If the 20th century was the age of astonishing cures,
the 21st may turn out to be the era in which those cures became irrelevant.
Fall, 2007---Prevention, the most advanced form of disease control, is the ultimate aim of medical science. However, benign prostatic hyperplasia (BPH), which is a progressive disease process, has throughout the 20th century been treated late in its course. Little has changed since the father of urology said:
In early cases, where the symptoms are not aggravated
. . . patients may be safely told that they may wait.
For the past century, the classic teaching has been that when the pathology of BPH progressed to the stage of BPH disease, the unfortunate men who developed complications were treated after the fact with surgical remedies (‘astonishing cures’). Until recently, control of the BPH process was not possible, and prevention was unthinkable.
 Now, in the 21st century, a safe, well-tolerated way to control the fundamental BPH process---5α-reductase inhibition (5ARI)---has become available. With selective, early 5ARI treatment, prevention of BPH disease appears feasible for many men, offering them the hope that the astonishing cures of the previous century have become, if not irrelevant, only a last resort. The discovery of 5ARI drugs, which came from study of a strange congenital anomaly, is described here.
BPH Disease vs BPH Histology
The tissue changes of BPH are a concomitant of aging and are nearly universal. Primary changes include an increase in the number of prostate cells---glandular, muscular, and fibrous. Secondary changes are common: cystic degeneration, lymphocytic infiltration, and development of corpora amylacea. These tissue changes are rarely seen in the prostate glands of young men, but they are increasingly common from the fourth decade onward. The tissue changes are like gray hair, a nearly- inevitable development as we age.
 However, BPH disease is another matter altogether. When the prostate enlarges past a critical volume, approximately 30-40 cc, the process becomes more serious. The condition then threatens to become more than an “inevitable concomitant of aging.” Increasingly, at that point the BPH process carries with it the likelihood of becoming a disease, which can become clinically manifest by acute urinary retention, urinary bleeding, urinary infection, bladder stones, functional and anatomic decompensation of the bladder wall, and difficulty urinating that interferes with life so severely that treatment is no longer optional.
5 Alpha Reductase Inhibitors (5ARI)
This stage of the process, BPH disease, is to an extent preventable by early administration of 5 Alpha Reductase Inhibitors. Two drugs in this class are currently approved by the U.S. FDA, finasteride (PROSCAR), and dutasteride (AVODART).
Their differences are shown here.
Their mechanism of action is shown in this movie.
Logic of BPH Prevention
Prevention of BPH disease, while not an FDA-approved indication for 5ARI drugs, has an appealing logic in certain men. That logic, first introduced in a “Point-CounterPoint” exchange published in 2003, rests upon four pillars, each of which is solidly based in fact.
First, in most men, BPH is a progressive disorder; left alone, over time the prostate grows larger, urinary flow becomes impeded, and voiding symptoms increase. - Second, BPH progression can lead to BPH disease in certain men at risk.
- Third, men at risk can be identified by elevated serum levels of PSA, generally 1.5 ng/ml or higher, reflecting a prostate volume of 30-40 cc or greater.
- Fourth, 5ARI drugs can prevent BPH disease in men at risk. Efficacy does not appear related to symptoms, only to prostate volume, as reflected by a serum PSA level >1.5 ng/ml.
Prostate cancer, PSA, and BPH Prevention
Prostate biopsy is, at the time of this writing, being driven largely by elevated serum levels of PSA. Of the one million men receiving biopsy annually in the U.S. (c2007), only one of three or four will have cancer. In the remainder, PSA is elevated because of increased numbers of prostate epithelial cells, ie, BPH, or occasionally prostatitis.
After cancer has been excluded---and that may require more than one set of biopsies or more sophisticated testing, e.g. PCA3 gene test---the patient is likely to ask, “What now, doctor?” At this point, assuming the serum PSA level exceeds 1.5 ng/ml, a discussion can be held with the patient regarding prophylactic use of a 5ARI drug. Other men with elevated PSA levels will also have to make decisions regarding prophylactic use of 5ARI (and biopsy), but those men returning for biopsy report appear to be the most highly motivated.
Reasons for Caution
Four reasons for caution in the prophylactic use of 5ARI drugs are as follows:
- First, these drugs have known side effects. The three most common side effects of the 5ARI drugs are diminished libido, erectile dysfunction, and decreased volume of ejaculation. Each of these occurs in 2-3% of men; they are reversible, and they do not occur with any frequency greater than with placebo after the first 6 months of treatment. Gynecomastia, a fourth side effect, is seen in less than 1% of men treated.
- Second, the cost of the drugs can be appreciable to some, especially when the need for the drug extends over many years. However, preventive costs are often returned manifold, when avoidance of hospitalization, surgery, and work loss is considered.
- Third, prevention is not uniformly successful. However, both drugs are clearly more than 50% effective in preventing acute urinary retention and the need for surgery in at-risk Individuals. Preventive use is intended primarily for the “at risk” group, ie those men with prostate volumes exceeding 30 cc and a serum PSA level >1.5 ng/ml. This restriction thus excludes from consideration approximately two-thirds of the adult male population.
Fourth is a concern, engendered by the Prostate Cancer Prevention Trial (PCPT), that the 5ARI drugs may somehow stimulate development of high-grade cancers.  In PCPT, a study of 18,000 men randomized to finasteride or placebo for 7-year, overall cancers
were reduced 25% by the 5ARI drug, but when cancer did occur, it was more likely to be of a high Gleason grade in the finasteride than the placebo group. Ian Thompson, the primary author of PCPT has attributed this finding to “ascertainment bias,” which is explained in the accompanying graphic.
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