The Natural History of Peyronie's Disease

1. Towards a more accurate definition of acute phase

According to International Guidelines [12], acute phase is characterized by various and dynamic signs and symptoms. In addition, the hallmark of the active phase is the presence of inflammatory infiltrate within the tunica albuginea of the penis [13]. The duration of active phase has been demonstrated to differ considerably across previous studies and no significant correlation between disease duration and spontaneous healing in penile curvature was shown. It is usually assumed that active phase can last up to 12 to 18 months, even if several series do not include a temporal factor at all in the categorization of acute phase [14]. In our opinion, this might have contributed to further undermine the efforts towards a correct definition of acute phase.

2. Clinical manifestations during acute phase

As mentioned before, plaque formation generally occurs during the active phase. In the early phase of the disturbance, patient may present with penile pain, especially during erection and sexual intercourse, penile curvature, or simply penile deformation (shortening or narrowing) without clearly palpable plaque. It should be kept in mind that most patients present with a palpable plaque, but some are unaware of it [15]. In some cases, non-palpable isolated septal plaques without deformity of the penis may be present. In such condition, ultrasonographic evaluation may allow earlier identification and treatment of occult septal injuries or lesions and prevent subsequent fibrosis and its associated symptoms [16, 17]. Location of the plaque considerably differs across previous studies, being dorsal location the most frequent at disease onset (Table 1) [18, 19, 20, 21]. Similarly, deviation of erect penis is significantly changeable according to previous reports (Table 2) [18, 20, 21, 22, 23]. Clearly, there might be some patients who traumatize their penis and, thus, develop a secondary curvature due to the inflammation process and loss of compliance. An association to trauma and position during sexual intercourse has been also suggested, based on the assumption that certain position of intercourse might be ultimately traumatic for the penis [12].

Table 1
Location of plaque in the penis

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Table 2
Erect penis curvature

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Active phase can manifest also with ED in a percentage of cases ranging from 22% to 54% [24]. Conversely, not all patients present with penile pain at disease onset. According to current available literature, its incidence ranges between 20% up to 70% of cases [24]. However, when penile pain is present, it generally tends to resolution within 12 to 18 months. On the contrary, when penile curvature is present, this tends to stabilize or even worsen during the natural course of the disorder [25].

As such, the watchful waiting approach of the acute phase could be dangerous for the patients due to the possible worsening of the curvature and penile shortening.

3. Molecular regulators during Peyronie's disease acute phase

As previously stated, it is hypothesized that repeated microtraumas might set off an inflammatory reaction in the tunica albuginea of the penis. In the last few years, a prominent role has been recognized in the extracellular matrix (ECM), as being both the main actor and part itself of the fibrotic process. More in detail, ECM is involved in pivotal functions to start and maintain the profibrotic cascade. The intricate milieu connecting ECM, fibroblasts and innate/adaptative immune system cells has been recently described in detail by Pakshir and Hinz [26]. In brief, in response to first mechanical insult and tissue damage, several damage-associated molecular patterns (DAMPs) are released either from stressed cells and the ECM itself. Binding between DAMPs and toll-like receptors (TLRs) displayed on the surface of macrophages/dendritic cells stimulates various inflammatory responses. Specifically, TLRs trigger necrosis factor-κB release, which in turn is responsible for the production of a wide range of proinflammatory cytokines, such as interleukin 1b (IL-1b), IL-6, and tumor necrosis factor α and elicit release of chemotactic and T-cell activating factors (primarily CD80 and CD86). In addition, in this phase macrophages/dendritic cells are able to chemically communicate with fibroblasts to start a myofibroblast phenotype transformation through release of transforming growth factor (TGF)-β1, ultimately resulting in ECM production.

On the other hand, myofibroblasts start depositing collagen in response to TGF-β1 and, thus, may play a significant role in plaque formation. Several animal models already confirmed that TGF-β1 overexpression is able to stimulate collagen deposition by myofibroblasts, finally leading to plaque development. Conversely, inhibitors of the TGF-β1 receptor kinase stimulate the involution of fibrotic plaques and, as a consequence, lead to a decrease in penile curvature [27]. In particular, IL-1b induces matrix metalloproteinase expression, while TGF-β strongly induces tissue inhibitors of matrix metalloproteinases (TIMP) expression, ultimately resulting in PD plaque progression. As such, the local increase of TIMPs together with decreased matrix metalloproteinase activity may represent, thus, the biochemical result of TGF-β overexpression [28].

A key role in PD pathogenesis is also attributed to reactive oxygen species (ROS). ROS are either released by damaged/stressed cells or through cytokine-mediated activation of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH)-oxidase. Indeed, several cells involved in innate and adaptive immune systems can participate to ROS production through NADPH-oxidase pathway. As further evidence, previous studies demonstrated that inducible nitric oxide synthase may play a role as a ROS-scavenging factor in PD, acting as an antifibrotic agent [29].

Proangiogenic factors are also considered to be pivotal for distribution of paracrine factors to surrounding endothelial cells to favour the myofibroblasts-induced fibrotic process. Neo-angiogenesis is stimulated by hypoxia, which elicits hypoxia-inducible factor 1 upregulation and subsequent release of vascular endothelial growth factor, ultimately leading to a fibrogenic response.

In summary, there are few crucial triggers for maintenance of fibrotic disease (1) chronic tissue damage stimulating myofibroblasts activation and release of ROS; (2) persistent recruitment of innate and adaptive immune systems, establishing a pro-fibrogenic environment; (3) ineffective remodeling modulated by hypoxia and subsequent neo-angiogenesis.

4. Transition to chronic phase

The second phase of PD generally starts approximately 12 to 18 months after disease onset. Transition to the chronic phase is defined when penile deformity remains stable for at least 3 months from its onset [6]. In some cases, chronic phase may start even earlier, within 5 to 7 months from disease onset [30].

During chronic phase, pain usually tends to complete resolution since acute inflammation process attenuates, and penile plaque is typically palpable. However, in this stage some patients may experience “torque pain,” or pain with rigid erections due to forcible straightening of the penis. Penile plaque becomes firmer due to protracted fibrosis or hard when calcification takes place. Penile curvature may continue to worsen in some subjects, and it hardly ameliorates in this second phase of PD [24].

5. Patient characteristics and disease course

Although PD is thought to be a disease that primarily afflicts older men, evidence suggests that PD may occur also in younger men. The prevalence may differ further in certain sub-populations (Table 3) [30, 31, 32, 33, 34, 35].

Table 3
Prevalence of Peyronie's disease from the literature in particular subgroups of population

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It has been shown that younger age at disease onset and the presence of baseline vascular comorbidities (i.e., diabetes and dyslipidemia) demand even more urgency for early recognition and prompt intervention because of a higher risk for disease progression [25, 36]. Retrospective series have proven that patients younger than 40 years are more likely to ask for treatment sooner, present with multiple palpable plaques and have at least one cardiovascular risk factors, as compared with older subjects. Moreover, in this subset of patients, PD might be more likely to progress rather than stabilize [37]. On the other hand, comorbid vascular diseases have been corroborated to significantly increase the risk for developing more severe PD, irrespective of age. In a study conducted by Kendirci et al [38], diabetes, was confirmed as a strong independent predictor of more severe penile curvature. More recently, also testosterone deficiency has been proposed to be involved in fibrotic process and wound healing, being correlated with more severe penile curvature [39, 40]. However, literature regarding this topic is restricted by small studies with methodological flaws and caution is required in the interpretation of data. Larger, prospective studies are warranted to clarify the role of testosterone deficiency in the development, evaluation, and treatment of PD.

6. Psychological and psychosocial distress

Current available data suggest negative impact of PD also on psychological sphere. Needless to say, the psychosocial repercussions of penile curvature on the patient, as well as on his partner, represent a non-negligible aspect to consider, although often underestimated.

PD can have a significant unfavorable emotional influence on men, secondary leading to depression, anxiety and low self-esteem [41]. In some reports, nearly 80% of men with PD were also diagnosed with clinically meaningful depression, due to reduction of penile length and the incapacity to have satisfactory sexual intercourse. In addition, more than 50% of patients described relationship difficulties, confirming that the burden of the disease falls also on patients' partners [6].

Some series suggest that early recognition and management of PD may ameliorate also psychological symptoms. In particular, subjects promptly notified about the disorder and its treatment options might be more likely to experience less distress and better quality of life [42].

7. Genetic factors and gene expression in Peyronie's disease

In the last few years, meaningful progresses have been performed towards an in-depth comprehension of the genetic factors related to PD [43]. Bias et al [44] in 1982 first proposed there might be a genetic predisposition to PD by analyzing three families presenting with both PD and Dupuytren's disease.

As mentioned above, high levels of TGF-β1 play a key role in PD pathogenesis. In some cases, TGF-β1 overexpression could possibly be justified in part by the presence of heritable single nucleotide polymorphisms (SNPs). To date, only one SNP has been clearly associated with PD, namely the G915C SNP, determining the replacement of arginine with proline at position 25 in the TGF-β1 protein [45].

Gene expression profile studies on both PD-associated lesions and healthy tunica albuginea have also been conducted [46]. The genes coding for pleiotrophin (a growth factor stimulating fibroblast recruitment and osteogenesis) and MCP-1 (a chemotactic factor for monocytes) were the ones showing the highest differential expressions. Conversely, the most important downregulated gene was the one coding for SMAD7, a part of the self-regulatory TGF-β1 pathway, normally acting as an antifibrotic factor [47].