Prostatitis

Prostatitis is an inflammation of the prostate. Because women do not have a prostate gland, it is a condition found only in men, although women do have microscopic paraurethral Skene's glands connected to the distal third of the urethra in the prevaginal space that are homologous to the prostate, and may cause symptoms.^[1]

A prostatitis diagnosis is assigned at 8% of all urologist and 1% of all primary care physician visits in the United States.^[2]

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Nomenclature

The term prostatitis refers in its strictest sense to histological (microscopic) inflammation of the tissue of the prostate gland, although historically the term has loosely been used as a rubric to describe a set of quite different conditions. To try to remedy this, the NIH devised a new classification system in 1999.

Classification

According to the 1999 National Institute of Health (NIH) Classification, there are four categories of prostatitis:

• Category I: Acute prostatitis (bacterial)
• Category II: Chronic bacterial prostatitis
• Category III: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)

Subdivisions of IIIa (inflammatory) and IIIb (non-inflammatory) exist based on levels of pus cells in expressed prostatic secretions, but these subcategories are of limited use clinically

• Category IV: Asymptomatic inflammatory prostatitis

Category I: Acute prostatitis (bacterial)

Signs and symptoms

Men with this disease often have chills, fever, pain in the lower back and genital area, urinary frequency and urgency often at night, burning or painful urination, body aches, and a demonstrable infection of the urinary tract, as evidenced by white blood cells and bacteria in the urine. Acute prostatitis may be a complication of prostate biopsy.^[3]

Diagnosis

Acute prostatitis is relatively easy to diagnose due to its symptoms that suggest infection. The organism may be found in blood or urine, and some times in both.^[3] Common bacteria are Escherichia coli, Klebsiella, Proteus, Pseudomonas, Enterobacter, Enterococcus, Serratia, and Staphylococcus aureus. This can be a medical emergency in some patients and hospitalization with intravenous antibiotics may be required. A full blood count reveals increased white blood cells. Sepsis from prostatitis is very rare, but may occur in immunocompromised patients; high fever and malaise generally prompt blood cultures, which are often positive in sepsis. A prostate massage should never be done in a patient with suspected acute prostatitis, since it may induce sepsis. Since bacteria causing the prostatitis is easily recoverable from the urine, prostate massage is not required to make the diagnosis. Rectal palpation usually reveals an enlarged, exquisitely tender, swollen prostate gland, which is firm, warm, and, occasionally, irregular to the touch. C-reactive protein is elevated in most cases.^[4]

Treatment

Antibiotics are the first line of treatment in acute prostatitis (Cat. I). Antibiotics usually resolve acute prostatitis infections in a very short time. Appropriate antibiotics should be used, based on the microbe causing the infection. Some antibiotics have very poor penetration of the prostatic capsule, others, such as Ciprofloxacin, Co-trimoxazole and tetracyclines penetrate well. In acute prostatitis, penetration of the prostate is not as important as for category II because the intense inflammation disrupts the prostate-blood barrier. It is more important to choose a bacteriocidal antibiotic (kills bacteria, eg quinolone) rather than a bacteriostatic antibiotic (slows bacterial growth, eg. tetracycline) for acute potentially life threatening infections.^[5] Severely ill patients may need hospitalization, while nontoxic patients can be treated at home with bed rest, analgesics, stool softeners, and hydration. Patients in urinary retention are best managed with a suprapubic catheter or intermittent catheterization. Lack of clinical response to antibiotics should raise the suspicion of an abscess and prompt an imaging study such as a transrectal ultrasound (TRUS).^[6]

Prognosis

Full recovery without sequelae is usual.

Category II: Chronic bacterial prostatitis

Signs and symptoms

Chronic bacterial prostatitis is a relatively rare condition (<5% of patients with prostate-related non-BPH LUTS) that usually presents with an intermittent UTI-type picture and that is defined as recurrent urinary tract infections in men originating from a chronic infection in the prostate. Dr. Weidner, Professor of Medicine, Department of Urology, University of Giessen, has stated: "In studies of 656 men, we seldom found chronic bacterial prostatitis. It is truly a rare disease. Most of those were E-coli."^[7] Symptoms may be completely absent until there is also bladder infection, and the most troublesome problem is usually recurrent cystitis.^[8]

Diagnosis

In chronic bacterial prostatitis there are bacteria in the prostate but usually no symptoms. The prostate infection is diagnosed by culturing urine as well as prostate fluid (expressed prostatic secretions or EPS) which are obtained by the doctor doing a rectal exam and putting pressure on the prostate. If no fluid is recovered after this prostatic massage, a post massage urine should also contain any prostatic bacteria. Prostate specific antigen levels may be elevated, although there is no malignancy.

Treatment

Treatment requires prolonged courses (4-8 weeks) of antibiotics that penetrate the prostate well (β-lactams and nitrofurantoin are ineffective). These include quinolones (ciprofloxacin, levofloxacin), sulfas (Bactrim, Septra) and macrolides (erythromycin, clarithromycin). Persistent infections may be helped in 80% of patients by the use of alpha blockers (tamsulosin (Flomax), alfuzosin), or long term low dose antibiotic therapy.^[9] Recurrent infections may be caused by inefficient urination (benign prostatic hypertrophy, neurogenic bladder), prostatic stones or a structural abnormality that acts as a reservoir for infection.

The addition of prostate massage to courses of antibiotics was previously proposed as being beneficial.^[10][11] It is though not without some risk,^[12][13] and, in more recent trials, was not shown to improve outcome compared to antibiotics alone.^[14]

Prognosis

Over time, the relapse rate is high, exceeding 50%. A 2007 study showed that repeated courses of combination antibiotics may eradicate infection in 83.9% of patients with clinical remission extending throughout a follow-up period of 30 months for 94% of these patients.^[15]

Category III: CP/CPPS

Signs and symptoms

In chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) there is pelvic pain of unknown cause, lasting longer than 3 months,^[16] as the key symptom. Symptoms may wax and wane. Pain can range from mild discomfort to debilitating. Pain may radiate to back and rectum, making sitting difficult. Dysuria, arthralgia, myalgia, unexplained fatigue, abdominal pain, constant burning pain in the penis, and frequency may all be present. Frequent urination and increased urgency may suggest interstitial cystitis (inflammation centred in bladder rather than prostate). Ejaculation may be painful, as the prostate contracts during emission of semen, although nerve- and muscle-mediated post-ejaculatory pain is more common, and a classic sign of CP/CPPS. Some patients report low libido, sexual dysfunction and erectile difficulties. Pain after ejaculation is a very specific complaint that distinguishes CP/CPPS from men with BPH or normal men.

Theories of etiology

Theories behind the disease include autoimmunity, for which there is little published evidence, neurogenic inflammation and myofascial pain syndrome. In the latter two categories, dysregulation of the local nervous system due to past trauma, infection or an anxious disposition and chronic albeit unconscious pelvic tensing lead to inflammation that is mediated by substances released by nerve cells (such as substance P). The prostate (and other areas of the genitourinary tract: bladder, urethra, testicles) can become inflamed by the action of the chronically activated pelvic nerves on the mast cells at the end of the nerve pathways. Similar stress-induced genitourinary inflammation has been shown experimentally in other mammals.^[17] However, there is no correlation between inflammation on histological examination of the prostate and the National Institutes of Health Chronic Prostatitis Symptom Index.^[18]

The bacterial infection theory that for so long had held sway in this field was shown to be unimportant in a 2003 study from the University of Washington team led by Dr Lee and Professor Richard Berger. The study found that one third of both normal men and patients had equal counts of similar bacteria colonizing their prostates.^[19] This view was endorsed by Dr Anthony Schaeffer, Professor and Chairman of the Department of Urology at Northwestern University, in a 2003 editorial of The Journal of Urology, in which he stated that "...these data suggest that bacteria do not have a significant role in the development of the chronic pelvic pain syndrome",^[20] and a year later with his colleagues he published studies showing that antibiotics are essentially useless for CP/CPPS.^[21][22] Since the publication of these studies, the focus has shifted from infection to neuromuscular and psychological etiologies for chronic prostatitis (CP/CPPS); a 2005 study showed that stress is correlated to Cat III prostatitis.^[23]

Additional theories and observations include:

Possible role of unculturable bacteria in CPPS

A 2007 Croatian study, without controls, suggested that "prostatitis syndrome"[sic] patients may be infected with a wide variety of microbes. The study used McCoy culture and Lugol stain or by immunofluorescent typing with monoclonal antibodies to come to these findings.^[24] If this study refers to men with Chronic Pelvic Pain Syndrome, it is not in line with major studies from other centres.^[19][25]

CPPS as a form of interstitial cystitis

Some researchers have suggested that CPPS is a form of interstitial cystitis. A large multicenter prospective randomized controlled study showed that Elmiron was slightly better than placebo in treating the symptoms of CPPS, however the primary endpoint did not reach statistical significance.^[26] Other therapies shown more effective than Elmiron in treating interstitial cystitis, such as quercetin and Elavil (amitriptyline), can help with chronic prostatitis.

Effect of cold exposure

Studies in 2007 showed that CPPS is associated with cold weather and exposure to cold.^[27][28]

Virus theory

The evidence supporting a viral cause of prostatitis and chronic pelvic pain syndrome is weak. Single case reports have implicated Herpes simplex virus (HSV) and Cytomegalovirus (CMV) but a study using PCR failed to demonstrate the presence of viral DNA in patients with chronic pelvic pain syndrome undergoing radical prostatectomy for localized prostate cancer. ^[29] The reports implicating CMV must be interpreted with caution because in all cases the patients were immunocompromised. ^[30][31][32] For HSV the evidence is weaker still and there is only one reported case and the causative role of the virus was not proven, ^[33] and there are no reports of successful treatments using antiviral drugs such as aciclovir.

Diagnosis

There are no definitive diagnostic tests for CP/CPPS. This is a poorly understood disorder, even though it accounts for 90%-95% of prostatitis diagnoses.^[8] It is found in men of any age, with the peak onset in the early 30s. CP/CPPS may be inflammatory (category IIIa) or non-inflammatory (category IIIb). In the inflammatory form, urine, semen, and other fluids from the prostate contain pus cells (dead white blood cells or WBCs), whereas in the non-inflammatory form no pus cells are present. Recent studies have questioned the distinction between categories IIIa and IIIb, since both categories show evidence of inflammation if pus cells are ignored and other more subtle signs of inflammation, like cytokines, are measured. In 2006, Chinese researchers found that men with categories IIIa and IIIb both had significantly and similarly raised levels of anti-inflammatory cytokine TGFβ1 and pro-inflammatory cytokine IFN-γ in their expressed prostatic secretions when compared with controls; therefore measurement of these cytokines could be used to diagnose category III prostatitis.^[34]

Normal men have slightly more bacteria in their semen than men with CPPS.^[25] The traditional Stamey 4-glass test is invalid for diagnosis of this disorder, and inflammation cannot be localized to any particular area of the lower GU tract.^[25]

Men with CP/CPPS are more likely than the general population to suffer from Chronic Fatigue Syndrome (CFS),^[35] and Irritable Bowel Syndrome (IBS). Prostate specific antigen levels may be elevated, although there is no malignancy.

Experimental tests that could be useful in the future include tests to measure semen and prostate fluid cytokine levels. Various studies have shown increases in markers for inflammation such as elevated levels of cytokines, myeloperoxidase, and chemokines.

Treatment

"Indeed, chronic abacterial prostatitis (also known as chronic pelvic pain syndrome) is both the most prevalent form and also the least understood and the most challenging to evaluate and treat. This form of prostatitis may respond to non-prostate-centered treatment strategies such as physical therapy, myofascial trigger point release, and relaxation techniques."^[36]

Physical and psychological therapy

For chronic nonbacterial prostatitis (Cat III), also known as CP/CPPS, which makes up the majority of men diagnosed with "prostatitis", a treatment called the Stanford Protocol,^[37] developed by Stanford University Professor of Urology Rodney Anderson and psychologist David Wise in 1996, has recently been published. This is a combination of medication (using tricyclic antidepressants and benzodiazepines), psychological therapy (paradoxical relaxation, an advancement and adaptation, specifically for pelvic pain, of a type of progressive relaxation technique developed by Edmund Jacobson during the early 20th century), and physical therapy (trigger point release therapy on pelvic floor and abdominal muscles, and also yoga-type exercises with the aim of relaxing pelvic floor and abdominal muscles).^[38][39] While these studies are encouraging, definitive proof of efficacy would require a randomized, sham controlled, blinded study, which is not as easy to do with physical therapy as with drug therapy.

Cat. III prostatitis may have no initial trigger other than anxiety, often with an element of Obsessive Compulsive Disorder or other anxiety-spectrum problem. This is theorized to leave the pelvic area in a sensitized condition resulting in a loop of muscle tension and heightened neurological feedback (neural wind-up). Current protocols largely focus on stretches to release overtensed muscles in the pelvic or anal area (commonly referred to as trigger points), physical therapy to the area, and progressive relaxation therapy to reduce causative stress. Biofeedback physical therapy to relearn how to control pelvic floor muscles may be useful.^[40]

Aerobic exercise can help those sufferers who are not also suffering from Chronic Fatigue Syndrome (CFS) or whose symptoms are not exacerbated by exercise.^[41]

Food allergies

Anecdotal evidence suggests that food allergies and intolerances may have a role in exacerbating CP/CPPS, perhaps through mast cell mediated mechanisms. Specifically patients with gluten intolerance or celiac disease report severe symptom flares after sustained gluten ingestion. Patients may therefore find an exclusion diet helpful in lessening symptoms by identifying problem foods. Studies are lacking in this area.

Pharmacological treatment

There is a substantial list of medications used to treat this disorder.^[42]

• Alpha blockers (tamsulosin, alfuzosin) are moderately helpful for many men with CPPS; ^[21] duration of therapy needs to be at least 3 months.^[43]
• Quercetin has shown effective in a randomized, placebo-controlled trial in chronic prostatitis using 500 mg twice a day for 4 weeks^[44] Subsequent studies showed that quercetin, a mast cell inhibitor, reduces inflammation and oxidative stress in the prostate.
• Pollen extract (Cernilton) has also been shown effective in randomized placebo controlled trials.^[45][46][47]
• Commonly used therapies that have not been properly evaluated in clinical trials are dietary modification, gabapentin, and amitriptyline.
• Therapies shown to be ineffective by randomized placebo/sham controlled trials: levaquin (antibiotics), alpha blockers for 6 weeks or less, transurethral needle ablation of the prostate (TUNA).
• At least one study suggests that multi-modal therapy (aimed at different pathways such as inflammation and neuromuscular dysfunction simultaneously) is better long term than monotherapy.^[48]

Surgery

Surgery (including minimally invasive) is recommended only for definitive indications and not generally for CP/CPPS.^[49]

Prognosis

In recent years the prognosis for CP/CPPS has improved greatly with the advent of multimodal treatment, phytotherapy and protocols aimed at quieting the pelvic nerves through myofascial trigger point release and anxiety control.

Category IV: Asymptomatic inflammatory prostatitis

Signs and symptoms

These patients have no history of genitourinary pain complaints, but leukocytosis is noted, usually during evaluation for other conditions.

Diagnosis

Diagnosis is through tests of semen, EPS or prostate tissue that reveal inflammation in the absence of symptoms.^[50]

Treatment

No treatment required. It is standard practice for men with infertility and category IV prostatitis to be given a trial of antibiotics and/or anti-inflammatories however evidence for efficacy are weak.^[51] Since signs of asymptomatic prostatic inflammation may sometimes be associated with prostate cancer, this can be addressed by tests that assess the ratio of free-to-total PSA. The results of these tests were significantly different in prostate cancer and category IV prostatitis in one study.^[52]

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See also

• Quercetin — a flavonoid which has anti-inflammatory and mast cell protective properties
• Trigger Points
• Neuromuscular Therapy
• Myofascial Release
• Myofascial Pain Syndrome
• Interstitial cystitis — men with IC may have prostatitis, and vice versa.