attribution applied still today to more than half of documented clinical cases [2], which he distinguished from forms of the disorder associated with neurogenic, vascular, neoplastic, and traumatic conditions. This inference itself, which the causation of priapism is multifaceted, is an important contribution. The disorder should be correctly viewed as originating from different causes and relating to multiple conditions, much as we today acknowledge that the more commonplace erectile disorder—erectile dysfunction—arises in association with different disease states and involves diverse pathophysiologic underpinnings. Contemporary 1539 Classic Citations scientists and practitioners in this field may do well to continue to demystify priapism and next reduce the notion that idiopathic priapism refers to a clinical disorder without an etiology but rather one that has an etiology awaiting scientific clarification. Hinman elucidated the natural history of priapism and its stages of progression common to erectile inability. He recorded that the disorder may also have a recurrent nature, sometimes allowing a return to normal erectile function. This suggested to him that the disorder in some situations could be typified as a “reversible over-function rather than a gross, pathologic derangement.” This insight, along with his additional observation that the recurrences frequently followed the conditional stimulus of excessive sexual activity, contributed to viewing priapism as a problem in the control of penile erection. This evolutionary view has now been supported by several investigators, who have postulated more concretely that upsetting or resetting the control mechanisms associated with corporal smooth muscle tone may account for some forms of priapism [2–5]. Accordingly, a contemporary thesis is that such forms of priapism involve dysregulatory mechanisms resulting in an unbalanced state of enhanced corporal smooth muscle relaxation and/or its impaired contraction. Very recently, the new science of priapism upholds that dysregulations of the activity level of phosphodiesterase type 5 (PDE5), a crucial molecular regulator of the nitric oxide-mediated erectile response [6], as well as signaling of RhoA/Rho-kinase, the main mediator of tonic vasoconstriction in the penis [7], are key factors in the molecular basis of priapism at the local penile tissue level. Hinman characterized the pathologic changes of the penis during episodes of priapism. This description included the features of dark, viscous blood in the corpora cavernosa, erectile tissue ischemia, and its edematous changes that progress to fibrosis. His “working hypothesis” about the pathophysiology of priapism was that vascular stasis and decreased venous outflow were the primary determinants operating mechanically to interfere with detumescence. He further proposed “changes in carbon dioxide tension” and “decreased oxygen tension” as pathophysiologic elements, which he contended caused erythrocytes to become increasingly deformed in the penis in patients, prominently in those with sickle cell 1540 disease, predisposing them to acquire priapism. While plausible at the time of Hinman’s review, we now appreciate that a more complex pathophysiology underlies many forms of the disorder. The priapism associated with sickle cell disease probably represents a penile vascular biologic process and pertains to disturbances in the regulatory mechanisms of penile erection. Additionally, for recurrent priapism, mechanisms of oxidative and nitrosative stress acting at a molecular level in the penile tissue are believed to be in play after repeated ischemic insults to the penis, and also condition the organ toward defective erection regulatory responses. Hinman also recognized that treatments for ischemic priapism in his day were woefully inadequate, an assessment that unfortunately still applies today. To improve outcomes when managing the disorder, he charged that “to be effective, measures aimed at increasing venous drainage must be applied early.” The recommendation is consistent with demonstrations that relief of pain and preservation of the health of the penis resulted from maneuvers to address its failed venous outflow. Over time, sundry descriptions of earlyadministered penile drainage procedures and shunts emerged in the literature, and have taken center stage in clinical practice. These interventions remain reactive in principle, however, and they fail to prevent the disorder from recurring or progressing in some individuals to an end stage presentation. For the future, it would seem appropriate to pursue at least a secondary preventative action as a definite management goal, and develop effective treatment aimed at correcting the underlying pathophysiology. Active research in the field should hopefully meet this new charge, thereby preserving the sexual health and psychological well-being of many individuals afflicted by the disorder. Arthur L. Burnett, MD In this landmark article [1], Hinman presented the study of seven patients with idiopathic priapism showing seven common features: (i) previous episodes of priapism or intense sexual activity, (ii) erection limited to the corpora, (iii) presence of dark, thick blood on aspiration, (iv) refilling of corpora with bright red blood after early aspiration, (v) limited subsidence after aspiration, (vi) eventual nonrefilling if treated late, and (vii) partial or complete impotency. J Sex Med 2007;4:1539–1543 Classic Citations This is the first systematic observation of idiopathic priapism events with an explanation of a possible pathophysiology. The author clearly expressed that the venous outflow is less than the arterial inflow, and in this case of stasis, carbon dioxide content rises, augmenting the blood viscosity. The author also supported Conti’s [8] observation of the vascular “polsters” as vascular inflow and outflow regulator. He suggested that another mechanism described by Kiss [9], being the compression of the veins against Buck’s fascia, could play a role. The latter is a closer approach to the current knowledge of corporeal venoocclusion. By that time, the tunica albuginea was not differentiated from Buck’s fascia. The fibrotic consequences of priapism were clearly stated, leading to irreversible erectile dysfunction. The author also presented a postulate for normal erectile mechanism, where the erection is mostly a consequence of an increased arterial inflow with a fixed venous outflow regulated by Conti’s “polsters.” At that time, the role of smooth muscle relaxation, endothelium, and corporal veno-occlusion were not known. The available treatments at that time were neural block, corporeal blood aspiration, pressure dressings to prevent refilling, anticoagulants, estrogens, and sedatives. The author recognized the poor results explaining that the reasons are that those treatments do not restore the venous drainage and do not eliminate the progressive tissue damage, stressing the need of early management. Current knowledge has allowed us to differentiate between low-flow (ischemic) and high-flow (arterial) priapism [10], and appropriate management of low-flow priapism with early aspiration and eventual use of a-adrenergic drugs and the rare need of percutaneous or surgical shunts. Edgardo Becher, MD Reflecting back over classic articles can be an incredibly enriching experience. As in the world of fashion, where not everything new is original, in the discipline of scientific research and investigation, ideas in various forms of development may have very humble beginnings. While researchers today are armed with powerful computers, microchip arrays, and molecular techniques, the knowledge, important observations, and hypotheses passed down from our mentors can be more powerful than any equipment available today. J Sex Med 2007;4:1539–1543 The classic article authored by Frank Hinman Jr in 1960 [1] remains an often-cited reference that has served as an essential thought-provoking manuscript leading to our contemporary view of priapism, but has also served as the nidus for future work on the physiology of erection [11–13]. While the article reports on seven cases of idiopathic priapism and provides the readership with Hinman’s theories of why therapy was not successful, his concepts of etiology of the condition and the impact of therapy on the end organ are the most valuable components of this landmark article. In my opinion, his thoughts and theories remain viable today as we continue to search for novel neurophysiologic pathways and pharmacological approaches to this common problem [14–16]. Whereas the article refers to cases of idiopathic priapism, we would likely classify them as ischemic or veno-occlusive priapism. In several parts of this report, Hinman described the development of increased viscosity of the blood leading to impaired drainage. He identified sickle cell disease as a prototypical example of this disordered state of normal physiology, and reflected on the potential of conservative management to be effective at times. In our own publication, more than three decades subsequently, we reported on the potential for conservative management approaches in cases of high-flow priapism [17]. Hinman’s article puts forth the hypothesis that normal erection is mediated primarily by arterial inflow, and that polsters or valves cannot be supported by histological studies performed at that time. This assessment and interpretation would be confirmed within two decades by a number of investigators using dog, monkey, and cadaveric models. Within the past decade, there has been a renaissance in the field of priapism research. Novel animal models and innovative therapeutic approaches have been reported in an attempt to reduce the morbidity that results from this condition. In contrast to Hinman’s article, a clear classification system based on physiologic findings within the penis now exists and serves as a foundation of management. Our genuine understanding of the cellular basis of this problem among many of those affected remains lacking. Finally, in his conclusions, he stated that therapy for priapism often fails owing to (i) failure to restore venous drainage and (ii) treatment does not eliminate the progressive damage to the local 1541 Classic Citations erectile mechanisms. These causes for treatment failure are as true today as they were more than 45 years ago. His summary states that prolonged erection leads to venous stasis, increased viscosity with venous outflow occlusion, and ultimately fibrosis. That impotency is the usual end result, is his final comment, a statement that remains as accurate today as it was then, disappointing as that is. Gerald Brock, MD “Those who do not read history are condemned to repeat it.” George Santayana As a fledgling urology resident keen on doing novel urologic research, Frank Hinman Jr impressed upon me that new ideas in science were rare; all one had to do was search the literature to find that most things had already been done. He was particularly fond of German researchers from the 19th century. Priapism (persistent penile erection without pleasure) and its treatments have been known since antiquity, as portrayed in Egyptian papyrus drawings. It was first recorded in modern literature by Petraeus in 1616, and successfully treated with leeches by Trife in 1845. In 1914, Frank Hinman Sr published his 27-page seminal treatise on the pathophysiology of priapism [18]. While Hinman Sr classified priapism into neurogenic, vascular, neoplastic, and traumatic as recognized etiologies, Frank Hinman Jr decided to focus on the idiopathic or unknown category in his 1959 and 1960 articles [1]. It must be appreciated that half a century ago, most urologists advocated delayed intervention for priapism, as many viewed treatment as the major cause of erectile dysfunction. Simple as it may seem, Hinman Jr tabulated features from seven men with idiopathic priapism, reviewed the pertinent literature on the subject, obtained conventional microscopy of cavernosal tissues, and deduced a workable hypothesis on the pathophysiology of idiopathic priapism. The cornerstone of his contribution was noting the progression of changes with time using light microscopy of sections from the afflicted cavernosal tissues. Initially, there was “edema of the myriad trabeculae in the corpora.” With time, fibrosis of the smooth muscle cells takes place, making recovery of erection impossible. Further corroboration of these findings was confirmed by Spycher and Hauri in 1986 [19]. Using electron 1542 microscopic analysis, they clearly showed trabecular smooth muscle being transformed into fibroblast-like cells or areas of necrosis after a 24-hour hypoxia. Hinman invoked many early scientific writings to unify his pathophysiologic concepts. He mentioned Conti’s polster theory [8] but more importantly referenced Kiss’ impedance of venous outflow by compression of the veins against the fibrous coats of Buck’s fascia [19]. He, in effect, described an overfunctioning veno-occlusive mechanism as being the major factor causing idiopathic priapism. Finally, Hinman identified fibrosis as causing permanent impotency, and identified the two basic reasons for its occurrence: 1. not restoring venous drainage 2. not eliminating the progressive damage to the erectile mechanism. He suggested that venous drainage must be applied early, irrespective of the arterial supply, and that prevention of fibrosis is paramount in preserving erectile function. Currently, research has moved to molecularbased concepts. Researchers have new molecules (e.g., nitric oxide), pathways (e.g., Rho-kinase), and treatment options (e.g., PDE5 inhibitors) to study priapism and similar idiopathic diseases. Young researchers will soon investigate conditions that have plagued urologists and patients for centuries, specifically the concept of “fibrosis” as noted by Frank Hinman Jr. As we deal with common conditions, such as Peyronie’s disease, cavernosal fibrosis, and urethral strictures, it will be important to study the past in order to move forward. Wayne Hellstrom, MD Corresponding Author: Sidney Glina, MD, Department of Urology, Instituto H. Ellis, Rua Almirante Pereira Guimarães 360, São Paulo, São Paulo-SP, 01250-000, Brazil. Tel: 55 11 387 12466; Fax: 55 11 387 12466; E-mail: glinas@terra.com.br References 1 Hinman F Jr. Priapism; Reasons for failure. J Urol 1960;83:420–8. 2 Burnett AL. Pathophysiology of priapism. Dysregulatory erection physiology thesis. J Urol 2003;170: 26–34. J Sex Med 2007;4:1539–1543 Classic Citations 3 Lue TF, Hellstrom WJG, McAninch JW, Tanagho EA. Priapism: A refined approach to diagnosis and treatment. J Urol 1986;136:104–8. 4 Levine JF, Saenz de Tejada I, Payton TR, Goldstein I. Recurrent prolonged erections and priapism as a sequela of priapism: Pathophysiology and management. J Urol 1991;145:764–7. 5 Melman A, Serels S. Priapism. Int J Impot Res 2000; 12:S133–9. 6 Champion HC, Bivalacqua TJ, Takimoto E, Kass DA, Burnett AL. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA 2005;102:1661–6. 7 Bivalacqua TJ, Liu T, Musicki B, Champion HC, Burnett AL. Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis. Eur Urol 2006 [Epub ahead of print]. 8 Conti G. L’erection du penis humain et ses bases morphologicovasculaires. Acta Anat 1952;14:217. 9 Kiss F. Anatomisch-histologische Untersuchungen über die erection. Ztschr F.d. ges Anat 1921;61:455 10 Lue TF, Hellstrom WJG, McAnich JW. Priapism: A refined approach to diagnosis and treatment. J Urol 1986;136:104. 11 Bivalacqua TJ, Burnett AL. Priapism: New concepts in the pathophysiology and new treatment strategies. Curr Urol Rep 2006;7:497–502. 12 Burnett AL. Nitric oxide in the penis—science and therapeutic implications from erectile dysfunction to priapism. J Sex Med 2006;3:578–82. J Sex Med 2007;4:1539–1543 13 Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology 2006;67:1043–8. 14 Berger R, Billups K, Brock G, Broderick GA, Dhabuwala CB, Goldstein I, Hakim LS, Hellstrom W, Honig S, Levine LA, Lue T, Munarriz R, Montague DK, Mulcahy JJ, Nehra A, Rogers ZR, Rosen R, Seftel AD, Shabsigh R, Steers W. Report of the American Foundation for Urologic Disease (AFUD) Thought Leader Panel for evaluation and treatment of priapism. AFUD Thought Leader Panel on Evaluation and Treatment of Priapism. Int J Impot Res 2001;13(5 suppl):S39–43. 15 Pautler SE, Brock GB. Priapism. From Priapus to the present time. Urol Clin North Am 2001;28:391– 403. 16 Chan PT, Bégin LR, Arnold D, Jacobson SA, Corcos J, Brock GB. Priapism secondary to penile metastasis: A report of two cases and a review of the literature. J Surg Oncol 1998;68:51–9. 17 Brock G, Breza J, Lue TF, Tanagho EA. High flow priapism: A spectrum of disease. J Urol 1993;150: 968–71. 18 Hinman F. Priapism. Report of cases and a clinical study of literature with reference to its pathogenesis and surgical treatment. Ann Surg 1914;60:689. 19 Spycher MA, Hauri D. The ultrastructure of the erectile tissue in priapism. J Urol 1986;135:142– 7. 1543