Guidelines For The Diagnosis And Treatment Of Chronic Prostatitis/chronic Pelvic Pain Syndrome

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological disease that has adverse effects on the physical and mental health of patients and seriously affects their quality of life. The pathogenesis of CP/CPPS is complex and diverse, the treatment options are complicated, and the efficacy is uncertain, which brings great trouble to clinical work. In recent years, this field has made rapid progress. In order to standardize the diagnosis and treatment plans and better guide clinical practice, the Chinese Medical Association's Andrology Branch organized experts to conduct extensive discussions on the basis of consulting the latest research results and referring to relevant domestic and foreign guidelines and expert consensus. A consensus was reached on issues related to CP/CPPS, especially the principles in clinical diagnosis and treatment, and a CP/CPSS diagnosis and treatment guideline was compiled, hoping to provide useful guidance and help for clinical workers in the diagnosis and treatment of CP/CPSS.

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1 Definition, classification, epidemiology, etiology and pathogenesis of CP/CPPS

1. 1 Definition and classification of CP/CPPS

In 1995, the National Institutes of Health (NIH) of the United States classified prostatitis into 4 types based on the research progress at that time. CP/CPPS belongs to type III in this classification, which refers to a group of syndromes caused by multiple factors, mainly characterized by pelvic pain or discomfort and lower urinary tract symptoms (LUTS). Among them, according to whether the level of white blood cells in prostate massage fluid (EPS), semen or urine after prostate massage (VB3) is elevated, it is further divided into inflammatory (type IIIA) and non-inflammatory (type IIIB) [1]. However, more and more studies have shown that the level of white blood cells in EPS, semen and VB3 cannot be used as the diagnostic criteria for CP/CPPS and the judgment of severity [2-4].

Because the NIH classification system is too general, it cannot fully reflect the different causes and heterogeneity of clinical manifestations of CP/CPPS. Shoskes et al. [5] proposed the UPOINT classification system in 2009. This system is different from the NIH classification system. It can more comprehensively reflect the clinical manifestations of CP/CPPS, thereby more accurately guiding clinicians to carry out targeted comprehensive treatment for different patients. The UPOINT classification system includes 6 independent factors, namely urinary symptoms, psychosocial symptoms, organ-specific symptoms, infection symptoms, neurogenic/systemic symptoms, and tenderness of muscles. Previous studies have also included sexual dysfunction in UPOINT, namely UPOINT (S), but it is still controversial [6-7] (Table 1). In recent years, domestic scholars have explored the mechanism of chronic pelvic pain and achieved positive results. They suggested that CP/CPPS be renamed as prostatic pelvic syndrome, which would be beneficial to the understanding, diagnosis and treatment of the disease. However, more clinical applications and verification are still needed [8].

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1.2 Epidemiology of CP/CPPS

Prostatitis is a common disease in adult men, accounting for 8% to 25% of outpatients in urology departments［9-10］. The prevalence of prostatitis reported abroad is 2.0% to 16.0%［9,11］, and the prevalence in China is 6.0% to 32.9%［10,12-13］.
CP/CPPS is the most common and difficult to treat type of prostatitis, accounting for more than 90% of all prostatitis, and the incidence of CP/CPPS tends to be younger［12-13］.
Studies have shown that occupation, environment, spicy food, drinking, long-term sitting, holding urine, sexual habits and mental factors are the main risk factors for the onset of CP/CPPS. The prevalence of CP/CPPS in some special occupations, such as drivers, is significantly higher than that in other occupations [14]; the possibility of CP/CPPS symptoms is higher in winter, cold climate, and short sunshine hours [15]; spicy food and drinking can induce the release of inflammatory factors, causing prostate congestion, inducing or aggravating CP/CPPS symptoms [16-18]; sitting for a long time can cause pelvic venous congestion and aggravate CP/CPPS symptoms; holding urine is significantly related to the occurrence of CP/CPPS, which may be related to increased posterior urethral pressure, causing urine to flow back into the prostate duct, leading to chemical inflammation of the prostate [19]; ​​long-term abstinence, excessive masturbation, ejaculation control, interrupted sexual intercourse and other bad sexual habits can also cause prostate congestion, induce aseptic inflammation, and aggravate CP/CPPS symptoms [17-18, 20]. Excessive mental stress, excessive psychological burden and staying up late often induce sympathetic nerve excitement; anxiety and depression can also lead to autonomic dysfunction, resulting in CP/CPPS symptoms such as pelvic floor muscle spasms, urination dysfunction and pelvic floor pain.

 

Table 1 UPOINT(S) classification system

 

Symptom	Main Manifestations
Urinary Symptoms	Urinary frequency, urgency, or nocturia; residual urine > 100 ml; urinary tract symptom score > 4 on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI).
Psychosocial Symptoms	Clinical evidence of depression "catastrophizing" (helplessness, hopelessness).
Organ-Specific Symptoms	Specific prostatodynia; increased white blood cells in expressed prostatic secretions (EPS), hematospermia, diffuse prostatic calcifications.
Infection Symptoms	Exclusion of type I and type II prostatitis; gram-negative rods or enterococci in EPS.
Neurological/Systemic Symptoms	Abdominal and pelvic pain outside the prostate; irritable bowel syndrome; fibromyalgia; chronic fatigue syndrome.
Myalgic Symptoms	Muscle spasms and trigger points in the pelvic floor and abdominal muscles.
Sexual Dysfunction	Erectile dysfunction (ED), premature ejaculation, orgasmic dysfunction, etc.

 

 

1.3 Causes and pathogenesis of CP/CPPS

The etiology of CP/CPPS is complex, and its pathogenesis has not been fully elucidated. There is widespread controversy: it may be caused by one initiating factor or by multiple factors, one or several of which play a key role and may interact with each other [21]; it may also be caused by many different diseases that are difficult to distinguish, but have the same or similar clinical manifestations [22]. It is currently believed that the main causes and pathogenesis of CP/CPPS include the following aspects.

 

1.3.1 Pathogen infection

Although routine bacterial culture of CP/CPPS patients usually cannot isolate pathogens, it may still be related to infection with some special pathogens [23]. In addition, the disruption of the microecological balance of the urogenital tract can also lead to the occurrence of CP/CPPS [24].

 

1.3. 2 Urinary reflux

Bladder outlet dysfunction, abnormal bladder neck structure, or spasm of the internal and external urethral sphincters and pelvic floor muscles can increase prostatic urethral pressure during urination, which can easily lead to urine reflux in the prostate [25]. Metabolites such as uric acid flow back into the prostate with urine, which will aggravate the symptoms of CP/CPPS [26].

1.3.3 Dysfunction of the lower urinary tract epithelium
Dysfunction caused by the imbalance of the potential protective factors and damaging factors of the lower urinary tract epithelium may cause the occurrence of CP/CPPS [27]. The expression of potassium ion channels in the prostate epithelium of CP/CPPS patients is abnormal. After potassium ions penetrate into the matrix through the epithelial gap, they can stimulate nerve fibers and cause clinical symptoms such as pain [28].

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1.3.4 Neuroendocrine factors

CP/CPPS patients are prone to fluctuations in heart rate and blood pressure, indicating that their autonomic nerve sensitivity is increased [29]. Changes in pelvic floor muscle function in CP/CPPS patients are related to abnormal excitability of the motor cortex and posterior insula of the brain [30]. Substances such as norepinephrine and prostaglandins released by sympathetic nerve endings can also lead to pelvic floor muscle dysfunction and cause pain symptoms [31].

 

1.3.5 Psychological factors

Depressed and anxious men often have higher prostatitis symptom scores [32], and long-term CP/CPPS patients usually have obvious changes in mental and personality traits [33]. The use of antidepressant and anti-anxiety drugs can improve CP/CPPS symptoms [34].

 

1.3.6 Pelvic disease factors

Studies have shown that CP/CPPS patients have a higher rate of varicocele and hemorrhoids [35], suggesting that pelvic venous disease may be one of the causes of CP/CPPS.

 

1.3. 7 Inflammation and immune response

CP/CPPS may be an inflammatory response or/and autoimmune disease mediated by cytokines［36-37］. The proportion of Th1 and Th17 cells in the peripheral blood of CP/CPPS patients is significantly higher than that of healthy people［36］, which causes the body to secrete more proinflammatory cytokines, thereby upregulating the expression of chemokines, thereby inducing local immune response in the prostate, causing adverse effects［37］.

 

1. 3. 8 Oxidative stress

CP/CPPS patients have excessive production of reactive oxygen species (ROS) or/and relatively insufficient clearance capacity, which will lead to an increase in oxidative stress products and/or byproducts, thereby causing symptoms to worsen［38］.

 

1. 3. 9 Genetic susceptibility

Some scholars have found that a short tandem repeat (STR) sequence polymorphism near the phosphoglycerate kinase gene at Xq11-13 is associated with CP/CPPS［39］, but whether genetic susceptibility is a potential pathogenic factor of CP/CPPS needs further study.

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2 Diagnosis and differential diagnosis of CP/CPPS

2.1 Medical history Comprehensive and detailed inquiry

The medical history of CP/CPPS patients not only helps to clarify the diagnosis, but also assists in the assessment of the condition, further analysis of the cause, targeted treatment and understanding of the prognosis. The collection of medical history mainly includes four main aspects: chief complaint, current medical history, past history and personal history.

 

2.1.1 Chief complaint

Including pain or discomfort symptoms, LUTS and sexual dysfunction symptoms, etc. Some patients may have mental and psychological symptoms. The duration of the above symptoms should also be inquired [40-43].

 

2.1.2 Current medical history

The focus should be on the length of the course of the disease, the cause of onset, the nature, location and degree of pain. LUTS, sexual dysfunction symptoms, mental and psychological symptoms and related accompanying symptoms should be inquired in detail [40-43]. It is necessary to inquire about the order in which different symptoms appear (primary and secondary), such as the order in which depression, anxiety and CP/CPPS symptoms appear, which can be used to distinguish whether it is a psychological problem that causes physical discomfort or emotional abnormality caused by CP/CPPS.

 

2.1.3 Past medical history

Patients should be asked whether they have a history of hypertension, diabetes, thyroid disease and urogenital surgery [41-42].

 

2.1.4 Personal history

Patients should be asked about smoking, drinking, staying up late, sitting for a long time, fatigue, spicy food addiction, holding urine, frequent sexual intercourse, delayed ejaculation, etc. Evaluation of the patient's quality of life, sexual life and mental health is also important, because it can affect the choice of treatment [40, 43].

 

2. 2 Physical examination CP/CPPS patients should focus on the following contents based on the whole body physical examination:

 

Examination of the urogenital system such as the lower abdomen, lumbosacral region, perineum, urethral orifice, penis, testicles, epididymis, spermatic cord, etc., paying attention to tenderness and abnormal masses, which is helpful for diagnosis and differential diagnosis. Pay attention to similar perineal pain caused by diseases such as epididymitis, epididymal nodules, varicocele, spermatic cord inflammation, testicular tumors, etc., which need to be differentiated from prostatitis.
The rectal examination has a certain value for prostatitis and helps to identify other prostate diseases and perineal, rectal, and neuropathy. At the same time, EPS can be obtained through prostate massage. Rectal examination can understand the size, texture, nodules, tenderness, and range, and degree of the prostate.
Rectal examination of CP/CPPS patients shows that the prostate is full and soft, and may have mild tenderness or enlargement; in patients with a long course of disease, the prostate is shrunk, hardened, uneven, and has small nodules. Check the tightness of the pelvic floor muscles and the tenderness of the pelvic wall, especially the trigger points of myofascial pain and possible muscle-referred pain.

 

2. 3 CP/CPPS clinical symptoms and related assessment tools

2. 3. 1 Clinical symptoms

Most CP/CPPS patients have prolonged and recurrent illnesses, often lasting more than 3 to 6 months, and the symptoms vary greatly from person to person. Most patients have one or more symptoms of pain, LUTS, mental and psychological symptoms, sexual dysfunction, etc.

 

2. 3. 1. 1 Pain or discomfort symptoms

Mainly located in the perineum, testicles, pubic area, penis and lower abdomen, followed by pain and discomfort in the urethra, perianal area, lumbar sacral area, and back. Ejaculation pain and pain and discomfort after penile erection may also occur.

 

2. 3. 1. 2 LUTS

Frequent urination, urgency, pain, incomplete urination, difficulty urinating, burning sensation in urine, etc.

 

2. 3. 1. 3 Mental and psychological symptoms

Symptoms such as anxiety, depression, sleep disorders, memory loss, etc.

 

2. 3. 1. 4 Sexual dysfunction

Symptoms such as ED, premature ejaculation, weak or difficult ejaculation, and low libido［20, 40, 44］.

 

2. 3. 2 Related assessment tools

CP/CPPS clinical symptoms are complex and varied, and there is a lack of objective diagnostic assessment indicators in actual clinical diagnosis and treatment. It is currently believed that the NIH Chronic Prostatitis Symptom Score (NIH-CPSI) can relatively objectively and comprehensively assess the symptoms of CP/CPPS patients［45］. The NIH-CPSI contains three sub-items, namely pain symptoms, urination symptoms, and the impact of symptoms on quality of life.
The NIH-CPSI can be used as an auxiliary diagnostic assessment tool for the severity of CP/CPPS symptoms, and can also be used as an important efficacy assessment tool in the follow-up of CP/CPPS treatment.

For patients with CP/CPPS and sexual dysfunction, the International Erectile Dysfunction Index (IIEF-5) can be used to assess erectile function [46], and the Premature Ejaculation Diagnostic Tool (PEDT) can be used to assess ejaculation function [47]. For patients with storage symptoms mainly characterized by frequent urination and urgency, the Overactive Bladder (OAB) Self-Assessment Scale (OABSS score) can be used first or in combination for assessment [48-49]. If patients have psychiatric symptoms such as anxiety and depression, the Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Self-Assessment Anxiety Scale (SAS) [50], and Generalized Anxiety Disorder Scale (GAD-7) [51] can be used for assessment, or the patient can be referred to a relevant department for assessment.

 

2. 4 Laboratory tests

2. 4. 1 Urine test

2. 4. 1. 1 Urine routine test

It can exclude other diseases such as urinary tract infection and hematuria.

 

2. 4. 1. 2 Prostatic exosomal protein (SEP) test

PSEP is secreted by the prostatic corpuscles. In recent years, studies have found that the PSEP level in the urine of CP/CPPS patients is elevated［52-53］, and the PSEP level is related to the NIH-CPSI score and the white blood cell concentration in EPS［54］. As a non-invasive examination item, PSEP still needs more clinical research to provide evidence-based medicine.

 

2. 4. 2 EPS test

EPS used to be an important indicator for the classification and diagnosis of prostatitis and has been widely used in clinical practice for a long time. However, increasing evidence shows that the number of white blood cells in EPS cannot reflect the severity of CP/CPPS, nor can it represent its outcome.
Before collecting EPS, sexual abstinence should be observed for 2 to 7 days. Usually, prostate massage is performed in the chest-knee position, and the specimen is sent for examination in time. If microbiological testing is required, aseptic operation should be performed, the vulva should be disinfected before massage, and the specimen should be collected in a sterile container and sent for examination in time. If tuberculosis, tumor or acute infection of the reproductive system is suspected, prostate massage should not be performed. It is not advisable to repeatedly massage the prostate for one test. If EPS cannot be collected after massage, the patient can be asked to collect the first urine after prostate massage for analysis.
The EPS white blood cells of healthy adult males are less than 10/HP, lecithin bodies are evenly distributed throughout the field of vision, pH is 6.4 to 6.7, and red blood cells and epithelial cells are occasionally seen. The EPS white blood cells of patients with inflammatory CP/CPPS are greater than 10/HP, while those with non-inflammatory CP/CPPS are normal. The number of white blood cells does not correlate with the severity of CP/CPPS symptoms.

Macrophages containing phagocytic lecithin bodies or cell fragments in the cytoplasm are also a unique manifestation of prostatitis.

 

2.4.3 Semen testing

For patients who have difficulty obtaining EPS, semen testing can partially replace the clinical diagnostic value of EPS testing. At the same time, patients with fertility demands can also understand the quality of semen.

 

2.4.3.1 Prostate secretion function testing

Prostate secretion fluid contains a large amount of zinc, citrate, calcium, phosphate, lipids, kininase, antioxidant enzymes, polyamines and interleukins. The World Health Organization's "Human Semen Examination and Processing Laboratory Manual" (5th edition) points out that the content of zinc, citrate or acid phosphatase in semen is a reliable indicator for detecting prostate secretion function, and there is a good correlation between these markers [55].

 

2.4.3.2 Semen leukocyte detection

When the semen leukocyte concentration is > 1 × 106 /ml, it indicates that there may be genital inflammation.

 

2.4. 3.3 Oxidation and antioxidant testing

Including ROS and antioxidant capacity testing.

 

2.4.4 Pathogenic microorganism testing

2.4.4.1 Bacteriological testing

The Meares-Stamey four-cup method or two-cup method is recommended for the diagnosis of CP/CPPS. It is also recommended to use the NIH-CPSI questionnaire to describe the disease characteristics in terms of pain, urination symptoms and quality of life [40].
The four-cup method is used to identify pathogens and quantify white blood cells in the first-stream urine (VB1), mid-stream urine (VB2), EPS, and urine after prostate massage (VB3). VB1 represents the urethra, VB2 represents the bladder, and EPS and VB3 represent the prostate. The four-cup method is the basis for the diagnosis and classification of CP/CPPS [56]. Inflammatory CP/CPPS patients have elevated EPS and VB3 white blood cells, while those with non-inflammatory CP/CPPS have normal white blood cells, and both have negative bacteriological tests.

The two-cup method is a simplified method that includes the detection of VB2 and VB3. For newly diagnosed patients, the two-cup method has similar diagnostic sensitivity to the four-cup method [57]. Inflammatory CP/CPPS patients have elevated VB3 white blood cells, while those with non-inflammatory CP/CPPS have normal white blood cells, and both have negative bacteriological tests.

Some scholars believe that semen analysis can provide additional information on reproductive tract infection, which may not be detected in four-cup method specimens or urethral swabs. Studies have shown that semen has a higher sensitivity than EPS when analyzing prostate infection [58]. Therefore, semen can be used as a sample of choice for diagnosing prostate infection, but inflammatory markers or microorganisms detected in semen are not necessarily from the prostate [58].

 

2. 4. 4. 2 Detection of other pathogenic microorganisms

Currently, common clinical tests include Ureaplasma urealyticum, Mycoplasma genitalium, Mycoplasma hominis, and Chlamydia trachomatis. Other pathogenic microorganisms, such as parasites, fungi, viruses, and Trichomonas, are also tested in small quantities.

 

2. 5 Imaging examinations and other special examinations

Imaging examinations are mainly used to identify other diseases that may cause pelvic pain and LUTS besides CP/CPPS, such as urinary tract infection, stones, obstruction, tuberculosis, pelvic organ tumors, and seminal vesicle, ejaculatory duct and scrotal diseases. Common imaging examination methods include ultrasound examination, CT and MRI, among which ultrasound examination is the most commonly used, including transcoronary ultrasound examination and transrectal ultrasound examination. Most imaging examinations of CP/CPPS patients show no positive findings. Ultrasound and CT examinations may sometimes reveal uneven prostate echo or density, as well as calcification or stones. However, these imaging findings are also common in asymptomatic men and cannot be used as a basis for confirming or excluding the diagnosis of CP/CPPS [59-61].

The main purpose of other special examinations is to exclude diseases that need to be differentiated from CP/CPPS, such as bladder outlet obstruction, neurogenic bladder dysfunction, bladder pain syndrome, bladder tumors, prostate cancer, etc. These examinations mainly include urodynamic examinations, urethral cystoscopy, and prostate puncture biopsy, which can be selected in a targeted manner according to the specific clinical situation [59].
Among the above examinations, urinary system ultrasound can be used to exclude most diseases that need to be differentiated from CP/CPPS. In addition to their differential diagnostic value, ultrasonic residual urine volume measurement and uroflowmetry are also valuable for evaluating lower urinary tract symptoms, function, and efficacy in patients with CP/CPPS, and are recommended for the diagnosis of CP/CPPS. Other imaging and special examinations are optional examination items［59］.