Jewish World Review July 8, 2002 / 28 Tamuz, 5762




Hormone Replacement Therapy
& the Risk of Disease

By Robert A. Wascher, M.D., F.A.C.S.

http://www.NewsAndOpinion.com | Based upon older observational studies of women taking estrogen replacement therapy for menopausal symptoms, most physicians have come to believe that estrogen replacement therapy reduces the risk of heart disease and osteoporosis (thinning of the bones). More recent studies, however, have called this assumption into question. In this week's Journal of the American Medical Association (JAMA), two new large scale studies further call into question the alleged benefits of postmenopausal hormone replacement therapy (HRT).

A total of 2,321 postmenopausal women with a history of coronary heart disease were studied for an average of nearly seven years. The study volunteers were assigned to receive either estrogen/progesterone (the primary female hormones) or a placebo (sugar pill). This study found no apparent benefit of HRT in terms of reductions in the risk of coronary artery disease progression or heart attacks. Although this study only included patients with a known history of coronary heart disease, other recent studies have looked at patients without evidence of cardiovascular disease, and have failed to find a significant reduction in the incidence of heart disease and stroke. Taken together, these recent studies appear to rather solidly refute the prior dogma that HRT reduces the risk of cardiovascular disease in women.

At the present time, there appears to be virtually no evidence that HRT has any role to play in the prevention of these diseases. A second study in this week's JAMA looked at the incidence of non-cardiovascular disease in the same group of 2,321 patients. This study found a two-fold increase in the risk of blood clots in the veins and lungs of the patients receiving HRT.

The risk of gallstone formation was also increased among the patients receiving HRT, by a factor of nearly two times the incidence seen in the women not receiving HRT. Estrogen has long been known to increase the risk of blood clots (particularly in women who also smoke), and has also been suspected as a contributing factor in gallstone formation (a disease that occurs far more frequently in women than in men). Interestingly, in this study there was no apparent benefit seen in the HRT group of patients with respect to the incidence of bone fractures.

This is somewhat surprising, as the loss of normal estrogen production by the postmenopausal ovaries is known to accelerate thinning of the bones (osteoporosis) which, in turn, is associated with an increased risk of fractures. Fortunately, there are several drugs that have recently been approved for patients at high risk of developing osteoporosis, and these drugs are highly effective in preserving bone density in such women.

These two HRT studies really call into question the "benefit-to-risk" ratio of HRT in postmenopausal women. Traditionally, the three most compelling reasons for prescribing HRT have been to reduce the symptoms of menopause, to prevent osteoporosis, and to reduce the risk of coronary heart disease. Based upon recent studies, HRT does not appear to significantly impact upon the risk of either of the two most serious diseases that it was previously thought to help prevent. Moreover, HRT has been associated with potentially significant complications, including blood clots, gallstone disease and an increased risk of breast cancer. I predict that HRT will soon begin to fall out of favor in view of the growing evidence against any significant disease-preventing benefits from estrogen replacement therapy, and in conjunction with the development of more effective preventive treatments for cardiovascular disease, osteoporosis and the symptoms of menopause.

MORE GOOD NEWS ABOUT STATINS

This week's Lancet features two interesting studies. The first study adds to the burgeoning evidence that the cholesterol-lowering statin drugs not only reduce the risk of heart attacks in patients with elevated cholesterol levels (and, more specifically, with elevated levels of LDL, the "bad cholesterol"), but they may also reduce the risk of heart attack in folks with normal or "high normal" cholesterol levels as well. The study assessed 20,536 adults in England.

These volunteers had either coronary artery disease, arterial disease of non-coronary arteries, or diabetes. (Not all patients in this study had elevated levels of LDL.) The patients taking the statin drug Simvastatin experienced a 25% reduction in the risk of heart attack, an 18% reduction in the risk of fatal heart attack, and 25% reduction in the risk of stroke. Of note, even those patients with a total cholesterol level below 193 mg/dl and those patients with LDL levels below 115 mg/dl experienced a significant and similar reduction in the incidence of heart attacks and stroke.

While all patients enrolled in this study had acknowledged risk factors that placed them at increased risk of developing a heart attack or stroke, the fact that Simvastatin reduced heart attack and stroke risks even in patients with normal to high-normal cholesterol and LDL levels is important. At the present time, it is unclear how much cholesterol and LDL reduction is desirable. There are potential side effects that can arise from excessively low cholesterol levels, and the statin drugs themselves are associated with potentially serious side effects in a small number of patients.

However, it appears that reducing total cholesterol and LDL levels below the range that is currently considered "normal" may further reduce the risk of heart disease and stroke, particularly in those patients with other preexisting cardiovascular disease risk factors.

ANTIOXIDANT VITAMINS & DISEASE PREVENTION

There are numerous studies showing that certain antioxidant vitamins, at relatively high doses, may reduce the risk of cardiovascular disease, cancer and other diseases (indeed, I am currently writing a book on the subject of cancer prevention, and address this issue in considerable detail). The same cohort of patients who were evaluated in the Simvastatin study (above) were also evaluated for the effects of antioxidant vitamins on the incidence of heart disease and cancer. The same 20,536 patients were followed for an average of 5 years, and were divided into two groups.

One group received antioxidant vitamin supplementation (600 mg of vitamin E, 250 mg of vitamin C, and 20 mg of beta carotene per day), and the second group received only placebo pills. The study's authors concluded that antioxidant vitamin supplementation did not appear to reduce the risk of heart attack, stroke or death due to coronary artery disease. The incidence of cancer in these patients did not appear to be different during the 5-year study either.

This large study joins three other recent studies that have failed to confirm a beneficial effect of antioxidant vitamins on the incidence of cardiovascular disease and cancer. However, they are in conflict with a large number of other studies that do appear to show disease prevention effects associated with antioxidant usage. There are a couple of important issues that should be considered when one looks at this particular study. First, all of the volunteers in this study either already had known coronary artery disease or had other diseases that are known to be associated with very high risks of coronary artery disease.

It is, therefore, difficult to generalize about cardiovascular disease prevention through the use of antioxidants when many of the study subjects were already likely to have preexisting coronary artery disease. Indeed, this study, as designed, is more likely to measure the impact of antioxidants on the progression of extant coronary heart disease rather than its prevention. Secondly, this same cohort of volunteers were simultaneously enrolled in a Simvastatin study, and the study's authors do not appear to include any clarifications or analysis regarding the potential confounding effects of Simvastatin in those patients who were also assigned to the vitamin supplementation group.

Thus, it is unclear to me what the impact of the antioxidant vitamins was with respect to the incidence of heart attack and stroke. Moreover, these two studies measured heart attack and stroke as the primary clinical outcome. This study did not perform any clinical or radiographic analysis of coronary artery plaque formation, heart function, or other evidence of subclinical coronary artery disease progression. Finally, the doses of antioxidant vitamins used in this study were rather modest, and the duration of follow-up (five years) was similarly modest. Still, this is a very large study, and its results are intriguing, its limitations notwithstanding.

BRIEFLY…

Science: Most cancers are thought to arise following multiple genetic mutations. Often, the genetic mutations most commonly associated with cancer involve either the activation or inactivation of genes that control cellular growth and division. With this fact in mind, one promising new approach to treating cancer has been to develop compounds that block the effects of mutated cancer genes, thus reversing the immortalizing effects of the abnormal gene or genes. However, some experts have questioned the likely success of this approach, fearing that withdrawal of the blocking drug will only allow the mutated gene(s) to spring back into action again. A new study, using mice that have a cancer-related gene mutation called MYC, appears to allay at least some of these fears. The study found that even brief inactivation of the MYC gene was sufficient to halt the growth of tumor cells in the mice. Even more interesting was the finding that withdrawal of the MYC-blocking drug did not cause a resumption of tumor cell growth. In fact, reactivation of the MYC gene by tumor cells actually resulted in rapid death of the cancer cells through a mechanism of cell death called apoptosis. This surprising finding needs to be reproduced in other laboratories, and with other cancer-related genes. However, this counterintuitive result is quite exciting!

JWR contributor Dr. Robert A. Wascher is a senior research fellow in molecular & surgical oncology at the John Wayne Cancer Institute in Santa Monica, CA. Comment by clicking here.

Up

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© 2002, Dr. Robert A. Wascher