Aetiology
The underlying cause of primary prostate pain syndrome (PPPS) is unknown, and it is also unclear if the prostate is the primary source of symptoms.[13] One theory is that PPPS may occur in men who are susceptible and are subsequently exposed to initiating factors.[4] This may cause acute and then chronic pain through a peripheral, self-perpetuating, immunological, inflammatory state and/or neurogenic injury.[4]
Factors that have been associated with PPPS, either as an underlying cause or subsequent effect, include:
Evidence has shown that men with PPPS are twice as likely to have had a previous sexually transmitted disease compared with those without PPPS.[15] PPPS is also associated with previous urinary tract infections.[14]
There is lack of evidence, however, for ongoing infection in men with PPPS.[15][16][17]
Pelvic floor muscular dysfunction[24]
Men with PPPS have been shown to have more muscle spasm and increased muscle tone, leading to pain on palpation of the pelvic muscles.[24] One study showed that 51% of patients with prostatitis symptoms had muscle tenderness by comparison with only 7% of controls, with tenderness in the pelvic floor muscles being exclusive to the test group.[25]
Intra-prostatic urinary reflux[26]
Intra-prostatic urinary reflux may be important both as a route of infection in bacterial prostatitis and as a cause of the inflammatory process in abacterial prostatitis.[26]
Hormonal imbalances[27]
There is evidence of adrenocortical hormone abnormalities in men with PPPS compared with healthy controls, with increased progesterone, androstenedione, and testosterone, and reduced corticosterone and aldosterone.[27] This suggests reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone and 17-hydroxyprogesterone to 11-deoxycortisol.[27]
Pathophysiology
The underlying pathophysiology of PPPS in men is unclear.[28][29] However, studies suggest there is overlap of the pathophysiology of PPPS with other non-urological chronic pain syndromes such as fibromyalgia and irritable bowel syndrome.[28][30] There is increasing evidence that an initial insult to the prostate in men who are susceptible may trigger central pain sensitisation involving neuroplasticity, leading to a persistent neuropathic pain state.[4][31] This theory is supported by the fact that tissue damage is not usually found in people with PPPS.[4] Functional brain imaging in patients with PPPS suggests changes in the grey matter, as well as the importance of the anterior insula and anterior cingulate gyrus in pain processing.[15]
There is also some evidence that oxidative stress may have a role in the pathogenesis of PPPS.[32] Available data indicate that there is increased concentration of 8-isoprostanes, lipid-derived mediators of oxidative stress, in prostatic secretions and urine in men with PPPS.[32][33]
[Figure caption and citation for the preceding image starts]: The anatomy of the normal prostate. Note the anatomical appearance of the prostate and surrounding tissues is normal in primary prostate pain syndrome (PPPS)Joe Brock, Research Illustration, Francis Crick Institute / Science Photo Library; used with permission [Citation ends].
Classification
The National Institutes of Health (NIH) classification system is commonly used to describe the various types of prostatitis. This classification was first introduced in 1999 and has been internationally recognised both for clinical practice and research.[3] Currently, there is some dispute regarding the terminology used to name the condition involving persistent pelvic pain in the region of the prostate and its usefulness to clinical practice. The condition is often referred to as chronic prostatitis and/or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS; as used in the NIH classification system); however, some experts disagree with the use of this term. In Europe and some other regions outside of the US, the condition is more commonly referred to as primary prostate pain syndrome (PPPS). In some instances the condition may also be referred to as chronic primary pelvic pain syndromes (CPPPS) of the male, but this term is less commonly used. Furthermore, the NIH classification system includes infection, which some experts feel should not be considered under PPPS.[4]
National Institutes of Health classification of prostatitis[3]
Type I: acute bacterial prostatitis
Acute infection of the prostate gland
Type II: chronic bacterial prostatitis
Chronic or recurrent infection of the prostate
Type III: chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)
No demonstrated infection. Type III can also be further classified as:
Type IIIa: inflammatory CP/CPPS. White blood cells in semen and/or expressed prostatic secretions or post‐prostatic massage voided bladder urine after prostatic massage
Type IIIb: non-inflammatory CP/CPPS. No white cells in semen, expressed prostatic secretions, or post‐prostatic massage voided bladder urine.
Type IV: asymptomatic inflammatory prostatitis
No subjective symptoms detected. Inflammation shown either by prostate biopsy or the presence of white cells in expressed prostatic secretions or semen during evaluation for infertility or other disorders.
European Association of Urology (EAU) classification of chronic pelvic pain syndromes[4]
The EAU classification of chronic pelvic pain syndromes is in accordance with the International Association for the Study of Pain classification of chronic pain.[1]
[Figure caption and citation for the preceding image starts]: EAU Classification of Chronic Pelvic Pain SyndromesAdapted from Engeler DS et al. EAU guidelines on chronic pelvic pain. Edition 2023. European association of Urology. Nijmegen, The Netherlands (https://uroweb.org/guidelines/chronic-pelvic-pain); used with permission [Citation ends].
The EAU classification of primary prostate pain syndrome (PPPS) broadly includes:
NIH classification type IIIa: inflammatory CP/CPPS (white blood cells in semen and/or expressed prostatic secretions or post‐prostatic massage voided bladder urine after prostatic massage)
NIH classification type IIIb: non-inflammatory CP/CPPS. No white cells in semen, expressed prostatic secretions, or post‐prostatic massage voided bladder urine.
Some patients who fall within the NIH classification of type II chronic bacterial prostatitis may also be covered by the EAU classification of PPPS.
UPOINT classification[5]
The urinary, psychosocial, organ-specific, infection, neurological/systemic, and tenderness (UPOINT) scale can be used to stratify patients with chronic pelvic pain syndrome into specific symptom-led phenotypes.[4][6]
[Figure caption and citation for the preceding image starts]: Phenotyping of pelvic pain using the UPOINT classificationAdapted from Engeler DS et al. EAU guidelines on chronic pelvic pain. Edition 2023. European association of Urology. Nijmegen, The Netherlands (https://uroweb.org/guidelines/chronic-pelvic-pain); used with permission [Citation ends].
The World Health Organization (WHO) International Classification of Diseases, 11th Revision (ICD-11)[7]
The WHO ICD-11 defines chronic pain as 'pain that persists or recurs for longer than 3 months'.[7]
ICD-11 uses the term chronic primary pain, where the pain is conceived as a disease in its own right, as opposed to chronic secondary pain, in which the pain symptoms are associated with another diagnosis. Chronic primary pain is further defined by ICD-11 as 'pain in one or more anatomical regions that is characterised by significant emotional distress (anxiety, anger/frustration, or depressed mood) or functional disability (interference in daily life activities and reduced participation in social roles). Chronic primary pain is multifactorial: biological, psychological and social factors contribute to the pain syndrome. The diagnosis is appropriate independently of identified biological or psychological contributors unless another diagnosis would better account for the presenting symptoms'.[7]
International Association for the Study of Pain (IASP)[1]
The IASP subdivides chronic pelvic pain syndromes (defined as chronic pelvic pain where there is no proven infection or other obvious local pathology that may account for the pain) according to whether the pain perceived in the pelvis is focused within a single organ, more than one pelvic organ, or associated with systemic symptoms. The pain must be continuous or recurrent for at least 6 months. However, if non-acute and central desensitisation pain mechanisms are well documented, then the pain may be regarded as chronic, irrespective of the time period.[1]
The IASP describes prostate pain syndrome as:
The occurrence of persistent or recurrent episodic pain (which is convincingly reproduced by prostate palpation), with no proven infection or other obvious local pathology. Prostate pain syndrome is often associated with negative cognitive, behavioural, sexual, or emotional consequences as well as with symptoms suggestive of lower urinary tract and sexual dysfunction.[1]
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