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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most common urologic morbidity in men younger than 50 years and is characterized by a diverse range of pain and inflammatory symptoms, both in type and severity, that involve the region of the pelvis, perineum, scrotum, rectum, testes, penis, and lower back. In most patients, pain is accompanied by inflammation in the absence of an invading infectious agent. Since CP/CPPS etiology is still not well established, available therapeutic options for patients are far from satisfactory for either physicians or patients. During the past two decades, chronic inflammation has been deeply explored as the cause of CP/CPPS. In this review article, we summarize the current knowledge regarding immunological mechanisms underlying chronic pelvic pain and prostate inflammation in CP/CPPS. Cumulative evidence obtained from both human disease and animal models indicate that several factors may trigger chronic inflammation in the form of autoimmunity against prostate, fostering chronic prostate recruitment of Th1 cells, and different other leukocytes, including mast cells, which might be the main actors in the consequent development of chronic pelvic pain. Thus, the local inflammatory milieu and the secretion of inflammatory mediators may induce neural sensitization leading to chronic pelvic pain development. Although scientific advances are encouraging, additional studies are urgently needed to establish the relationship between prostatitis development, mast cell recruitment to the prostate, and the precise mechanisms by which they would induce pelvic pain.
Chronic Pelvic Pain
Chronic pelvic pain is generally defined by chronic pain in the region of the pelvis. It is a common symptom of several structural and functional disorders affecting the anorectal area, urinary bladder, reproductive system, and pelvic floor musculature and its innervation. In contrast to structural diseases such as endometriosis, the pelvic pain in functional disorders cannot be explained by an organic or other specified morphological pathology. Functional disorders are classified into anorectal (e.g., proctalgia fugax, levator anisyndrome, and unspecified anorectal pain), bladder [e.g., interstitial cystitis (IC)/bladder pain syndrome], and prostate syndromes [e.g., chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)]. IC/bladder pain syndrome is primarily diagnosed in women, whereas CP/CPPS is a diagnosis exclusive to men. Although IC and CP/CPPS have been largely considered different, they share many clinical features and are currently classified under the umbrella term, urologic chronic pelvic pain syndromes.
Chronic pelvic pain experienced by patients bearing CP/CPPS presents as chronic pain (that lasts for at least 3–6 months) in the region of the pelvis, perineum, scrotum, rectum, testes, penis, and often associated to ejaculatory pain, pain in lower back and abdomen, often associated to lower urinary tract symptoms, erectile dysfunction, and psychosocial symptoms. Lower urinary tract symptoms may include obstructive and/or irritative voiding symptoms. Erectile dysfunction is a major concern for CP/CPPS patients, which is defined as the persistent inability to attain and maintain a penile erection that is sufficient for satisfactory sexual performance. All these complaints lead to patient frustration, diminished quality of life as well as impairments in primary intimate relationships. Moreover, there is a common association of CP/CPPS with other systemic syndromes such as irritable bowel syndrome, fibromyalgia, cardiovascular disease, stress, depression, and anxiety. In fact, in terms of pain and deteriorated quality of life, CP/CPPS patients have shown to have a quality of life comparable with that of patients who have suffered myocardial infarction or bear Crohn disease.
Chronic Prostatitis/Chronic Pelvic Pain Syndrome
The term prostatitis defines as a state of inflammation of the prostate gland. The currently used classification of prostatitis was proposed by the National Institutes of Health (NIH) in 1999. Prostatitis syndromes are divided in four categories: acute and chronic bacterial prostatitis (types I and II), CP/CPPS (type III), and asymptomatic inflammatory prostatitis (type IV). Acute and chronic bacterial prostatitis are characterized by uropathogenic infections in which causative pathogens can be detected in the semen, in expressed prostate secretions (EPS), or urine after prostatic massage; and these infections respond well to antibiotic therapy. In contrast, CP/CPPS or NIH type III prostatitis is a complex and frustrating disease for both, patients and physicians, with symptoms that are difficult to quantify as well as to effectively treat. CP/CPPS is defined by chronic pelvic pain and signs and symptoms of prostate inflammation, lasting for at least 3–6 months, in the absence of any detectable infection. These features distinguish it from the other types of prostatitis. CP/CPPS presents with a mixture of chronic pelvic pain, lower urinary tract symptoms, and ejaculatory/sexual complaints with no uniformly effective therapy. Noteworthy, CP/CPPS is one of the most common diseases frequently diagnosed in the fields of urology and andrology. Moreover, it has been revealed that CP/CPPS may have significant consequences in male fertility . It accounts for more than 90% of all cases of prostatitis diagnosed and it has been estimated that affects 9–16% of men of all ethnic origins and is the most common urologic morbidity in men younger than 50 years old.
Chronic prostatitis/chronic pelvic pain syndrome is a syndrome, thus patients may be very heterogeneous and present a widely variable array of symptoms. In response to that, two multimodal approach systems are currently used to assess CP/CPPS symptom severity and to help physicians to manage patients: the CP Symptom Index from the NIH (NIH-CPSI) and the urinary, psychosocial, organ specificity, infection, neurologic, and tenderness (UPOINT) system. On the one hand, the NIH-CPSI intends to assess symptoms severity and to quantify their impact on the patients’ quality of life. However, it should be noted that is generally based on a subjective questionnaire and overall scores are determined by a cumulative scoring of symptoms that might and might not be related to one another, or indeed to the underlying causes of pathology. The NIH-CPSI is a validated nine question survey that covers the following three domains: pain (location, frequency, and severity), urinary symptoms, and quality of life. Using this system, CP/CPPS is diagnosed when patients present with pelvic pain and an index score higher than 4. A six-point improvement in total score is considered clinically significant correlates with patient reported improvement. On the other hand, the UPOINT system can be used to identify clinical phenotypes and can also be used to direct therapy. This system considers each group of patients’ symptoms and divides them into six categories: urinary, psychosocial, organ specificity symptoms, infection, neurologic/systemic, and tenderness. The characteristics and advantages of this classification system and its implications in therapy prescription were excellently analyzed in a recent review by Polackwich and Shoskes. As a reflex of the diversity of patients’ symptoms, the median number of positive UPOINT domains is 3 and only 22% of patients have a single positive domain. In addition, UPOINT domains involved have been shown to correlate with NIH-CPSI scores, and also help in guiding the practitioner to prescribe therapy. The use of this system treatment strategy is starting to become more widespread and is proving its effectiveness significantly improving the patients’ quality of life.
Possible Causes of CP/CPPS
Available therapeutic options for CP/CPPS are far from satisfactory for either physicians or patients. A novel, effective therapeutic approach is urgently needed. The main reason for the lack of effective and uniform therapies is that the etiology of CP/CPPS still remains unknown. Most likely, CP/CPPS comprises similar clinical phenotypes resultant from a combination of different pathophysiological mechanisms. During the last two decades, research in the field has experienced a notable growth. Several hypotheses have been proposed to explain CP/CPPS pathogenesis including defective urothelial integrity and function, cryptic infections, autoimmunity, endocrine imbalances, pelvic floor muscle spasm or tenderness, voiding dysfunction, peripheral and central sensitization and neuroplasticity, and psychosocial conditions.
Infection
Infection has been historically assumed to be the cause of CP/CPPS; thus, it has been empirically treated with antibiotics although with limited success. In this regard, several studies have systematically failed to identify infectious agents as causative agents of this pathology. Moreover, most patients’ symptoms are refractory to antibiotic therapy. In a recent study and using molecular techniques, Nickel et al. found that the overall species and genus composition differed only in the initial urine stream of CP/CPPS patients versus controls, being Burkholderia cenocepacia overexpressed in CP/CPPS patients. In contrast, midstream or postprostatic massage samples were not significantly different. Although the presence of an active infection in patients was not evident in almost all studies carried out up to date, CP/CPPS patients were found to have a significantly greater history of urethritis compared with age-matched controls. While a primary infectious agent may not be the cause of the ongoing symptoms, infection may be the precipitating factor. In this regard, different microorganisms have been implicated such as Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Trichomonas vaginalis, Candida spp., herpes simplex virus, etc. In susceptible men, infectious urethritis or prostatitis could serve as the initial stimulus for chronic inflammation, although chronic inflammation and pain may persist after the infection has been cleared, possibly by an autoimmune, and/or neurogenic mechanism. If this is the case, infection would be the triggering factor rather than the cause of the pathology. In fact, using an animal model of prostatitis, the uropathogenic CP1 strain of Escherichia coli, isolated from a patient with CP/CPPS, has been shown to induce and sustain chronic pelvic pain that persisted long after bacterial clearance from the mouse genitourinary tract. Pelvic pain was produced in the NOD strain of mice but not in C57BL/6 mice despite similar invasion and proliferation in each species. This indicates a genetic susceptibility to chronic inflammation and pain but not to the infection itself. The NOD mice that developed pain are genetically prone to develop chronic inflammatory conditions in different organs. As stated above, infections may act as triggering factors. Consequently, patients may develop inflammation and/or neuronal damage confined to the prostatic or pelvic area, which may be further augmented by the localized chronic inflammatory milieu. The unresolved chronic inflammation may potentiate tissue injury leading to pelvic floor dysfunction and central sensitization resulting in chronic pelvic pain.
Pelvic Floor Dysfunction
Pelvic floor dysfunction as increased pelvic floor muscle spasm or tenderness has been also proposed as responsible for CP/CPPS symptoms. In fact, spasms or tight knots or trigger points in the pelvic floor muscles lateral and anterior to the prostate have been shown in CP/CPPS patients. It is recommended that practitioners should perform careful palpation of these muscles during the rectal exam in order to reproduce the patient’s primary pain and to distinguish pain due to spasm from pain consequence from inflammation or other conditions. Besides, assessment of chronic pelvic pain tenderness by ultrasonography has linked pelvic floor muscle spasm to CP/CPPS. However, whether pelvic floor muscle spasm is the causative agent or direct mediator of CP/CPPS symptoms still remains to be established.
Chronic Inflammation/Autoimmunity
Chronic inflammation has been deeply explored as the cause of CP/CPPS during the past two decades. Cumulative evidence points to the possibility that this syndrome is a consequence of dysregulated inflammation in the form of autoimmunity directed against prostate antigens (PAg). Indeed, an autoimmune basis for CP/CPPS is a very prominent theory based on substantial evidence from studies in patients and animal models.
Inflammation and Pain Development in CP/CPPS
One of the main and currently unanswered questions in CP/CPPS is how chronic pelvic pain develops and whether a mechanistic link with inflammation exists. Due to the unknown pathophysiological pain mechanisms involved and to the diverse range of symptoms, both in type and severity, presented by patients, no standard, and completely effective therapeutic approach exists. Wide ranges of therapies for pain control have been tested, but most have shown heterogeneous efficiency, particularly in pain management.
As for any organ system, male pelvic pain occurs as a physiological alarm to withdraw from an injurious (infectious, irritative, inflammatory, or traumatic) condition to reduce tissue damage. However, chronic pain may start after tissue damage or inflammation and remain subsequent to tissue healing, becoming harmful, and detrimental to health. Chronic pain is commonly triggered by chronic peripheral inflammation and nerve injury. These results in the release of neurotransmitters, lipid mediators, fragments of the complement system, neuropathic factors, cytokines, and chemokines in both the central and peripheral nervous system. Both, inflammatory and neuropathic pain can cause peripheral and central sensitization that can lead to allodynia, hyperalgesia, and spontaneous pain. Several authors specialized in this area suggest that inflammatory/neuropathic pain may play a central role in CP/CPPS. Chronic pelvic pain include a combination of spontaneous visceral and referred somatic pain characteristics (i.e., pelvic visceral and referred perineal pain), and also the involvement of central sensitization in the spinal cord and brain. CP/CPPS patients have shown specific patterns of functional and pain-related brain activation and anatomical reorganization, which correlated with clinical pain intensity. These changes were evident in regional and global scales, suggesting an ongoing reorganization of brain circuitry similar to other chronic pain morbidities such as musculoskeletal and neuropathic pain, chronic low back pain, postherpetic neuralgia, complex regional pain syndrome, and knee osteoarthritis. These findings suggest that the chronic presence of pelvic pain leaves specific brain neural imprints that persist for years. Alternatively, some of these neural abnormalities may be predisposing factors for CP/CPPS. However, it is unclear if these central changes are the cause or consequences of disease progression.
Concluding Remarks
Chronic prostatitis/chronic pelvic pain syndrome is a complex and frustrating syndrome because of the unknown underlying pathophysiological mechanisms and the lack of appropriate and effective therapies. The emergence of interest and new research on the field has allowed a significant improvement in the understanding of this syndrome. Data obtained from studies in patients and animal models have confirmed the involvement of immune mechanisms in the etiology, pathogenesis, and chronic pelvic pain development. Several factors may trigger chronic inflammation in the form of autoimmunity directed against PAg and foster chronic prostate inflammation with the recruitment of different leukocytes including mast cells. The local inflammatory milieu and the secretion of inflammatory mediators may induce neural sensitization leading to chronic pelvic pain development. Further study of the available experimental animal models together with more extensive research in the human syndrome will shed light on the precise physiopathology of CP/CPPS, something that in turn may help in finding more rational and effective therapies.