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. | 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.


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.


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.


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.


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06/21/02: Sex & violence and Advertising: Do Advertisers Get What they Pay For?; Don't Drink the Water (or the Salsa Either!); Vasectomy & Prostate Cancer Risk; Update on Smoking & Disease

06/14/02: Young Men, Obesity & Heart Disease; Breastfeeding & Obesity; Irritable Bowel Syndrome & rectal pain threshold; more data on cox-2 inhibitors & cancer; more

06/07/02: New coronary artery stent reduces risk of restenosis; possible cause of Parkinson's Disease identified; more

05/31/02: New biological insights into obesity & weight loss; broccoli kills cancer-causing stomach bug; anti-inflammatory drugs and the risk of heart attack

05/24/02: Molecular detection of tumor cells in the blood & prognosis; Cox-2 & breast/lung cancers; BRCA2 gene mutations & the risk of breast cancer; breast density & the risk of breast cancer

05/19/02: Moderate alcohol intake and blood sugar levels; more good news for tea drinkers; blood potassium levels & the risk of cardiovascular disease; ethnic differences in diabetic complications

05/10/02: Tea drinkers and the risk of death following heart attack; duration of breastfeeding & adult intelligence; abdominal aortic aneurysms: surgery or observation?

05/03/02: Risk of adverse drug reactions from newly released medications; preoperative beta-blockers may reduce heart bypass deaths; shape-shifting plastics may alter surgical practice; weight loss supplement may cause liver damage
04/26/02: Angry young men & risk of premature cardiovascular disease; stay-at-home dads & risk of cardiovascular disease; more on the effects of statins; dairy consumption and the risk of pre-diabetes; smallpox vaccine: good to the last drop?
04/19/02: Change your sex by drinking water?; Anti-inflammatory RXs may reduce growth of breast cancer cells; radiation treatment reduces repeat narrowing of bypass grafts
04/05/02: Fish & Omega-3 fatty acid consumption and cardiac health; news briefs
04/05/02: Can coffee reduce your risk of tooth decay?; exercise & blood pressure; a single high-fat meal reduces coronary artery function
04/01/02: Pre-diabetes: a newly defined category of health risk; teen television viewing and subsequent aggressive behavior; the benefits of strength training in the elderly; more ...
03/22/02: Bacteria, antibiotics & heart disease; mammograms: the debate continues; calcium & the risk of colon cancer ... and more
03/15/02: Mammography debate continues; statins & fracture risk; physical fitness & the risk of death; other intriguing findings
03/08/02: Blows to the chest & sudden cardiac death; air quality & the risk of lung cancer; tomatoes and your prostate
03/01/02: Diet & the risk of ovarian cancer; lifetime risk of developing high blood pressure; Osteoporosis prevention with a once-a-year injection?
02/26/02: The continuing controversy regarding screening mammography
02/22/02: Lowering body temperature after heart attack improves outcome; A silver lining for the chronically sleep-deprived?
02/15/02: Hormone replacement therapy & the risk of breast cancer; use it or lose it: Alzheimer's disease & cognitive stimulation; stress, divorce & death; child daycare, infections & parental guilt
02/08/02: Possible breakthrough in early cancer diagnosis; mammography: the controversy continues; CPR techniques revisited
02/01/02: Antibiotics in livestock feed & human disease; genetic detection of early colon cancer in the stool; genetic analysis of breast cancers may help decide treatment
01/25/02: Drug increases lifespan (if you're a fly...); workplace attitudes and smoking cessation; effects of inadequate sleep on surgeons
01/18/02: Lifelong effects of premature birth; smokers under the knife; aspirin and cardiovascular health
01/11/02: Estrogen levels in the blood & breast cancer risk; Heart attack: sex and survival; dangerous lettuce invaders
01/09/02: Cancer & aging: Two sides of the same coin?
01/04/02: Vitamin a & the risk of hip fracture in postmenopausal women; ovarian cancer risk and oral contraceptives
12/28/01: Magnetic Resonance Imaging (MRI) detects coronary artery disease; new development in obesity research; adverse childhood experiences & the risk of suicide attempts
12/21/01: Vaccination of children controls hepatitis a in the community; a possible cure for sickle cell disease; leptin and the risk of heart attacks
12/14/01: Chernobyl and the Risk of Thyroid Cancer in hildren; children & obesity; gastroesophageal reflux disease update
12/07/01: Update on school shootings; new implantable heart-assist device approved for further evaluation; prevention of fungal infections in pre-term babies
11/30/01: Flu vaccination in asthmatics; low-tar cigarettes are not less harmful; beans and your heart
11/21/01: Modified smallpox vaccine may reduce risk of cervical cancer; New approach to breast cancer diagnosis; New non-invasive prenatal diagnostic test for down's syndrome
11/16/01: Cholesterol-lowering drugs reduce risk of heart attack; supplemental radiation therapy reduces risk of breast cancer recurrence; brains of women may answer age-old questions
11/09/01: Bio-warfare (redux); my gray matter is bigger than yours; mad elk disease?
11/02/01: Making sense of bio-warfare
10/26/01: The impact of mammography on deaths due to breast cancer; diet & exercise may slow cancer cell growth; antidepressants and the risk of heart disease
10/19/01: New insights into autism; the wiley appendix
10/12/01: More bad news about obesity links to other diseases…Hey dad, can I borrow the car keys?
10/05/01: California leads nation in reduction of tobacco-related disease; exercise as an antidepressant?
09/25/01: Advances in the detection of breast cancer; primary care physician awareness of peripheral arterial disease; arsenic in the water
09/17/01: In perspective
09/12/01: Genes may hold secret to long life; men and women: cognitive function in the elderly; physical activity, obesity and the risk of pancreatic cancer
09/05/01: English milk cows prefer Beethoven and Simon & Garfunkel over Bananarama; new prostate cancer prevention study: looking for a few good men; exercise & diet can help prevent diabetes
08/28/01: Arthritis drugs may be linked with increased risk of heart disease; errors in blood clotting tests can be fatal; infant soy formula not associated with reproductive side effects

© 2002, Dr. Robert A. Wascher