Från den amerikanska medicintidskriften JAMA

Prostate Disease Begs Understanding

Vol. 286 No. 4, July 25, 2001  Brian Vastag, Washington.

Sometimes a diagnosis is a dead end, a label with little guidance. So it goes with chronic prostatitis also called chronic pelvic pain syndrome, the newer term which prompts some 2 million office visits in the United States each year (J Urol. 1998;159:1224-1228).

A catch-all term to describe an array of symptoms that include pain in various places, urinary problems, and sexual dysfunction, "prostatitis" reflects a lack of knowledge regarding origins and effective treatments that led urologist Thomas Stamey, MD, to call the diagnosis a "wastebasket of clinical ignorance."

To illustrate the point, Leroy Nyberg, MD, PhD, head of urology research at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), sketched a typical scenario: a man complains of prostate symptoms and, after ruling out obvious bacterial infections, urethral strictures, bladder disorders, and cancer, the physician shrugs his shoulders, calls it chronic nonbacterial prostatitis, and prescribes an antibiotic like ciprofloxacin or an -blocker like tamsulosin although neither has ever been tested against the disease.

That scene is slowly changing. This summer, the NIDDK will begin the first placebo-controlled clinical trial of antibiotics and -blockers, to finally determine whether the standard treatments provide any relief. The study comes 6 years after the Prostatitis Foundation patient group convinced Congress to prod the National Institutes of Health to furnish some funding. "Because it isn't a deadly disease, it required a lot of momentum from the outside to get us going," said Nyberg."But now we've realized the impact of the disease". To back his words, Nyberg oversees some $2 million in annual grants aimed at probing the most basic questions: what is prostatitis, who gets it and will anything treat it? 

Answers are appearing, some from small treatment studies and others from the NIDDK's Chronic Prostatitis Collaborative Research Network, six centers tracking the natural history of the condition in a cohort of 450 patients. For starters, researchers want to define the breadth of the problem. A small study from Ontario reported that 10% of men in the general population had symptoms of chronic pelvic pain syndrome (J Urol. 2001;165:842-845). Another study from Finland reported a prevalence nearing 15% (BJU Int. 2000;86:443-448), and other reports suggest that up to half of all men will experience some type of prostatitis during their lifetime (Eur Urol. 1992;22:14). If those figures hold in a larger epidemiological study planned by the NIDDK, chronic pelvic pain syndrome would be among the most common ailments in men, a fact that makes the dearth of understanding all the more disturbing.

NEW IDEAS
Over the years, yeast, viruses, calcium deposits, stress, and psychosomatic illness have all been proffered as causes. Desperate for relief, patients from across the globe have journeyed to the Philippines and to Ukraine to partake in undocumented cures, mail-ordered powerful magnets to sit on, and drunk gallons of carrot juice, all in hope of lessening pain and restoring a normal sex life. Frustrated by not having much to offer, urologists and primary care physicians often advise symptomatic treatments like anti-inflammatory drugs, hot baths, frequent ejaculation, and regular prostate massages.

After surveying this sorry state, the NIDDK brought together prostatitis researchers there were only a handful at the time at a 1995 conference. The participants immediately realized that de facto clinical definitions held little meaning and proposed a new system of nomenclature. They settled on three categories: acute and chronic bacterial prostatitis (with documented infections) and chronic pelvic pain syndrome. While the first two generally respond to antibiotics, they account for just 5% to 10% of cases. Since then, a handful of new ideas have been getting attention and, finally, the scrutiny of rigorous testing. While some researchers maintain that difficult-to-find bacterial infections are to blame, others document evidence of autoimmune activity. A third camp holds that chronic tension in the pelvic floor muscles, not the prostate itself, accounts for the problem. And some think that all three processes could be at play.

A BACTERIAL CONNECTION?
Daniel Shoskes, MD, a transplant surgeon and urologist at the Cleveland Clinic Florida in Fort Lauderdale, said that many physicians are missing a bacterial connection by failing to culture prostate secretions. "It's the reasoning that if the culture is positive, they'll treat with antibiotics, and if it's negative, all they have to offer is antibiotics, so why culture?" But he said that culturing is important because he's seen patients with infections resistant to standard antibiotics improve after switching drugs. He added that even if physicians do culture, current techniques are a problem growing bacteria from prostate secretions (collected after a digital rectal exam) takes as long as 5 days, said Shoskes, whereas many laboratories grow samples for only 48 hours. "Some people with negative cultures have true infections," he said. 

Shoskes and other researchers also report evidence of chronic inflammation or autoimmunity in patients with no evidence of infection. Shoskes became intrigued with the idea when he noticed parallels between kidney transplant rejection and chronic prostatitis. "In both cases you have some type of initial injury or event . . . and then weeks or months later you still have this progressive inflammatory condition."

POSSIBLE AUTOIMMUNITY
Richard Alexander, MD, a urologist at the University of Maryland Medical Center, Baltimore, has published several articles supporting the idea. He reports abnormal T-cell activity and high levels of inflammatory cytokines in patients with chronic prostatitis compared with controls. Most recently, his laboratory identified T cells from patients with prostatitis that switch on in response to prostate-specific antigen (Prostate. 2000;44:49-54). Earlier, he found that the semen of prostatitis patients held large amounts of tumor necrosis factor and interleukin 1-; both promote inflammation (Urology. 1998;52:744-749). "This is all consistent with the idea of autoimmunity directed toward the prostate," said Alexander, whose laboratory is now looking for similar patterns in samples from all of the men in the NIDDK network. But he emphasized that he does not believe that autoimmunity will explain the majority of cases. Given the evidence of chronic inflammation, both Shoskes and Alexander are testing novel agents directed at the process. 

In 1999, Shoskes published a small study with the dietary supplement quercetin, a bioflavonoid antioxidant and anti-inflammatory agent. After taking 500 mg of the supplement twice daily for a month, two thirds of men in the treatment group (and only 20% in the control group) reported a 25% or greater improvement in symptoms (Urology. 1999;54:960-963). But the study was small (30 patients) and remains to be replicated. While quercetin can be bought off the shelf, the agent under study by Alexander and other urologists costs more than $10 000 per year. Called etanercept (Enbrel, Immunex Corp, Seattle), the drug binds to and sops up excess molecules of tumor necrosis factor. Approved by the US Food and Drug Administration in 1998 for treatment of rheumatoid arthritis the most common autoimmune disease in the country the drug reduces joint pain in most patients with that disease. Data from the etanercept prostatitis trial should be available next year.

MUSCLE TENSION STUDIED
In the meantime, David Wise, PhD, of Stanford University Medical Center's urology department, believes that chronic pelvic muscle tension explains many cases of prostatitis. He presented data at last fall's third international prostatitis meeting in Arlington, Va, that showed men with prostatitis have more muscle tension than controls. Wise is testing a months-long regimen of intense pelvic muscle massage and relaxation training. 

Ultimately, all or none of these ideas may lead to proven, effective treatments. "Right now, the evidence for any etiology is minimal," said the NIDDK's Nyberg. "It's a level playing field, and there are a lot of ideas around." While the new ideas shake out, some of the old especially that antibiotics and -blockers are helpful may fall into disfavor after the NIDDK clinical trial. Maryland's Alexander, for one, thinks that the results will pick prostatitis out of the clinical trash bin. "In the next year or two, the data from the [NIDDK] cohort study are going to debunk a lot of the myths about this problem," he said. "And it's going to be clear that the assumptions are wrong and that we need to start all over again." 

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