Abstract
Peyronie’s disease (PD), more commonly known as penile curvature, is caused by plaque formation in the connective tissue of the penis. PD affects 0.3% to 8.9% of men, most commonly between ages 40 and 60 years and can cause significant psychological distress, regardless of severity. There is a rich history behind the initial reports of PD, initial beliefs about pathogenesis, and initial treatment. This article aims to discuss the history of PD as well as the evolution of causes and treatments throughout time up to present-day theories of pathogenesis and treatment.
Peyronie’s disease (PD) is a connective tissue disorder where a plaque forms in the tunica albuginea of the corpora cavernosa, resulting in a penile abnormality (Hauck & Weidner, 2001). This is most commonly an upward deviation of the penis causing penile pain, and in some patients, erectile dysfunction (Mulhall, Schiff, & Guhring, 2006). Men between 40 and 60 years of age are most commonly affected, with an incidence of about 0.3% to 8.9% (Hauck & Weidner, 2001; Mulhall et al., 2006). This number may be a low estimate due to patient underreporting secondary to embarrassment of the condition or because of belief that it is part of normal aging (Mulhall et al., 2006). The most common location of these plaques is along the dorsum of the penis where it causes the classic upward deviation during erection (Hauck & Weidner, 2001).
PD is believed to be caused by an inflammatory reaction with thickening of the tunica, increased fibrin deposition, excessive production of collagen, and loss of elastic fibers that later become a calcified plaque (Hauck & Weidner, 2001). In 1957, Furey proposed that repeated penile trauma, typically during sexual intercourse, causes microvascular injury causing subsequent fibrin deposition (Furey, 1957; Jalkut, Gonzalez-Cadavid, & Raljfer, 2003). This fibrin deposition, along with immature type 3 collagen cells with reduced and fragmented fibers, has been identified in these plaques (Jalkut et al., 2003). The limited mobility caused by this sequence of events creates an environment less accommodating to blood engorgement during erection (El-Sakka, Hassoba, Pillarisetty, Dahiya, & Lue, 1997).
Besides the obvious change in physical appearance, PD can affect those afflicted with this disease in psychological aspects; even patients with a slight deformity can have a high level of bother and distress. In an effort to explore the psychological aspects and affects on the quality of life of patients with PD, Hellstrom et al. (2013) used the PDQ along with other criteria such as objective penile curvature measures. The Peyronie’s Disease Questionnaire (PDQ) is a disease specific, patient reported outcome measure to quantify the psychosexual impact of PD. The PDQ is used to measure three domains—(a) psychological and physical symptoms, (b) penile pain, and (c) symptom bother. Using data from two phase 3 clinical trials, Hellstrom et al. validated the use of the PDQ and the importance of treating the multiple angles of life that this disease can affect.
The Founding Father
While the disease bears the name of LaPeyronie, the Dutch had described the disease in two separate reports in 1687 and 1688 (Haneveld, 1979). In 1743, Francois Gigot de LaPeyronie most famously described the disease and no discussion of it can be complete without discussion of its namesake. LaPeyronie first described a man with “rosary beads” of scar tissue along his penis, which created an upper curvature of the penis (LaPeyronie, 1743). Born in Montpellier, France, in 1678, LaPeyronie was the son of Raymond LaPeyronie, a barber surgeon. The role of the barber surgeon during this period was one of a wartime surgeon. Barber surgeons, known for their technical skills with sharp blades, were trained through an apprenticeship while physicians, known for their vast knowledge of disease, were academically trained at a university. For this reason, physicians refused to acknowledge surgeons as legitimate professionals, needless to say, the field of medicine was divided between the university-trained physicians and the apprenticed barber surgeons. LaPeyronie received his education from a Jesuit institution, studied philosophy for 2 years and then began his study as a surgeon. After obtaining his license to practice in 1693, he moved to Paris to practice under Georges Marechal, the leading surgeon in Paris at the time. After this training, LaPeyronie decided to move back to Montpellier. LaPeyronie eventually became the surgeon in charge of St. Eloi Hospital. His obvious talent for teaching and surgery earned him the honor of chair of both anatomy and surgery at the University of Montpellier. In 1706, despite tensions that existed between physicians and surgeons, LaPeyronie founded the Royal Society of Sciences of Montpellier, which became an academic center for men of all fields (Dunsmuir & Kirby, 1996).
In the search for a more lucrative career, LaPeyronie moved back to Paris in 1715. While in Paris, his fame grew rapidly and soon he was treating kings of Poland and Prussia, and even Peter the Great. One of LaPeyronie’s greatest contributions to medicine was the novel surgical technique for removing devitalized, obstructed, or gangrenous bowel. Many of the principles he used for abdominal surgery paved the way for techniques currently used in modern-day surgery. For someone who contributed to medicine both through education and through establishing medical training facilities, LaPeyronie published only surgical case reports. The most famous is his report on the disease that would later be named after him, PD. In this case report, he described a patient with a “rosary bead” pattern of scar tissue on the dorsum of his penis and a stricture that caused the patient to ejaculate into his bladder (Dunsmuir & Kirby, 1996).
After the death of Georges Marechal in 1737, LaPeyronie became first surgeon to King Louis XV and through this position, influenced the king to separate the surgeons from the barbers. This allowed the surgeons their own doctorship and freed them from the tutelage of the medical faculty. This action allowed surgeons to become doctors, and the physicians no longer had exclusive control over medical academic titles (Dunsmuir & Kirby, 1996).
After his passing in 1747, LaPeyronie left his vast wealth to the surgical communities of Montpellier and Paris. Through his many contributions to the field of surgery and medicine, LaPeyronie set the stage for the future of surgery in France (Dunsmuir & Kirby, 1996).
Cause of Disease
Throughout the long history of PD, many factors have been theorized and proposed as potential causes of this disease. Despite all the experimentation and testing, the true cause of this disease still remains a mystery to the medical community.
During the time of Heraclius, a Byzantine Emperor in the seventh century, the cause was believed to be incest. Another theory suggested that Heraclius’s marriage to his niece caused him to urinate on his face due to his penile curvature (Lascaratos, Poulakou-Rembelakou, Rembelakos, & Marketos, 1995; Murphy, 1972). In 1267, Theodoric described “hard tubercles” of the penis, a distinct entity from “black warts,” a suggested contagious disease. The tubercles did not fall off like warts, but rather caused a “heaviness” during penile distension. This was an early infectious theory of PD (Campbell & Colton, 1960).
In the 18th and 19th centuries, several authors (Hunter, Abernethy, Baillie, and Wardrop) had associated PD with gonorrhea and syphilis. Abernethy proposed the association of Dupuytren’s contracture and PD during this time as well (Dunsmuir & Kirby, 1996). Because of Dupuytren’s contracture’s autosomal dominant pattern of inheritance, a new genetic theory was introduced (Levine, 2007). Bidgood reported another notable manifestation of the disease, where severely burned pilots that had received transfusions through the penis developed this disease. By the 19th and early 20th centuries, gout and diabetes had been added to the accepted possible causes of PD. Studies during the 19th and 20th centuries demonstrated that most cases of PD had no relation to any particular disease state (Dunsmuir & Kirby, 1996).
In 1942, Wesson reviewed the current literature and summarized the American view, which centered on the patient’s sexual history (Dunsmuir & Kirby, 1996). He believed that when a “youth is addicted regularly to sessions of prolonged ungratified sexual desires, his prostate, being in a constant state of engorgement, will develop prostatic hypertrophy”. Similarly, Wesson believed that if the patient evolved/progressed to become a chronic violator of “Nature’s Laws” in middle age, he would develop PD (Dunsmuir & Kirby, 1996; Yachia, 2007). In addition, the latter situation was believed to be associated with menopause and physiologic changes of the consummate partner’s ability to lubricate. Rightly, trauma was suspected and was a described as being a result of the “annoying resistance” experienced during intercourse while penetrating a “bored acquiescence.” Sir William Osler believed the explanation for the onset of the disease in the fourth decade of life was directly related to the onset of the female partner’s menopause. Similarly, in an earlier publication, Van Buren and Keyes (1874) reported that the condition was absent in patient whose “consort [was] enthusiastically co-operative.” At the end of the 19th century, PD was also called Van Buren’s disease in the United States in honor of one of the American investigators of this disease (Yachia, 2007).
A more modern theory behind the causality of PD involves micro- or macrotrauma and the relationship between plaque formation and transforming growth factor-β1 (TGF-β1). TGF-β1 increases fibroblast activity, which increases collagen synthesis while concomitantly inhibiting collagenase, thus inhibiting connective tissue breakdown. Also, TGF-β1 induces its own production and thus the process is self-propagated (Jalkut et al., 2003). A study by El-Sakka et al. (1997) examined penile tissue from the tunica albuginea of 30 patients with PD and from 6 patients without the disease. TGF-β1 expression was present in 26 of the patients with the disease and in one of the patients without the disease (the one patient in the non-PD group with TGF-β1 expression had undergone two previous penile surgeries). In a follow-up study, this group successfully demonstrated a relationship between trauma and increased TGF-β1 production by artificially inducing expression after incision of rat tunica albuginea (El-Sakka et al., 1997). Questions as to the specifics of pathogenesis remain.
Natural History of the Disease
Since Peyronie first reported on PD, much is still unknown about the natural progression of the untreated disease. The disease has been divided into an early/acute phase and a late/stable phase (Mulhall et al., 2006; Safarinejad, Hosseini, & Kolahi, 2007). Pain in the flaccid or erect state without much curvature is the hallmark of the early phase, which can last for 12 to 18 months. The late phase has less pain with a more significant plaque present and the classic penile abnormality with erection (Mulhall et al., 2006).
In 1970, Williams and Thomas reported a series of 12 patients with untreated PD. Interestingly, pain resolved over time in all patients. More significantly, half of patients achieved spontaneous resolution of the plaques (Mulhall et al., 2006). These findings became the backbone for conservative treatment in patients with this disease, despite the small sample size.
Gelbard et al. (2013) evaluated 97 patients with PD using a questionnaire. 94% had spontaneous pain resolution but disease resolution was reported in only 13% (47% reported no change and 40% described the condition as worse). While this evidence opposes conservative therapy, there were some obvious flaws in this study, including self-reported assessments without physical exam by a urologist experienced with PD (Gelbard et al., 2013).
In an attempt to remove confounding factors and possible sources of error, Mulhall et al. (2006) recreated Williams and Thomas’s study with stricter inclusion criteria and a more objective and quantifiable method of measuring progression or regression of the disease. Patients included carried a diagnosis of PD (defined by a palpable plaque at examination by a single urologist experienced with PD management), presented within 6 months of the onset of PD, and elected to defer medical treatment. These patients were followed at least 12 months after the baseline assessment and were able to achieve erectile rigidity sufficient for penetration after intracavernous medication administration. Patients were assessed at baseline and follow-up visits using intracavernous Trimix (phentolamine, papavarine, and prostaglandin E1) to achieve maximal erection. After achieving maximum rigidity, they measured plaque dimensions, penile length, and degree of curvature (Mulhall et al., 2006).
After including 246 patients (217 with penile curvature as the primary complaint), Mulhall et al. (2006) demonstrated that 12% of patients improved, 40% remained stable, and 48% worsened at follow-up. Also, at the follow-up visit, pain was assessed and penile length was measured with a goniometer, before and after administration of intracavernous Trimix. The plaque was also assessed for progression. In contrast to Williams and Thomas’s initial report, which reported a 50% chance of spontaneous remission, Mulhall et al. demonstrated that a conservative approach offers little benefit to the patient.
Treatment
Starting during the time of LaPeyronie, many treatments have been proposed for PD. LaPeyronie had suggested that his patient should have spa specific treatments with mineral water from Baréges, France. In the 19th century, Curling attempted to use oral and topical mercury and iodides. Mercury was hypothesized to be effective because of the supposed relationship of PD with syphilis, iodides because of the reported healing action of both agents. Wesson, who believed acidification could dissolve the plaques, prescribed oral disodium phosphate with no success (Dunsmuir & Kirby, 1996). Other attempts have been attempted and are discussed below.
Medical Treatments
As reported above, conservative management offers little benefit to patients with PD, thus intervention should be pursued. Attempts at experimentation with different oral agents in the early stages of PD have been difficult and mostly unsuccessful. This may be due to difficulty in assessing response due to spontaneous pain resolution and rare but reported spontaneous improvement in curvature (Mulhall et al., 2006).
Two commonly used treatments for PD are oral vitamin E and oral propionyl-
Another commonly prescribed drug for PD is potassium aminobenzoate (Potaba). The mechanism of action is not clearly understood but is thought to decrease fibrinogenesis through altered serotonin levels. The typical dose to treat PD is 20 g per os (by mouth) daily for 3 to 12 months. Barriers to this treatment include the cost and gastrointestinal side effects. Potaba was reported to have a success rate of 57% in a noncontrolled study (Jalkut et al., 2003).
Colchicine, an oral agent effective in the treatment of gout, has been used in the treatment of PD as well. Colchicine binds to tubulin and inhibits the process of mitosis. This action is believed to slow the progression of PD. In a randomized double-blind, placebo-controlled study, 87 men were divided into two groups, receiving either placebo or 0.5-2.5 mg oral colchicine. After 4 months of treatment, there was no difference between groups with respect to improvement of pain, curvature angle, or plaque size (Safarinejad, 2004).
Using the theory that TGF-β1 plays a key role in the scarring and fibrosis of PD, tamoxifen has been proposed as a treatment option. In a placebo-controlled study by Teloken et al. (1999), 25 men were divided into two groups receiving either placebo or tamoxifen. After 3 months, there was no difference between groups (Teloken et al., 1999).
As reported in the multiple studies previously described, the use of oral medications does not seem to be a fruitful treatment option for PD at this time. Perhaps these null results are due to the decreased vasculature of the plaques, which limits drug delivery to the site of interest. A summary of oral agents is included in Table 1.
Oral Treatment Options Proposed for Peyronie’s Disease.
Note. IU = international unit; po = per os (by mouth); qd = once daily PLC = propionyl-
Source. Adapted from Jalkut, Gonzalez-Cadavid, and Raljfer (2003); Safarinejad (2004); Safarinejad, Hosseini, and Kolahi (2007); and Teloken et al. (1999).
Intralesional Injections
Beginning in the late 19th century, Walsham and Spencer experimented with injections of mercury and iodides into PD plaques. In 1954, Teasley pioneered the idea of intralesional steroid injections. The difficulty of these injections led Hinman to create the “high-pressure” screw threaded injection device that made the injections easier to perform. In more recent studies verapamil, a calcium channel blocker and collagenase, used in the treatment of Dupuytren’s contracture, have been used and are discussed in the following section (Dunsmuir & Kirby, 1996).
Levine, Goldman, and Greenfield (2002) demonstrated that intralesional injection of verapamil improves many symptoms of PD. Patients received injections every 2 weeks for a total of 12 treatments. Of the 156 patients who started the study 140 patients finished the treatments and 60% had an objective measured decrease in curvature, 83% reported an increase in girth, 83% noticed an increase in rigidity distal to the plaque, and 71% noticed improved sexual function (Levine et al., 2002).
In an attempt to evaluate the efficacy of intralesional injections of interferon alpha-2b in PD, Trost et al. (2013) performed a retrospective chart review of 127 patients who had undergone intralesional injections from 2001 to 2012. Some of the variables analyzed in this study were patient demographics, disease characteristics (e.g., duration), penile duplex ultrasound findings, objective measurements of curvature, and plaque location. The treatment consisted of biweekly injections of 2 × 106 units of interferon suspended in 10 mL of normal saline. 83% of patients underwent one cycle of treatment (12 injections), while 17% underwent two cycles (24 injections). Patients whose penile curvature was greater than 90 degrees, had erectile dysfunction refractory to phosphodiesterase-5 inhibitors, or those with multiple, complex, or multiplanar curvatures were excluded. At the conclusion of this study, 68 (54%) of patients experienced ≥20% improvement in curvature, with an average improvement of 9% overall for the study. 13 (10.2%) patients’ curvature worsened, 24 (18.9%) had no change, and 90 (70.9%) improved through the course of this study. This suggests no significant associations between the likelihood of ≥20% response and plaque location, pretreatment vascular status, individual penile ultrasound parameters, age, or pretreatment erectile function. Although only 54% of patients experienced ≥20% improvement in curvature, the study did identify a trend of increasing improvements with greater pretreatment curvature although this did not reach statistical significance (Trost et al., 2013).
Because of its natural ability to break down collagen and other extracellular matrix proteins, collagenase has been a drug investigated in the treatment of PD. Collagenase is currently approved for the treatment of Dupuytren’s contracture. A recent post hoc meta-analysis of the IMPRESS (Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies) I and II trials (a phase 3, double-blind, randomized, placebo-controlled study using intralesional injection of collagenase, created by Clostridium histolyticum) reported significant improvement in the treatment group. The treatment consisted of intralestional collagenase injections a maximum of 8 times, followed by penile modeling after each injection. There was a mean penile curvature improvement of 34% compared with a mean curvature improvement of 18.2% in the control group (placebo injection and penile modeling). Limitations of this study include a population base of mostly White men with mature plaques and moderate penile curvature and the exclusion of men with calcified plaques (Gelbard et al., 2013).
The investigation and trials of different agents injected directly into the plaques, which cause PD are positive and may offer a better means of non-surgical treatment in the future.
Surgical Interventions
Surgical intervention in PD is typically limited to cases of PD that are refractory to other treatments or that cause significant impairment in sexual function. Many options have been explored in the search for the best treatment of this disease, ranging from simple plaque excision to implantation of an inflatable penile prosthesis (IPP).
One of the more common surgical interventions for PD is the Nesbit operation. An ellipse is excised from the tunica albuginea, 1 mm for every 10° of curvature. Patients with good erectile function, adequate penile length and without an hourglass narrowing achieve the best results (Jalkut et al., 2003). Several modifications have been applied to this procedure in an attempt to increase the precision and success rate. Rolle et al. (2005) proposed that plication sutures be placed on the convex aspect of the penis before tunica albuginea resection. Using this technique on 18 men with a mean angle of 48°, all cases of penile curvature were completely corrected (Rolle et al., 2005).
Implantation of an IPP in PD is usually reserved for men who also have erectile dysfunction not responsive to medical therapy. Modern-day IPPs provide excellent results with no need for further operation in mild cases of PD (Jalkut et al., 2003). In a large multi-institutional study, Wilson, Cleves, and Delk (2001) reported that PD was the second most common diagnosis leading to IPP implantation following vascular disease (Rolle et al., 2005). Implantation has also been combined with some surgical remodeling techniques to maximize results (Jalkut et al., 2003; Rolle et al., 2005).
The rich history of PD offers a rare insight into the historical perspectives of causality and treatment that allows us to reflect on the advancements made in the management and treatment of PD as the 21st century begins. The elusive cause of PD has generated interest in research and resulted in varied approaches to its treatment. From the days of LaPeyronie where he suggested mineral water to the refined surgical and medical techniques of present, countless ideas for treatment have been tried and tested. The inability to find a definitive treatment and the grave psychological impact of this disease will undoubtedly fuel future endeavors into finding the unknown cause of this disease. The disease’s rich historical history allows us to appreciate how far investigations come and allow us to consider how much more remains to be uncovered.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.