Chronic Prostatitis and Chronic Pelvic Pain Syndrome in Men

Hannah Pendegast; Stephen Leslie; Derek Rosario

Chronic Prostatitis and Chronic Pelvic Pain Syndrome in Men

Author: Hannah J. Pendegast Author: Stephen W. Leslie Editor: Derek J. Rosario Updated: 1/11/2024 1:43:13 AM

Introduction

Symptomatic inflammatory conditions of the prostate are quite common, accounting for about 2 million outpatient visits annually in the United States.[1] These visits are evenly split between primary care and urology.[1]

Prostatitis is clinically divided into acute bacterial prostatitis and various types of chronic prostatic infectious and inflammatory conditions, including chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men.[2] This review will cover all such symptomatic prostatic conditions except acute bacterial prostatitis (NIH Category I), which will be described separately. (See our companion Statpearls reference article on "Acute Bacterial Prostatitis.")[1][3]

Chronic prostatitis is the most common urological diagnosis in men younger than 50 and the third most commonly diagnosed male urological condition.[4][5] This condition accounts for up to 25% of all outpatient urology consults and outpatient visits and is estimated to have affected 5% of all men aged 20 to 50 years.[6]

The term "prostatodynia" is not encouraged or recommended in current practice, as it carries the negative historical connotation of being a "wastebasket" designation for a melange of symptoms.

Chronic prostatitis has a significant negative impact on quality of life and, in this respect, is comparable with other major long-term health conditions (eg, ischemic heart disease and diabetes mellitus).[7][8] Despite being common in clinical practice, chronic prostatitis is often misdiagnosed, misclassified, and poorly managed, resulting in significant morbidity, prolonged symptoms, and overall patient dissatisfaction. Understanding the classification, presentation, evaluation, and optimal management of the various types of chronic prostatitis is necessary at all levels to improve outcomes. Early recognition and the correct clinical classification of the condition with prompt and appropriate treatment improves outcomes and minimizes patient morbidity.

Etiology

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Etiology

Like acute bacterial prostatitis, chronic bacterial (NIH Category II) prostatitis has an identifiable infecting organism, whereas the etiology of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) is poorly understood. Pathogen exposure, comorbidities, anatomical variances, physiological changes, and immune deficiencies help explain the etiology of chronic bacterial prostatitis (NIH Category II).

Gram-negative organisms, especially E. coli, are the most common cause of urinary tract infections and bacterial prostatitis. The role of atypical organisms, including Chlamydia and other sexually transmitted infections, is important to consider in some populations, and alternative rare pathogens like M. tuberculosis have also been implicated in some at-risk groups, especially in areas of the world where healthcare is less accessible.[9][10]

Granulomatous and viral chronic prostatitis are associated with HIV infections and will generally demonstrate negative standard urine and semen cultures. Granulomatous prostatitis is associated with BCG instillations and M. tuberculosis infections.[11][12][13][14]

Altered host defense mechanisms increase the likelihood of the pathogens causing a clinical infection. These can be categorized into mechanisms associated with the urinary tract and systemic factors.

Factors that promote the bacterial colonization of the urinary tract include phimosis, incomplete or insufficient bladder emptying, and indwelling urinary catheters. Instrumentation, including transurethral procedures such as cystoscopy and transrectal procedures such as prostate biopsy, also bypass the usual host defense mechanisms by directly translocating pathogens into higher urinary tract areas.

Intraprostatic ductal reflux of urine is also an important mechanism associated with the development of chronic bacterial prostatitis (NIH Category II) in which there is retrograde propulsion of urine and bacteria into the prostate ducts during micturition.[10][15] The presence of prostatic calculi is evidence of such reflux, as prostatic secretions do not form calcium phosphate concretions.

Systemic risk factors are not unique to prostatitis but to all infections and include increased age, smoking, chronic medical conditions such as HIV and cancer, hematological disorders, and the use of certain drugs, including steroids, DMARDs, biologic immunosuppressive medications, and chemotherapy agents.

Ten percent of patients with acute bacterial prostatitis (NIH Category I) will progress to chronic bacterial prostatitis (NIH Category II), with a further 10% of this group subsequently developing chronic prostatitis/chronic pelvic pain syndrome (NIH Category III).[16]

Mechanisms for this progression include inadequate, partial, or incomplete treatment of acute bacterial prostatitis, untreated urinary or voiding problems, and infected prostatic calculi. The cause of the incomplete treatment may be poor antibiotic selection, low drug bioavailability, insufficient prostatic tissue penetration, bacterial antimicrobial resistance, inadequate duration of therapy, weakened host immune defense mechanisms, or re-infection.[15][16]

Given the wide range of clinical manifestations as well as the unpredictable response to treatment, the etiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is likely to be multifactorial, including anatomical variances, genetic susceptibility, abnormal immune response, neuroinflammation, altered host defense mechanisms, dysfunctional voiding, prostatic ductal reflux, toxic or inflammatory urinary chemicals or drugs, neuroendocrine disturbances, pelvic floor myofascial disorders, and psychological factors. Chronic pain is the common factor across these conditions.[17][18]

An inflammatory response provides a logical basis for the subclassification of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) based on the assumption that symptoms associated with infection or inflammation represent a different etiology. On this basis, CP/CPPS is subdivided into inflammatory and non-inflammatory categories based on the presence or absence of significant leukocytes in the urine, seminal fluid, or expressed prostatic secretions according to the Meares and Stamey 4-glass test (described below).[19]

Conclusive evidence of an infectious etiology is often missing in inflammatory CP/CPPS despite the possible presence of WBCs in the expressed prostatic secretions or semen. Specific polymerase chain reaction (PCR) technology looking for atypical organisms such as Neisseria gonorrhoeae, Mycobacterium tuberculosis, Mycoplasma, and Chlamydia trachomatis, as well as human papillomavirus (HPV), Herpes Simplex virus type 2 (HSV-2) and Cytomegalovirus, has been used to provide evidence of infection not obtainable by routine urine cultures. Therefore, it is a target for treatment, but the response to specific antibiotic therapy is not always predictable.[20]

In common with many other chronic pain syndromes, neuroinflammation, associated reactive astrocytes, and increased expression of chemokines and cytokines have been implicated. Emerging evidence suggests that the symptoms can reflect a multifactorial condition initiated by a transient infection involving other pelvic organs, including the bladder, seminal vesicles, and pelvic musculature.[17][20][21]

Epidemiology

After benign prostatic hyperplasia and prostate cancer, chronic prostatitis is the third most common condition affecting individuals possessing a prostate gland.[4][5] Eight percent of all urology clinic visits and 1% of all primary care outpatient appointments are due to chronic prostatitis.[1]

A prostatitis diagnosis is 13 times greater if patients are seen by urology than primary care.[1] Primary care physicians are more likely to use antibiotics to treat chronic prostatitis patients than urologists.[1]

Worldwide, approximately 8 million outpatient physician visits annually are due to chronic prostatitis, representing an overall global incidence of 8.2% in men.[22][23] In the US, the prevalence was reported as high as 16%.[24] Only about 60% of all men with symptoms of chronic prostatitis seek medical help, suggesting that the actual incidence is much higher than reported.[25]

Chronic prostatitis affects all age groups, with predominance for the middle age group in contrast to the other prostatic pathologies, which predominantly affect older men.[7][22][26][27] There is no racial predisposition or preference.

Prostatitis appears to be more frequently found in men with prostate cancer and benign prostatic hyperplasia (BPH). Those with BPH were 8 times more likely to have had at least one prior episode of prostatitis.[1] A history of prostatitis is also associated with a higher incidence of lower urinary tract symptoms, a previous episode of a sexually transmitted infection, and a high stress level.[1]

Classification of Prostatitis

The National Institutes of Health (NIH) classification system was developed in 1998. Although initially designed as a research tool, it effectively clarifies the different presentations and etiologies of prostatitis and similar pelvic disorders in men. According to this classification system, chronic prostatitis is classified into 4 main categories as described below:[2][28][29]

National Institutes of Health (NIH) Prostatitis Classification [28][29]

Acute bacterial prostatitis (NIH Category I).
Chronic bacterial prostatitis (NIH Category II).
Chronic prostatitis/chronic pelvic pain syndrome (NIH Category III).
- Inflammatory (NIH Category IIIa).
- Non-inflammatory (NIH Category IIIb).
Asymptomatic inflammatory prostatitis (NIH Category IV).

Acute Bacterial Prostatitis (NIH Category I)

A Gram-negative infection of the prostate caused by E. coli and typically associated with systemic signs of a significant infection such as chills, fever, malaise, muscle aches, nausea, vomiting, and pelvic pain as well as symptoms of a serious urinary tract infection including severe dysuria, trouble with urination, urinary hesitancy, frequency, and urgency.[3]

Men aged 20 to 40 are often affected, although the incidence increases around 60.[30] Risk factors include frequent unprotected sexual intercourse, instrumentation of the urinary tract, Foley catheters, and especially transrectal prostate biopsies, which carry an increased risk of sepsis even when performed with antibiotic prophylaxis.[31][32][33][34]

The prostate is usually somewhat enlarged and incredibly tender to palpation in acute bacterial prostatitis.[3] About 10% of patients will develop acute urinary retention requiring indwelling catheterization. Suprapubic drainage reduces the risk of developing chronic bacterial prostatitis more than urethral catheterization.[35]

Transurethral resection of the prostate (TURP) can sometimes be helpful in selected cases of intractable, recurrent acute bacterial prostatitis, where it enjoys a reported success rate of about 60%. Still, the resection must be extended to the surgical capsule.[36][37]

Up to 10% of all men presenting with prostatitis may have acute bacterial prostatitis (NIH Category I).[38]

Chronic Bacterial Prostatitis (NIH Category II)

Chronic urogenital pain in the presence of evidence of an ongoing urinary tract infection. Symptoms will typically persist for at least 3 months or longer.

Patients often have a history of recurrent urinary tract infections that respond to antibiotics at least temporarily and are caused by identical microorganisms. Bacterial localization (4-glass, 2-glass, EPS) studies will likely demonstrate positive cultures in the expressed prostatic secretions, VB3, or semen.[39] (See the 4-glass test described below under "Evaluation.")

Chronic bacterial prostatitis (NIH Category II) is frequently found with 10 or more WBCs/HPF on urinalysis, but this is a very non-specific finding and not considered definitive.

Among all the men with symptoms of chronic prostatitis, only about 5% to 10% will have chronic bacterial prostatitis.[40][41][42]

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (NIH Category III)

Formerly called prostatodynia, and defined as recurrent or chronic genitourinary, prostatic, or pelvic pain without evidence of a urinary tract infection.[2] This is by far the most common form of chronic prostatitis, accounting for about 90% of all cases, and is the most frequent urologic diagnosis in men younger than 50.[3][43][44]

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is further subdivided into 2 categories:

Inflammatory or NIH Category IIIa prostatitis (Greater than or equal to 500 WBC/cubic mm on expressed prostatic secretions (EPS) or a concentration of at least 1 million WBCs/cubic mm in the seminal fluid).

Non-inflammatory or NIH Category IIIb prostatitis if there are insufficient or no WBCs.

Asymptomatic Inflammatory Prostatitis (NIH Category IV)

Characterized by histological evidence of inflammation in a biopsy sample or positive findings (excessive WBCs or a positive culture) found on examination of the expressed prostatic secretions or semen (leukocytospermia) in patients without any symptoms where it does not appear to cause any harmful effects.[7][40] This condition is often associated with elevated PSA levels.

It is primarily an incidental histological diagnosis and generally needs no treatment. About 70% of men will be found to have asymptomatic inflammatory prostatitis (NIH Category IV) on prostate histological examinations at autopsy.[45]

Pathophysiology

Chronic inflammation is a well-understood process whereby inflammation is persistent with evidence of attempts at tissue repair and regeneration. Histologically, chronic prostatitis shows evidence of chronic inflammation with lymphocytes and macrophages within the prostatic tissue in men affected by chronic bacterial prostatitis and CP/CPPS.

Similarly, the expression of inflammatory proteins, including IL-1, IL-6, IL-10, TNF-α, IL-8, and IL-17, are higher in patients with chronic prostatitis when compared with control groups.[46][47][48] However, there is little correlation between the presence of an inflammatory response and the severity of symptoms associated with chronic prostatitis symptoms, so they are not utilized clinically.[18][49][50][51]

The pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) is poorly understood. An abnormal immune response to past bacterial infections, neurological inflammation, and neuropathic damage in response to an initiating factor have all been implicated. A link between acute bacterial prostatitis and associated inflammation with the subsequent development of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) has been proposed.[49]

The prostate has significant natural host defenses to prevent infection, and it is thought that in some patients, a breakdown in these processes and mechanisms may open the door to infection and inflammation. These natural defenses include regular rinsing of the prostatic urethra by voiding, ejaculation that empties the prostatic ducts and seminal vesicles, and natural antimicrobial agents in the semen that have high levels of seminal polypeptides containing zinc, spermine, and spermidine. High zinc levels are found in normal, healthy prostates, and low levels are seen in prostatitis. Unfortunately, oral zinc supplementation does not appear to be beneficial.

Chronic bacterial prostatitis (NIH Category II)

This condition is caused by an initiating pathogen followed by incomplete eradication or a recurrent infection. Uropathogens may enter the prostate via either an ascending urethral infection, intraprostatic ductal reflux, or direct migration of rectal bacteria during transrectal prostatic procedures. Transmission of bacteria is common after sexual encounters, but infecting organisms may also spread by hematogenous or lymphatic means as well as from contact with surrounding organs.[3]

The most commonly implicated organism is E. coli, but other bacteria include Klebsiella, Proteus, Pseudomonas, Staphylococcus aureus, enterococci, and the occasional, rare anaerobe such as Bacteroides.[52] Acute bacterial prostatitis, especially after urological instrumentation, has a much higher incidence of Pseudomonas (20%).[53]

In sexually active men, Chlamydia trachomatis should be considered, and more atypical organisms can be identified in immunocompromised and HIV-positive patients, including Candida, Cryptococcus, Mycoplasma, M. tuberculosis, Cytomegalovirus, Coccidiodes, Blastomyces, and Histoplasma.[10][21][38][54][55][56][57][58][59]

The role of prostatic calculi appears significant in at least some patients with chronic bacterial prostatitis, particularly those with intractable or recurrent infections. Prostatic stones are common and frequently identified in patients with chronic bacterial prostatitis (NIH Category II). They appear more common in men with chronic bacterial prostatitis than those without prostatic inflammation.[60]

Biofilm formation on the surface of these prostatic stones provides a further challenge for adequate clearance of infection and can be a factor in chronic bacterial prostatitis treatment failures.[10][61] These prostatic calculi, composed of calcium phosphate, act as a bacterial nidus and sanctuary, protected by the calculus itself and their bacterial biofilm, which leads to relapsing and recurring prostatic infections, treatment failures, the persistence of symptoms, and the need for much longer antimicrobial treatment durations than for other lower urinary tract infections.[9][10][61]

Biofilms form in bacterial prostatitis, often deep within the prostatic passages and obstructed ducts. Bacteria can hide within these biofilms and obstructed ductal passages yet still produce sterile cultures on testing, even in patients with persistent symptoms.[62] Hemolysin, a virulence factor produced by E. coli, facilitates the production of biofilms in chronic bacterial prostatitis.[63] Highly virulent and persistent bacterial strains are more likely to progress to CP/CPPS even after bacterial eradication.

A persistent nidus of infection, such as prostatic calculi, should be considered when an initial favorable clinical response to chronic bacterial prostatitis treatment relapses shortly after antibiotic cessation. The presence of significant prostatic calculi can be determined easily by transrectal ultrasonography.[60][64]

In addition to the role of prostatic calculi, infections within the gland also tend to be lengthy and persistent due to the altered chemical makeup of the prostatic secretions in response to inflammation and infection, reducing antimicrobial penetration and effectiveness. Additionally, specific bacterial mechanisms contribute to the persistence of colonization and subsequent recrudescence of the infection. For example, bacterial P fimbriae (fimbrial cell surface appendages used for bacterial adherence and found in many E. coli strains) bind to urothelial receptors, and mannose-sensitive fimbriae bind to mannose receptors.[65][66][67]

Intraprostatic reflux of urine via the secretory ducts impairs dependent drainage of prostatic secretions, can lead to obstruction of the prostatic ducts, and promotes calculus formation. Reflux of infected urine provides not only a route for pathogens to enter the prostate but also a mechanism whereby trapping of bacteria might occur.

Granulomatous and viral chronic prostatitis are associated with HIV infections and will typically demonstrate negative standard urine and semen cultures.

Chronic prostatitis/chronic pelvic pain syndrome (NIH Category III prostatitis)

This pathophysiology is poorly understood but is thought to involve occult or atypical infections, autoimmune factors, abnormal or muted immune responsiveness, neuropathy, neuropathic damage in response to an initiating factor or trigger, psychological issues, or neuromuscular conditions.[7][68][69] A link between acute bacterial prostatitis and associated inflammation with the subsequent development of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) has been proposed.[49]

The symptoms of CP/CPPS can be best divided into the domains of urogenital pain, lower urinary tract voiding symptoms, sexual dysfunction, and psychological response.[18][49][50][51]

Pain, usually experienced in the pelvis, perineum, or genitalia, is the primary symptom for the diagnosis of CP/CPPS. The pain may be persistent, relieved by voiding or precipitated by intercourse with ejaculation. The development of chronic pain is thought to be associated with an initiating factor followed by sensitization of the peripheral and central nervous system, which leads to the development of a centralized neuropathic pain state. Pain, described as “an unpleasant sensory and emotional experience associated with actual or potential harm,” is a complex process influenced by physiological, psychological, and social factors. Initiators implicated in CP/CPPS include infection, dysfunctional voiding, neuromuscular conditions, and trauma.[17][18]

Lower urinary tract symptoms, including hesitancy, poor flow, and frequency, are often present in CP/CPPS. In around 10% of cases of CP/CPPS, urodynamic evidence of outflow obstruction, most commonly primary bladder neck obstruction (PBNO) characterized by a fibrous narrowing or bladder neck muscular hyperplasia, can be identified.[17][18]

Sexual dysfunction is common in men with CP/CPPS. Except for ejaculatory pain, which has a direct effect on libido and erectile function, most of the data suggest that CP/CPPS impairs overall quality of life, and this contributes indirectly to erectile dysfunction.[17][18]

Patients with chronic prostatitis/chronic pelvic pain syndrome often have low male fertility, demonstrating abnormal semen parameters with reduced sperm counts and concentrations, impaired sperm motility, and abnormal morphology thought to be caused primarily by higher levels of inflammatory cytokines in the seminal fluid of patients with CP/CPPS.[43][44][70][71]

In many cases of CP/CPPS, chronic pain, lower urinary tract symptoms, and sexual dysfunction are associated with sleep pattern disturbances and impaired psychological health. Psychological stress can exacerbate the symptoms of CP/CPPS. The exact mechanisms underlying this association are unclear. But in line with most pain syndromes, the severity of symptoms and degree of impact is amplified in patients from more deprived socioeconomic populations, supporting the complex interaction of biological, psychological, and social factors in this disorder.[49]

Asymptomatic inflammatory prostatitis (NIH Category IV)

This condition also has a poorly understood etiology. Precipitating factors may include an old, mild, or transient infection, neuromuscular dysfunction, or urinary reflux into the prostatic or ejaculatory ducts during voiding.

History and Physical

The presenting features overlap significantly between chronic bacterial prostatitis (NIH Category II) and chronic prostatitis/chronic pelvic pain syndrome (NIH Category III). A careful history and physical examination are essential to gather all the required information to reach a diagnosis.

Specifically, when considering a diagnosis of CP/CPPS, it is essential to understand that this is a diagnosis made based on the exclusion of other conditions, including chronic bacterial prostatitis (NIH Category II prostatitis), PBNO, bladder outlet obstruction, ejaculatory duct obstruction, and prostate cancer. A diagnosis of CP/CPPS should be considered where symptoms are persistent or recurrent for more than 6 months and refractory to initial pharmacotherapy in the absence of an alternative diagnosis.[18]

Urogenital pain is the most common presenting complaint in chronic bacterial prostatitis and CP/CPPS. The pain described most frequently affects the perineum, suprapubic region, genitalia, penile tip, and ano-rectum. The pain may be associated with voiding or with ejaculation. Pelvic pain, particularly with ejaculation, is the most common overall presenting symptom of chronic prostatitis, reported in about 70% of patients.[72][73]

Associated urinary symptoms should also be explored. Urinary symptoms may include abnormal voiding or urine storage problems. Irritative urinary symptoms (urgency, frequency) may sometimes be associated with bladder carcinoma-in-situ and warrant a urine cytology examination.

It is also important to inquire about the presence of blood in the ejaculate (hematospermia). Additionally, patients may report ejaculatory dysfunction (including premature or delayed ejaculation), erectile dysfunction, and decreased libido. A holistic assessment of the patient is essential. Associated anxiety, depression, and the impact of the patient's symptoms on behavior and quality of life should be explored.[17][18]

Red flag symptoms such as strangury and hematuria indicate possible significant unrelated pathology, and the patient work-up should be modified appropriately. Patients with persistent dysuria should have a urine cytology, EPS, or semen culture, and a cystoscopy should be considered.[74][75]

Various validated assessment tools can be used to quantify and classify the symptoms frequently described. Such quantification and classification of symptoms, while not diagnostic, do allow an objective assessment of response to therapy.[16][18] These include:

The International Prostate Symptom Score (IPSS) (for assessment of urinary symptoms)
The UPOINTS (urinary, psychosocial, organ-specific, infectious, neurological, tenderness) classification (for phenotype determination)
The Sexual Health Inventory for Men (SHIM) for erectile dysfunction
The Patient Health Questionnaire-9 (PHQ-9)
The Generalized Anxiety and Depression-7 (GAD-7) questionnaires for psychosocial elements

The presence of associated systemic features, including fever, rigor, chills, and malaise, indicates that the patient is most likely suffering from an acute or generalized infection such as acute bacterial prostatitis (NIH Category I) as chronic bacterial prostatitis (NIH Category II) and chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) do not present in this fashion. (See our companion StatPearls article on "Acute Bacterial Prostatitis.")[3][10]

Relevant past medical history to explore includes previous urinary tract infections and prior urological or medical investigations. Any history of urological procedures or regular instrumentation of the urinary tract, for example, in the form of intermittent self-catheterization, should also be established as both increase the risk of introduction of pathogens to the lower urinary tract and the development of a urethral stricture disease, which can significantly impact standard host defense mechanisms.

A focused social history, including detailed sexual health history, is a vital part of the patient assessment to determine the risk of sexually transmitted and atypical uropathogens.[20]

Examination of the patient should include a thorough abdominal examination, including examination of the hernial orifices, external genitalia, and perineum, and be completed with a digital rectal examination (DRE). Examining the abdomen might reveal a palpable bladder indicating urinary retention, a recognized risk factor for recurrent urinary tract infections.

On digital rectal examination, in addition to examining the prostate gland for size, texture, asymmetry, nodules, and tenderness, attention should be paid to seminal vesicle sensitivity/discomfort and the presence or absence of any myofascial trigger points that may suggest CP/CPPS. The clinical finding of an unusually tender, swollen, "hot" prostate suggests the possibility of acute bacterial prostatitis, and further prostatic manipulation should be immediately halted.

The DRE should also facilitate the primary assessment of the rectum and exclude a rectal mass that could contribute to anorectal pain and symptoms.

Examination of the external genitalia should take into account circumcision status, the presence of phimosis, testicular issues, and features suggestive of sexually transmitted infections, such as skin changes or ulcerations.[10][18][20][76]

Evaluation

In clinical practice, distinguishing between infectious chronic bacterial prostatitis (NIH Category II) and noninfectious chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) can be challenging.

Chronic bacterial prostatitis (NIH Category II) patients will have a history of multiple or recurrent urinary tract infections or a positive culture from the expressed prostatic secretions, VB3, or semen culture. This diagnosis is relatively uncommon.

Chronic prostatitis/chronic pelvic pain syndrome (NIH Category III) patients will generally not have a history of urinary tract infections, and their localization cultures will be negative.

The recognition that atypical organisms might be implicated in symptomatic prostatic inflammation and the availability of modern techniques (polymerase chain reaction, or PCR) for identifying potential pathological infecting organisms where "standard microbiological investigations" have not been helpful should assist in differentiating infectious from noninfectious causes of prostatitis.

From a practical point of view, once acute bacterial prostatitis has been ruled out, the next steps are to determine if the condition is inflammatory, infectious, or neither. This affects treatment because antibiotics are not likely to be helpful clinically if there is no evidence of infection. However, there is evidence of their efficacy in some previously untreated, newly diagnosed cases, even with negative cultures.[77][78]

The symptoms of chronic bacterial prostatitis and CP/CPPS are challenging to separate from those caused by other common conditions such as bladder outflow obstruction or stricture disease. Further evaluation of the patient is indicated and can be divided into investigations performed by primary care practitioners and those offered by urologists.[18]

Primary care evaluations should include a urinalysis, urine culture and sensitivity, a sexual health inventory, and an infection screen. Routine blood biochemical investigations are unnecessary unless a specific alternative diagnosis is suspected.[16][18][20] Urine cytology is recommended for patients with irritative voiding symptoms to help identify carcinoma-in-situ of the bladder.[79][80]

Urologists are likely to proceed with additional investigations, including the following:

Four-Glass Test

First described by Meares and Stamey, it is considered the gold standard procedure for evaluating suspected prostatitis, although it is difficult to perform, cumbersome, and time-consuming.[19] This test requires the collection of 4 separate specimens for microscopic evaluation with individual leukocyte counts and cultures, including expressed prostatic secretions from a prostatic massage:

First voided urine (VB1). Represents the urethral specimen.
Mid-stream urine (VB2). Represents the bladder urine.
Expressed prostatic secretions (EPS). Represents prostatic secretions.
Post-massage first voided urine (VB3). Represents prostatic secretions.

Prostatic Massage

This is used to obtain an expressed prostatic secretion sample for testing. This is not always easy, but even if not successful in obtaining a specimen, a post-massage urine specimen may be able to culture pathogenic organisms for identification. The patient is asked to lean forward over the examining table.

The prostatic massage begins with a digital rectal examination where the examining finger is used to press on the prostate from lateral to medial and then from the base (deep) to the apex (distal).

The massage is continued until some milky fluid is obtained for testing, and a collection cup should be held during the procedure.

The patient should be warned that this procedure may be uncomfortable and will require at least a few minutes of massaging to be successful.

In addition to classifying inflammatory versus non-inflammatory, the 4-glass test distinguishes between urethral, bladder, and prostatic pathology. The threshold for finding inflammation is based on the number of leukocytes in the specimen. (Greater than or equal to 500 WBC/cubic mm on expressed prostatic secretions (EPS) or a concentration of at least 1 million WBCs/cubic mm in the seminal fluid).[28]

No white blood cells should be observed in healthy subjects in any of the 4 collected samples.

A detectable organism in any of the specimens supports a diagnosis of an infectious etiology.

Organisms in all specimens suggest a general urinary tract infection.
- This can be treated and eliminated by using an antibiotic that does not penetrate the prostate, such as nitrofurantoin, or using intravesical antibiotics (gentamicin) via catheterization. Then, the 4-glass test may be repeated.

A positive EPS or VB3, compared to VB1 or VB2, supports a diagnosis of chronic bacterial (NIH Category II) prostatitis. A positive result would be an increase in bacterial count at least 10 times higher in the EPS or VB3 than in VB1 or VB2.

The presence of inflammatory cells (WBCs) in the specimens' absence of identified infectious organisms would support a diagnosis of inflammatory category III prostatitis. However, it is important to consider atypical organisms that might be missed by standard microbiological methodology.[16][18][19][20]

Two-Glass Test

Compared to the 4-glass test, this is easier and much more helpful in daily clinical practice, as performing the 4-glass test is difficult due to the time-consuming and cumbersome logistics of specimen collection and testing and cost.

The 2-glass test analyzes and compares specimens from pre-prostatic and post-prostatic massage urine. This test offers similar diagnostic sensitivity to the traditional Meares and Stamey 4-glass test but is much more practical and easier to perform in modern clinical practice.[81][82][83][84][85]

A positive result would be a 10-fold or greater increase in bacteria counts in the post-massage specimen compared to the pre-massage urine. Cultures and colony counts need not be at least 100,000/mL to identify chronic bacterial prostatitis. Communication with the microbiology laboratory may be necessary to perform cultures on these specimens, even if the colony counts are low.

The main drawback of the 2-glass test is the lack of culture results from the expressed prostatic secretions, which can be overcome for bacterial identification by performing a culture on a fresh semen specimen.[86] Applying this in clinical practice depends on when the test is administered. These tests are most valuable when performed at the first patient presentation rather than after repeated courses of antibiotics.

Prostatic massage is contraindicated in acute bacterial prostatitis due to pain and the risk of inducing bacteremia.[3][10][81]

Patients with chronic bacterial prostatitis (NIH Category II) have a similar presentation to chronic prostatitis/chronic pelvic pain syndrome (NIH Category III). However, organisms would be expected to be grown and identified on the 4-glass and 2-glass tests and expressed prostatic secretions or semen sample cultures.[19][86]

Semen Cultures

The utility of semen cultures is still somewhat uncertain as they tend to lack sensitivity, although they can be helpful when the results are positive.[58] They are much simpler to perform than the 4-glass or 2-glass tests and avoid the need for an unpleasant prostatic massage. Semen cultures are useful in diagnosing chronic bacterial prostatitis (NIH Category II) when they grow pathogenic bacteria but do not necessarily rule it out if the results are negative.[58][87][88][89] The testing laboratory may need to be specially instructed to culture all organisms, even if the colony counts are low.

A large study of 895 patients with chronic prostatitis compared the semen culture findings with the expressed prostatic secretions or VB3 specimen culture results.[90] The semen cultures were found to have the highest sensitivity for detecting pathological prostatic organisms in chronic bacterial prostatitis.[90]

Further evaluation may include non-invasive limited urodynamics such as an automated flow rate and post-void residual urine determination estimation. Flexible office cystoscopy to exclude an obstructive etiology, such as a stricture disease, may also need to be performed in selected patients.

Recent evidence suggests that a significant proportion of patients labeled with CP/CPPS have detectable bacterial and protozoal DNA encoding sequences on PCR testing, even in the presence of extensive negative microbiological investigations which could implicate an untreated infection or chronic bacterial prostatitis (NIH Category II) as the underlying cause of some patient's symptoms.[91][92] Urinary PCR testing, particularly in those patients with risk factors for urogenital infections with persisting symptoms, should be considered to exclude the presence of atypical organisms such as Trichomonas species.[91][92]

Imaging studies are not routinely recommended in the evaluation of patients with chronic prostatitis but may be used selectively in refractory cases to rule out abscesses, prostatic calculi, or anatomical abnormalities.[93] Magnetic resonance imaging (MRI) is the best modality for diagnosing developmental anomalies of the male genital tract, especially ejaculatory duct obstruction. An advantage of MRI is the ability to delineate the presence of lesions associated with a high risk of prostate cancer. The Prostate Imaging-Reporting and Data System (PI-RADs) system for the assessment of prostate MRI allows stratification of cancer risk based on MRI findings. The appearance of prostatitis can mimic changes associated with cancer, particularly in younger men. Both of these conditions can co-exist.[18][94][95][96]

Transrectal ultrasound is an alternative that is becoming more readily available in doctor's offices and is helpful in the context of suspected prostate abscesses both for diagnostic and therapeutic purposes. Prostatic stones can be identified on transrectal ultrasound of the prostate but can be missed on MRI. The presence of prostatic calculi, which are frequently seen in patients with chronic prostatitis, is not by itself a reliable diagnostic indicator, as these are also commonly found in patients with BPH.

The prostate-specific antigen (PSA) test results should be carefully considered in the testing context, and the patient should be appropriately counseled. PSA levels are likely to be elevated in the context of prostatitis, particularly acute prostatitis, and active inflammation or infection will cause up to approximately 70% of patients to have elevated titers. Routine PSA testing is discouraged when infection is suspected, and a waiting period of at least 6 weeks is recommended before performing another assay. However, PSA levels may remain abnormally elevated for as long as 6 months.[97] Where there is a substantial concern about prostate cancer, a risk-stratification bioassay can be performed in low-risk patients, or a prostate biopsy should be considered.[10][16][18][98][99][100]

The timing of such a biopsy depends on the clinical context and should be avoided in patients with untreated bacterial prostatitis. A biopsy may also exacerbate symptoms in patients with CP/CPPS.

A prostate biopsy with definitive histology is arguably the most reliable test for demonstrating prostatic inflammation (prostatitis). A biopsy does not clearly distinguish between infectious and noninfectious causes and is not helpful in clinical practice. Prostate biopsies carry a significant risk of potentially serious complications, including prolonged bleeding, infection, and sepsis. A prostate biopsy, particularly transrectal, can introduce pathogens that can initiate acute or chronic bacterial prostatitis even with appropriate antibiotic prophylaxis, resulting in new or worsening pelvic symptoms. The role of a prostate biopsy in this context is limited to the diagnosis or exclusion of suspected prostate cancer.

Treatment / Management

Treatment of chronic prostatitis starts with determining whether or not an infectious agent is involved. The use of antibiotics and other antimicrobial agents is well supported in the treatment of chronic bacterial (NIH Category II) prostatitis, whereas antibiotic therapy is contraindicated for chronic prostatitis/chronic pelvic pain syndrome (NIH Category III).[18] However, patients newly diagnosed with chronic prostatitis appear to have good initial responses to antibiotics, even with negative cultures.[77][78] Patients who have had previous antibiotic treatment or whose symptoms are of long duration are unlikely to benefit from antibiotics except possibly in culture-proven cases or where an infectious source (nidus) can be surgically removed or eliminated.(A1)

Regarding prostatic calculi, these can be a nidus for infection and are often implicated in relapses of chronic prostatitis infections. Continuous low-dose antibiotic prophylaxis may help manage this, but source control by removing infected prostatic calculi by TURP may provide a better outcome. Careful weighing of the associated risks and benefits in the context of the individual patient is important.[96][101][102] These calculi are typically found posteriorly and near the surgical prostatic capsule, so they can be challenging to remove.

Chronic Bacterial Prostatitis (NIH Category II)

This condition is a challenge to treat due to the scarcity of agents with adequate prostate penetration to achieve sufficient bactericidal concentrations. In inflammation, prostatic secretions become more alkaline and disrupt the diffusion of antibiotics along the usual pH gradient. Many antibiotics lack lipid solubility, are relatively ineffective in an alkaline environment like the prostatic interior, or fail to cover the most likely pathogens. Highly alkaline prostatic secretions also contribute to a decrease in their anti-bacterial properties.

Antibiotics typically work only at a particular point in the bacterial reproductive cycle. If bacteria are rapidly multiplying, there are frequent opportunities for an antibiotic to interrupt bacterial cell reproduction and kill the organism. If bacterial reproduction is slowed in the prostatic ducts and interior due to elevated pH or other factors, it will take a much longer course of antibiotics to achieve the same number of bacterial reproductive cycles to eradicate the infection effectively. This has been suggested as one reason for extended treatment periods.

An extended course of treatment (typically 6 weeks duration) is indicated for all previously specified reasons, but up to 12 weeks may be used.[103] A review of the response after completion is essential. A second course is not unreasonable if the patient has shown improvement. Twelve-week antibiotic courses have the highest cure rates for chronic bacterial prostatitis, but it can be difficult for many patients to comply with such a long treatment period. Up to 6 months of treatment can be used if a specific organism is identified by appropriate cultures, after which the dosage should be reduced to the minimum necessary for symptom relief.[31](A1)

Some experts will slowly taper antibiotic treatment once symptoms have entirely resolved. About 20% of patients who fail an initial course of antibiotics will respond to a different antimicrobial.[104]

In the case of a relapse of symptoms after completion of antibiotic treatment, efforts should be directed at establishing whether this is due to a recurrent infection, a new infection, or the possible development of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III). Risk factors for recurrent conditions, such as urinary retention, bladder outlet obstruction, urolithiasis, phimosis, and prostatic calculi, should be addressed as part of the initial treatment plan, particularly if the chosen therapy is ineffective.

The most effective antibiotics are non-ionized, lipid-soluble, and not heavily protein-bound.[9][10][105]

In addition to adequate penetrance of prostatic tissue, antibiotic therapy for chronic bacterial prostatitis (NIH Category II) should consider the most likely organism and local resistance patterns. Resistance patterns will vary according to geography, so a careful understanding of local microbiology protocols is essential when treating chronic prostatitis.[10][18](A1)

When a patient is healthy, waiting for the final culture and full antimicrobial sensitivity results, rather than initiating empiric treatment, will increase the chance of treatment success and prevent unnecessary exposure to ineffective antibiotics. Where waiting for the definitive culture and sensitivity results is impractical, empiric antimicrobial therapy should be adjusted according to the likely organism and suspected mechanism of infection (recent transrectal prostate biopsy, transurethral instrumentation, or a recently treated UTI).[18][38](A1)

Antibiotics for Chronic Bacterial Prostatitis

Fluoroquinolones have traditionally been the agent of choice for prevention (during iatrogenic instrumentation of the urinary tract and prostate) and treatment of prostatic bacterial infections associated with typical urinary tract organisms due to their broad spectrum and excellent prostatic penetrance.
- They are clinically effective in about half of all prostatitis patients and demonstrate bacterial eradication rates of about 75%.
- Increasing resistance to fluoroquinolones is impacting their efficacy.
- Overall, fluoroquinolones appear to be equally beneficial. However, levofloxacin may be slightly more effective with less bacterial resistance and, on a once-daily dosage schedule, is likely to have better compliance than ciprofloxacin, which requires twice-a-day dosing.[106][107][108]
- The development of increasing fluoroquinolone resistance (reportedly over 50% in Asia), multi-drug resistant organisms, and extended-spectrum-beta-lactamase (ESBL) producing bacteria is changing practice and driving research in support of alternative agents.

(A1)

Doxycycline is a tetracycline that has shown effectiveness in treating chronic bacterial prostatitis, particularly due to susceptible organisms such as Chlamydia.[109][110][111] However, its effectiveness against Gram-negative organisms and Staphylococci is less reliable and has no activity against Pseudomonas. Doxycycline combined with fosfomycin has been very effective in a few otherwise intractable cases of chronic bacterial prostatitis.[103][105][110]

(A1)

Fosfomycin has been successfully used to manage intractable chronic bacterial prostatitis due to organisms highly resistant to other antimicrobials and has been proposed as a first-line agent for the disease.[9][10][105][109][112][113][114][115] This medication has a unique mechanism of action; it blocks intracellular peptidoglycan production, an early step in cell wall biosynthesis, which results in bacterial cell death.[115] This unique mechanism of action allows fosfomycin to work synergistically with many other antibiotics, such as beta-lactams, aminoglycosides, tetracyclines, carbapenems, and fluoroquinolones.[116]
- While there is no standardized dosage schedule for fosfomycin in chronic bacterial prostatitis, a frequently used regimen is fosfomycin 3 grams daily for 1 week, then 3 grams every 48 to 72 hours for 6 to 12 weeks.[105][115][117][118]
- Despite many reports of disease resolution, further randomized controlled studies are needed to determine optimal dosing schedules, treatment duration, efficacy, and optimal combination therapy.[9]

(A1)

Macrolides (eg, azithromycin and clarithromycin) work well for chlamydial infections, and complete eradication has been reported in up to 80% of patients with prostatic chlamydial infections using these drugs.[42] They also have good penetrance into prostatic tissue.[10][18] Macrolides are not indicated as first-line therapy for prostatitis unless cultures show Gram-positive organisms or Chlamydia.[103] Using macrolides and fluoroquinolones together should be done cautiously, as both drugs can prolong the QT interval.[119]

(A1)

Sulfamethoxazole/trimethoprim was previously used extensively in chronic bacterial prostatitis but reported efficacy rates have dropped to only 30% to 50% even with treatment lasting up to 3 months.

Carbenicillin has been used for chronic bacterial prostatitis (NIH Category II) and may be effective for Pseudomonas and Gram-negative infections. No large-scale or randomized controlled studies are available, and it is infrequently used clinically. Other penicillin-based antibiotics generally have poor prostatic tissue penetration and are therefore not usually recommended.

Other antibiotics are unlikely to be effective in the treatment of chronic bacterial prostatitis, but for acute bacterial prostatitis (NIH Category I), combination therapy with aminoglycosides, carbapenems, cefepime, cefotaxime, ceftazidime, ceftriaxone, doxycycline, fluoroquinolones, and piperacillin/tazobactam is typically used.[42][58][120][121] Metronidazole should be used for prostatitis caused by trichomonas.[42][122][123]

(A1)

Long-term, low-dose antibiotic suppressive therapy is often used to control symptoms when chronic prostatitis patients develop frequent or rapid recurrences, even though efficacy for this practice has not been definitively confirmed in clinical studies. Reasonable antibiotic choices include cephalexin, nalidixic acid, nitrofurantoin, tetracycline, and trimethoprim.

Surgical therapy (transurethral resection of the prostate, TURP) has been successful in eradicating symptoms for selected patients with chronic bacterial prostatitis who have been refractory to medical and other less invasive treatments.[124][125](B2)

Bacteriophage therapy has successfully treated otherwise intractable chronic bacterial prostatitis in a limited number of patients.[126][127][128] In such cases, various bacteriophage preparations are tested for efficacy against the causative organism in the laboratory, and treatment with an effective agent is utilized clinically.[126][127][128] Bacteriophage endolysin has been used successfully for chronic prostatitis/chronic pelvic pain syndrome (NIH Category III).[129](B3)

Anti-nanobacterial therapy has shown efficacy in treating chronic prostatitis, and experimentally, antibiotic-loaded reactive oxygen species-responsive nanomedicine has effectively eradicated chronic bacterial prostatitis (NIH Category II).[130][131]

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (NIH Category III)

This is best treated with a multimodal, multidisciplinary approach addressing the patient's specific symptoms, signs, and expectations, as there is no acceptable standardized effective monotherapy.[21][132][133]

It is generally accepted that the use of antibiotics in the absence of proven infection is unhelpful in the treatment of chronic prostatitis/chronic pelvic pain syndrome (NIH Category III prostatitis). However, a short 2 or 4-week clinical trial of antibiotics in newly diagnosed, previously untreated symptomatic prostatitis patients is reasonable as many patients will respond.[134] However, prolonged antibiotic use without culture-specific evidence of infection or significant symptomatic improvement is not warranted.[134]

It is hard to avoid prescribing antibiotics when patients ask for relief and expect at least one antimicrobial trial. Generally accepted principles of antimicrobial stewardship should be practiced, and an antibiotic that is effective in chronic bacterial prostatitis should be selected.[16][18] A 2 or 4-week clinical trial of antibiotics is reasonable in newly diagnosed patients not previously treated for prostatitis with antimicrobials.(A1)

When chronic bacterial prostatitis (NIH Category II) has been excluded on careful evaluation and microbiological testing, the UPOINT classification system to determine the clinical phenotype provides a good starting point for identifying optimal initial therapy.[135][136][137][138]

As no single treatment, procedure, or arbitrary combination of therapies has proven universally beneficial in fully and permanently resolving the symptoms and curing chronic prostatitis/chronic pelvic pain syndrome (NIH Category III), the best evidence-based management approach is to customize treatment individually for each patient after a full assessment of their specific symptoms, signs, history, experience, phenotype, psychosocial situation, psychological factors including anxiety and stress issues, family dynamics, co-morbidities, dietary habits, and expectations.[132][133][139]

The UPOINTS phenotype classification system was designed to separate CP/CPPS patients into subgroups to assist with selecting the best and most appropriate treatments.[58][140][141][142][143][144] The classification system includes urinary, psychosocial, organ-specific, infection, neurologic/systemic, tenderness of muscles, and sexual dysfunction phenotypes.[140][141][142][143][144] Overall, the UPOINTS system appears to help optimize outcomes by tailoring and customizing treatment selection, thereby improving the response to therapy.[58](B3)

Specific Therapies for Chronic Prostatitis/Chronic Pelvic Pain Syndrome (NIH Category III)

Patients are neither expected nor required to undergo all of these treatments. Instead, they are encouraged to take advantage of the available selection, utilizing the most effective for them.

After a comprehensive shared decision-making discussion, treatment selection will be based on availability, cost, local expertise and equipment, initial therapy results, and individual patient preferences.

For many patients, it can be difficult to accept that their condition is not curable simply with antibiotics or any other monotherapy and will likely require long-term multimodal treatment for symptom control. This often involves a combination of treatments, including those listed below. Each therapy listed has at least some evidence of a symptomatic or therapeutic benefit in some CP/CPPS patients, but a combination of treatments is typically necessary for optimal results.[145][146][147](B3)

Acupuncture has shown good efficacy in treating the symptoms of CP/CPPS in several studies, particularly when combined with other treatment modalities, suggesting it is a realistic and reasonable therapy for chronic prostatitis/chronic pelvic pain syndrome in men.[148][149][150][151][152][153][154][155][156][157](A1)

Botulinum toxin A (Botox) therapy, including intraprostatic injections, has shown some promising results in early studies, but there is insufficient data to recommend it for general use.[158][159][160][161][162](A1)

Dietary adjustments, supplements, and nutraceuticals are intended to reduce known or possible irritants to the prostate and lower urinary tract. Caffeine is probably the most significant dietary prostatic irritant for most patients, but each individual will likely have specific and unique sensitivities. Other possible nutritional prostatic irritants include alcohol, high potassium foods like dried fruit and bananas, cranberries and cranberry juice, colas and other carbonated beverages, dairy, red meat, spicy foods like "hot sauce," salt, coffee, highly acidic foods (citrus, vinegar), chocolate, and lemon juice.

A higher fluid intake is recommended as dehydration makes the urine more concentrated and irritating.[163][164] Tomatoes and tomato products are somewhat controversial because, while acidic, they also contain high levels of lycopene, which is considered beneficial.

(B2)

Quercetin, lycopene, selenium, curcumin, Cernilton (a pollen extract), Serenoa repens (saw palmetto), rapeseed bee pollen, various other flower pollen and plant extracts, and many other nutraceuticals, bioflavonoids, and phytotherapeutics, have shown at least some limited benefit in treating the symptoms of CP/CPPS. Definitive studies are lacking, and there is no consensus on the best ingredients or dosages.[165][166][167][168][169][170][171][172][173][174][175][176]

(A1)

Exercise and increased physical activity have been shown to improve symptoms of CP/CPPS in at least one randomized study.[177] This underutilized treatment modality is easily implemented, has no side effects, and provides substantial additional health benefits beyond reducing bothersome symptoms of CP/CPPS.

Extracorporeal shockwave therapy to the perineum at low-intensity levels has been successful in relieving symptoms of CP/CPPS in several reports, but adequate controlled randomized studies have not yet been done, and the treatment protocol has not been standardized.[178][179][180][181][182][183][184][185][186](A1)

Local anti-inflammatory therapy and lifestyle changes may have significant, if temporary, benefits. They are also low-cost, can be immediately adopted by all prostatitis patients, and have no side effects.

Quitting smoking will help as smokers are more likely to demonstrate chronic prostatitis than non-smokers.[163][187] Cigarette smoking increases pro-inflammatory systemic chemistries, mainly involving IL-18 and the nuclear factor-kappa B (NF-κB) family of chemical mediators and is associated with greater vascular resistance, resulting in significantly reduced perfusion of the prostate, exacerbating CP/CPPS symptoms, delaying recovery, and prolonging disease resolution.[188][189][190] Increased oxidative stress from smoking increases prostatic fibrosis, inflammation, and other negative cellular changes.[188][190][191] There are also many other health benefits to quitting smoking.

(B2)

Hot sitz baths offer significant relief, but the effects are temporary, and the water must be hot. This thermal treatment must be a bath rather than a heating pad or hot shower to facilitate deeper heat penetration. Ten minutes is usually sufficient. Most patients find multiple sitz baths helpful daily, particularly during symptom exacerbation. As symptoms improve, the frequency of the sitz baths can be reduced. An initial frequency of 3 or 4 times daily is recommended for patients with significant symptoms.

Soft but supportive cushions when sitting, including inflatable "donuts," are recommended as they often help, have no side effects, and are quite inexpensive. Inflatable cushions and donuts should be inflated just sufficiently to minimize perineal pressure.

Patients should avoid sitting on cold, hard surfaces such as a stone bench, and bicycle riding should be avoided as the narrow seat puts undue pressure directly on the sore and inflamed perineum.

Medications have a relatively limited role in treating CP/CPPS empirically and are best used selectively for specific symptoms as indicated.

5-α reductase inhibitors (eg, finasteride, dutasteride) are hormonal medications that block the intracellular formation of 1,25 dihydrotestosterone in prostate cells. They can reduce the size of the prostate by about 20% to 25% over time, reduce prostatic vascularity, and lower PSA levels by 50%.[192] They have demonstrated benefit in relieving CP/CPPS symptoms and appear helpful in some patients with no significant side effects.[192][193][194] They are likely to be most effective when used in larger prostates.[192]

Alpha-blockers relax muscle tension in the prostate and bladder neck, improving urinary flow.[195] They may also be beneficial for long-term pain control.[196] They will be most useful in CP/CPPS patients with urinary symptoms of a weak stream or urinary hesitancy.[197][198][199][200] They can be used empirically, based on symptoms, or after additional testing, such as an automated uroflowmetry and a post-void residual determination.[197][198][199][200][201][202] Failure of an α-blocker to relieve urinary flow suggests a urethral stricture or some other form of outflow obstruction, and a retrograde urethrogram or cystoscopy should be considered.

(A1)

Mast cell stabilizers (eg, cromolyn, cetirizine, quercetin, curcumin) may have a role to play in treating patients with CP/CPPS, at least for those who exhibit mast cell dysfunction.[203][204][205] Their role in treating prostatitis is still being determined, but a 30-day clinical trial is reasonable.

Nonsteroidal anti-inflammatory medications (NSAIDs) have shown some limited, short-term benefits in relieving pain and other uncomfortable symptoms in CP/CPPS. They do not completely resolve the disorder, and their effects diminish over time.[197][206][207][208] Despite evidence of increased expression of pro-inflammatory cytokines in patients with chronic pelvic pain syndrome, there is little supporting evidence for the use of other anti-inflammatories in CP/CPPS, such as steroids, monoclonal antibody therapies, or leukotriene receptor antagonists.

(A1)

Overactive bladder drugs (eg, oxybutynin, mirabegron) may be used selectively in patients with evidence of urinary frequency and urgency who do not have high post-void residual urine volumes.[209][210][211][212]

Phosphodiesterase type 5 (PDE-5) inhibitors (eg, sildenafil, tadalafil) and similar therapies can be beneficial for CP/CPPS patients with erectile dysfunction but will not affect other chronic prostatitis symptoms. (See our companion StatPearls reference article on "Erectile Dysfunction."[139])

Tricyclic antidepressants (eg, amitriptyline, fluoxetine) have shown efficacy in treating neuropathic pain associated with CP/CPPS, in addition to the use of some anticonvulsant-type drugs such as gabapentin and pregabalin.[17][50][51][213][214][215][216] They may also incidentally help treat any associated depression or anxiety issues.

(A1)

Medications without significant therapeutic benefits include allopurinol, leukotriene antagonists (eg, zafirlukast), muscle relaxants (eg, baclofen, diazepam), and pregabalin.[58]

Pain management specialists should be involved where painful discomfort is not easily managed with standard treatments, as they can incorporate unique analgesic therapies (eg, TENS, neuromodulation, trigger point injections) early in patient care resulting in improved outcomes.[17][18][217](A1)

Regarding pharmacological pain management, where there is evidence of a nociceptive or inflammatory component, simple analgesics such as nonsteroidal anti-inflammatories may offer some benefit. In some patients, continuous use of NSAIDs is beneficial, but early recognition that the pain may be neuropathic and treating it as such with gabapentin, amitryptiline, and duloxetine yields better and more positive outcomes.[18][218] Pain control in patients with CP/CPPS is critically important and often the most challenging aspect of providing care. (A1)

Physiotherapy and pelvic floor-related interventions for CP/CPPS include pelvic floor physical therapy with trigger point injections, myofascial release procedures, external myofascial mobilization, and paradoxical relaxation treatments.[219][220] These will be most useful in patients with pelvic floor spasms, levator ani syndrome (pelvic floor tension myalgia), or other pelvic floor myofascial dysfunctions and should be considered for patients not responding to alternative initial therapies or medications.[221][222] (B2)

Pelvic floor tension myalgia is characterized by a vague, dull, aching sensation in or near the rectum that is relieved somewhat by standing, and worsened by anxiety, stress, and tension.
Pelvic floor functional problems can best be determined by a physical therapy pelvic floor therapeutic evaluation.

Psychological and psychosocial aspects need to be addressed and evaluated as CP/CPPS is worsened by unresolved anxiety, tension, stress, and depression.[219][223][224][225] Patients who exhibit depression, anxiety, suicidal thoughts, or significant relationship problems should be referred for psychological evaluation and treatment. Strategies that address catastrophizing and feelings of helplessness are critical in providing symptom relief as they otherwise will significantly contribute to an increased perception of pain and, ultimately, treatment failure. (A1)

However, it can be challenging to persuade patients to undergo a psychological assessment to identify these problems voluntarily. Explaining the important role of an evaluation in identifying stress and anxiety-causing factors, critical relationship issues, and other underlying psychosocial contributing factors can be helpful, but many patients will still decline this critical part of the diagnostic protocol.

One useful persuasive technique is to explain that a single visit to an expert in "behavioral management issues" for a "stress" evaluation is routine in these cases, and it's just for an "opinion," which will be very helpful in treatment selection.
Cognitive behavioral therapy alongside pharmacotherapy for anxiety and depression has been described and appears to be beneficial.[16][138][226][227]

Sacral neuromodulation, biofeedback, and percutaneous tibial nerve stimulation have all demonstrated reasonable beneficial value in treating the symptoms of CP/CPPS, but definitive studies proving long-term efficacy are lacking.[228][229][230][231][232][233][234][235][236][237][238][239][240](A1)

Surgery has no place in the treatment of CP/CPPS unless there is clear evidence of urinary outflow obstruction, as there is insufficient evidence to support urological procedures (prostatectomy, TURP, or bladder neck incision) in the management of chronic prostatitis/chronic pelvic pain syndrome. Injudicious surgical interventions can exacerbate symptoms, cause undesirable side effects, or produce uncomfortable complications.[18][36](A1)

Therapeutic ejaculation on a regular or scheduled basis, typically at least once every 3 days, is suggested. This avoids uncomfortable and awkward prostatic massages and accomplishes similar beneficial effects in minimizing prostatic fluid stasis and buildup in the prostatic ducts by facilitating drainage. While the benefit is unproven, the treatment is simple, the rationale is not unreasonable, and it may be of some therapeutic benefit while avoiding the discomfort and awkwardness of prostatic massages.

Prostatic massage for CP/CPPS remains somewhat controversial. The intent is to facilitate drainage from the prostatic ducts, and while there is some evidence of efficacy, studies are conflicting; therefore, prostatic massage cannot currently be recommended.[241][242][243]
Massaging or strenuously manipulating an infected or inflamed, painful prostate is uncomfortable for the patient and could exacerbate problems.
A similar benefit can reasonably be obtained from regular therapeutic ejaculations.

(A1)

Summary of Treatments for Chronic Prostatitis/Chronic Pelvic Pain Syndrome (NIH Category III):

Overall, there is limited evidence of significant benefits from empiric oral medications for the treatment of CP/CPPS, suggesting that a more targeted and specific approach, together with other non-drug-based therapies, should be utilized preferentially.[107]

For many patients, an initial combination of selected dietary changes (low potassium, no caffeine, etc.), lifestyle modifications (eg, hot sitz baths, seat cushions, stress reduction techniques, quitting smoking), therapeutic ejaculation, and targeted medications that include α-blockers for voiding issues, 5-α-reductase inhibitors for prostate enlargement, NSAIDs or amitriptyline for pain relief, mast cell stabilizers, and PDE-5 inhibitors for ED is a reasonable starting point.

Phytotherapy and selected supplements may also be used, but the lack of adequate studies or data makes it difficult to recommend any specific product or dosage.[21]

Some newly diagnosed CP/CPPS patients will respond to a short (2 to 4-week) clinical trial of antibiotics even without any evidence of infection, but this should not be continued without positive cultures or substantial symptom relief.[134] Patients who've had multiple courses of antibiotics previously are unlikely to respond, which will only increase bacterial resistance.

Patients who fail to improve after the initial round of treatments may still benefit from physical and myofascial therapy, trigger point injections, pain management services, neuropathic medications, acupuncture, neuromodulation, biofeedback, psychological counseling, and extracorporeal shockwave procedures.

An individualized, multidisciplinary, evidence-based, multimodal approach will provide optimal outcomes when managing patients with CP/CPPS. Non-medication-based therapies are usually suggested before using drugs.[244] Treatment generally includes some combination of the following:[245][246](A1)

Acupuncture
Alpha-blocker medications
Anti-inflammatory medications (NSAIDs)
Biofeedback
Bladder training/retraining
Botulinum toxin A
Cognitive behavioral treatment
Dietary therapy (to remove all potentially prostate-irritating foods)
Extracorporeal shockwave therapy (low-intensity)
Hormonal therapy (5-α reductase inhibitors)
Localized anti-inflammatory treatments (hot sitz baths, cushions, donuts, etc.)
Mast cell stabilizers
Neuropathic pain medications (antidepressants, gabapentin, etc.)
Pain management services
PDE-5 inhibitors
Pelvic floor physical therapy with trigger point, myofascial release, and paradoxical relaxation treatments
Percutaneous tibial nerve stimulation
Psychotherapy
Sacral or spinal neuromodulation therapy
Supplements and phytotherapy
Therapeutic scheduled or regular ejaculation
Transcutaneous electrical nerve stimulation (TENS)

Differential Diagnosis

Acute bacterial prostatitis (NIH category I)
Bladder calculi
Bladder and urethral cancer
Bladder outflow obstruction (BPH)
Chemical (chemotherapy) cystitis
Interstitial cystitis
Pelvic floor tension myalgia (levator ani syndrome)
Primary bladder neck obstruction
Prostate cancer
Prostatic abscess
Pudendal neuralgia
Radiation cystitis
Sexually transmitted infections
Tuberculous prostatitis
Urinary retention
Urethral stricture
Urinary tract infection
Viral prostatitis

Prognosis

Bacterial eradication can be achieved in up to 70% of chronic prostatitis with careful selection of appropriate anti-microbial agents. However, bacterial eradication does not always correlate with complete resolution of symptoms. Chronic bacterial prostatitis will progress into CP/CPPS in 10% of cases.[16][18]

There is still much to learn about the natural course of CP/CPPS, and patient-reported outcomes are highly variable. Most patients derive significant symptomatic benefits from various combinations of previously mentioned therapies. Others will significantly decrease their quality of life despite an optimal multidisciplinary, multimodal management approach.

Complications

The negative impact of chronic prostatitis on male fertility has been noted. Studies have demonstrated a negative impact of chronic prostatitis on multiple semen quality parameters, including sperm concentration, motility, and morphology, when compared with controls.[43][44] The mechanism involves multiple pathophysiologies, including inflammation of male accessory glands, metabolic syndrome, inflammatory bowel disease, prostatic dysfunction, chemical changes in the prostatic secretions, HPV infection, greater oxidative stress, and increased cellular autoimmunity reactions to prostatic antigens.[43][44][247][248][249]

It is important to consider the role of chronic prostatitis when evaluating male infertility in a patient with this condition.[21][43][70]

Increased morbidity can be associated with long-term antibiotic use. Toxicity and colonization with multidrug-resistant organisms are recognized consequences of long-term unnecessary antibiotic use.

Indirect complications associated with pharmacological dependence on opioids and other analgesics in patients with chronic, refractory pain should also be considered.

Psychological disorders, stress, anxiety, depression, and problematic relationship issues can all be exacerbated by chronic prostatitis.[224]

Deterrence and Patient Education

Patients and their families must be educated about this troublesome condition and its treatments. In particular, they must have realistic expectations that even the best possible treatment and care cannot guarantee a permanent cure, and recurrences are common. Therapy tends to be prolonged, and antibiotic use is limited as it may be harmful, contributing to increased bacterial resistance. The need for regular and frequent ejaculation (usually at least once every 3 days) should be explained (it's to minimize stasis and buildup within the prostatic ducts).

Stress reduction is an important part of the overall treatment plan. Dietary advice must be customized for each patient, although caffeine reduction is almost universally recommended.

Local anti-inflammatory and pressure-relieving therapies should be emphasized, such as daily hot sitz baths, "donuts" and soft cushions to sit on, avoidance of bicycle riding, etc.

Discussing the vital role of a psychological evaluation in identifying stress and anxiety-causing factors, underlying relationship issues, and evaluating for depression as well as other underlying psychosocial contributing factors can be critical in obtaining an optimal outcome. Explanation should be given that an opinion from an expert in "behavioral management" is routine and only requires a single visit, and this evaluation will be very helpful in helping decide which treatment options will be most effective. If something is causing significant stress, fear, tension, or anxiety, it's far better to identify it so it can be treated; otherwise, it will interfere with symptom relief and a successful outcome.

Pearls and Other Issues

Chronic prostatitis is a syndrome with varying presentations and etiologies.
An early distinction between bacterial and non-bacterial pathology is essential for initiating timely, appropriate therapy.
Antibiotics are not helpful where there is no evidence of infection, with a few exceptions, and repeated unnecessary courses of antibiotics contribute to increasing antimicrobial resistance.
Semen cultures are an underutilized clinical resource for identifying infecting organisms.
The effectiveness of antibiotics in chronic bacterial prostatitis (NIH Category II) is rapidly changing with the development of antimicrobial-resistant organisms. Judicious antimicrobial stewardship is essential to limit new resistance patterns.
Fosfomycin should be considered early in chronic bacterial prostatitis (NIH Category II) alone or in combination with fluoroquinolones or doxycycline.
Sulfamethoxazole/trimethoprim has only a limited role in the management of chronic prostatitis at this time.
There is no role for transrectal ultrasound in the evaluation of chronic prostatitis except to identify a possible prostatic abscess and to evaluate for intraprostatic calculi.
Significant prostatic calculi may need to be removed surgically by TURP to treat patients with chronic bacterial prostatitis who are not responding to appropriate antibiotics.
If unsure, a 2 to 4-week clinical trial of antibiotics in a previously untreated, newly diagnosed patient is not unreasonable.
Male patients with documented UTIs are candidates for developing chronic bacterial prostatitis.
Granulomatous and viral chronic prostatitis are associated with HIV infections and will demonstrate negative standard urine and semen cultures.
HIV-positive patients are likely to have negative urine and blood cultures.
They are also at higher risk for Cytomegalovirus, Tuberculosis, and Candida.
Most patients diagnosed with prostatitis have CP/CPPS, for which antibiotics are not indicated.
Treatment of CP/CPPS uses a multimodality approach focused on managing symptoms using multiple therapies, as necessary.
5-α reductase inhibitors, NSAIDs, mast cell stabilizers, therapeutic ejaculation, quitting smoking, dietary adjustments, and appropriate lifestyle changes can be offered to virtually every patient with CP/CPPS.
Alpha-blockers should be given to patients with voiding issues such as a weak urinary stream, incomplete emptying, or hesitancy.
There is little harm in allowing patients to try supplements, phytotherapies, and nutraceuticals as long as they don't interfere with recommended treatments.
Management of pain can be quite challenging, and a multidisciplinary approach is recommended, including early pain management and physical therapy consultations.
When the usual treatments are unsuccessful, think outside the box and try less conventional modalities like extracorporeal shockwave therapy, acupuncture, biofeedback, bacteriophages, and neuromodulation.
The role of botulinum toxin A and direct intraprostatic antibiotic injections is still being explored.

Enhancing Healthcare Team Outcomes

Successful management of patients with chronic prostatitis relies on the integrated workings of the whole multi-disciplinary team to achieve the most superior outcomes for patients and to reduce the morbidity and costs associated with this syndrome.

A urological assessment to exclude other pathological processes (supported by microbiology, pathology, and radiology colleagues) forms the initial evaluation and diagnosis basis.

Further interventions and long-term management of the patient may require the input of pharmacists, pain management specialists, psychologists, psychiatrists, primary care physicians, dietitians, urologists, and physiotherapists. Patients can achieve their best outcomes only by working together using a coordinated, multifaceted approach.

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Level 2 (mid-level) evidence