UPDATE ON BENIGN ENLARGEMENT OF THE PROSTATE

As men age, their prostate glands gradually enlarge under the year-to-year influence of the male sex hormones. The prostate gland is a walnut-sized organ that is situated at the base of the bladder. Since the urethra passes through the prostate gland, significant enlargement of the prostate gland can prevent the bladder from emptying properly. When benign prostatic hypertrophy (BPH) is sufficiently advanced, urinating can become very difficult. The bladder then becomes distended with urine, causing discomfort, as well as an increased risk of infection, bladder stones and kidney damage.

Based upon previous autopsy studies, BPH occurs in about 50% of men in their 60s, rising to more than 90% among men 85 years of age and older. Symptoms of BPH occur in approximately 14% of men in their 40s, 24% of men in their 50s, and in more than 40% of men in their 60s. In the US, an estimated 15 million men experience symptoms of BPH. At the present time, most experts believe that there is no significant link between BPH and prostate cancer, although both diseases arise due to, at least in part, the lifelong effects of exposure to male sex hormones.

There are several medications that have been shown to improve the urinary symptoms of BPH. In general, two classes of medications have been used most frequently: alpha-adrenergic blockers and 5-alpha reductase inhibitors. The former class of medications relax the muscle fibers at the base of the bladder, and within the urethra, to improve urine flow. The latter class of BPH medications inhibit the actions of male sex hormones in the prostate gland, as well as in other cells of the body that respond to testosterone and related androgenic hormones. This androgen hormone blockade results in gradual shrinkage of the enlarged prostate gland. Various other non-prescribed remedies have also been touted for BPH, most of them herbal in origin. These include saw palmetto fruit, South African star grass roots, African plum tree bark, stinging nettle roots, rye pollen and pumpkin seeds. Among these, saw palmetto has, arguably, the largest following. Unfortunately, there has been little scientific evidence to support the use of these alternative therapies for the treatment of BPH.

Two interesting studies that were reported this week may be helpful to men with symptomatic BPH. The first, in the New England Journal of Medicine, looked at the effects of combining the alpha-adrenergic blocker doxazosin with the 5-alpha reductase inhibitor finasteride as combined therapy for symptomatic BPH. This was a double-blind placebo-controlled study, where neither patients nor their doctors knew if the study volunteers were receiving one of the BPH drugs, both of them, or just sugar pills. A total of 3,047 men were followed for an average of almost 5 years during this study. The study found that the men who took doxazosin alone experienced a 39% reduction in the severity of their BPH symptoms, while those who took finasteride alone experienced a 34% reduction in symptoms (both results were relative to the symptom severity reported by the men who received only placebo pills). The men who received both BPH medications during the study reported a rather dramatic 66% reduction in the severity of their symptoms, however. This is a rather unusual case where the combination of two different classes of drug therapy prove to be completely additive in their benefit when compared to each drug given alone. In most cases, combined therapies for virtually all human diseases may be somewhat more effective than each individual drug given by itself, but the additive effect of the two drugs are rarely on the order of the sum of their individual beneficial effects. An interesting side note from this study: patients who received doxazosin alone experienced fewer symptoms of BPH, but did not experience a lower risk of acute episodes of urinary tract obstruction or the need for surgical intervention when compared to placebo. However, finasteride, whether given alone or in combination with doxazosin, did significantly reduce the incidence of these events.

This study, therefore, strongly supports the combined use of both 5-alpha reductase inhibitors and alpha-adrenergic blockers to treat symptomatic BPH, and may offer a non-surgical alternative to many men now contemplating surgery to relieve their BPH symptoms.

The second study, as reported in the Journal of Urology, compared saw palmetto and finasteride as individual therapies for BPH in men with symptomatic prostate gland enlargement. Study volunteers were randomized to receive either saw palmetto (325 mg per day) or finasteride (5 mg per day) for a period of 1 year. The patients then had their BPH-related symptoms reassessed at 3 months, 6 months and 12 months. At 12 months, 56 of the original 64 patients continued to participate in this study. The results of this study were consistent with other similar recent studies. The group assigned to take saw palmetto experienced no improvement in their BPH symptoms when compared to placebo pills, while the group of men who received finasteride did experience considerable improvement in symptoms. This is a rather small study, but it adds to other studies that call into question the use of saw palmetto as a treatment for BPH.

EFFECTS OF DISCONTINUATION OF HRT FOLLOWING THE DIAGNOSIS OF BREAST CANCER

Hormone replacement therapy (HRT) following menopause has declined precipitously since last summer’s release of the interim results from the huge Womens’ Health Initiative Study (WHIS), The study found a significantly increased risk of breast cancer, colon cancer, heart disease and dementia in women who had chronically taken combined HRT with estrogen and progesterone tablets. These adverse effects were so significant that this portion of the WHIS was prematurely terminated so that the women who were taking combination HRT could be warned about the worrisome findings. (Another subgroup of women who took only estrogen pills are still being followed by the study.) While many women without a personal history of breast cancer have subsequently opted to go back on their Prempro tablets following the initial WHIS scare, another subgroup of women, women with breast cancer, tend to be more ambivalent. Even so, many women who have been diagnosed with breast cancer ultimately choose to resume HRT, although usually against the recommendations of their doctors.

A new study reported in the journal Cancer looked at the impact on their breast cancer tumors of discontinuing HRT after they were diagnosed with breast cancer. A total of 140 women, all of whom had been taking HRT, participated in the study after they were diagnosed with breast cancer with a needle biopsy. Following an average subsequent duration of 17 days, the women all underwent surgical removal of their breast tumors. Twenty-five of the 140 women elected to continue HRT during the interval between their core needle biopsies and the surgical removal of their breast cancers. An additional 55 women who were not taking HRT at the time of their diagnosis of breast cancer (also by core needle biopsy) were included in this study as “controls.”

In the 125 women who discontinued HRT following their needle biopsy, there was a significant decrease in their breast tumors’ expression of a protein, Ki-67, that reflects how fast the cancer cells are dividing and growing. This decrease in the so-called proliferation of breast cancer cells was identified by comparing the levels of Ki-67 in tumor cells recovered from the needle biopsy with the tumor cells subsequently removed by definitive surgery. Further evidence that HRT was stimulating breast tumor cell growth was the finding that the reduction in Ki-67 expression seen in the surgically removed breast tumors taken from women who stopped HRT occurred only in cancers that were chemically sensitive to the female hormone estrogen. The estrogen receptor-negative tumor cells did not appreciably differ in their expression of Ki-67 protein between the needle biopsy specimens and the surgical excision specimens, even among the women who stopped taking HRT after their initial needle biopsy. In addition to a reduction in the levels of Ki-67 protein expressed in estrogen-sensitive tumors following withdrawal of HRT, the scientists found that other proteins linked with more aggressive growth of breast cancer cells declined after discontinuing HRT in the women with estrogen-sensitive tumors. This result is exactly what the majority of oncologists would have predicted, but this innovative little study is the first to actually show a correlation between HRT withdrawal and a subsequent biochemical improvement in the aggressiveness of estrogen-sensitive breast cancers in living human beings. The results of this study, while not proving or disproving that HRT cessation reduces the risk of recurrent or second breast cancers, does add powerful evidence to the growing awareness (among both patients and physicians) that estrogen-sensitive breast cancers are likely to respond to continued HRT by behaving more aggressively.

Dr. Robert A. Wascher