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E-Newsletter No. 28

Major U.S. Study Halted Abruptly Over Health Concerns

The recent announcement (JAMA, 2002;228:321-333) that the Womens' Health Initiative (WHI), a National Institutes of Health?sponsored multi-centered, prospective, longitudinal, randomized trial of 16,608 postmenopausal women comparing hormone replacement therapy with placebo, has been terminated early because the overall health risks exceeded benefits from use of combined estrogen plus progestin over a 5.2 year follow-up. It clearly showed the use of hormones increased the risk for blood clots, heart attacks, strokes, and breast cancer.

Just one week earlier, the results of the Heart and Estrogen/progesterin Replacement Study (HERS and HERS II), (JAMA, 2002;288:49-57), found no overall benefit of reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year and a decreased risk during years 3 to 5. These lower rates did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. 

In addition, another report examined, (JAMA, 2002;288:58-66), follow-up outcomes over a total of 6.8 years of observation during and following the HERS randomized trial of hormone therapy in postmenopausal women with coronary disease (CHD). The noncardiovascular disease outcomes found an increased risk of venous thromboembolism (blood clot) and biliary tract (gall bladder) surgery among women randomized to hormone therapy. None of the differences between groups in cancer incidence was statistically significant. Another surprise was that women randomized to hormone therapy had more hip fractures than women randomized to placebo. However, estimates of vertebral, wrist and other fractures were not any higher in the hormone group than in the placebo group. Death rates were not statistically different between the two groups, although death rates were high and increasing in this population of older women with coronary disease.

More Bad News from the National Cancer Institute Study

The drumbeat of bad news about estrogen replacement therapy continued (July 17, 2002) with the release of a new study from the National Cancer Institute showing that long-term use of estrogen increases the risk of ovarian cancer. The new study shows that the increased risk of contracting ovarian cancer is real and substantial; an 80% increase in risk form women who have used estrogen for at lease 10 years and a 220% higher risk for those who have used it at least 20 years.

The latest study did not show an increased risk among women using a combination of estrogen and progestin, but study author, James V. Lacey, Jr. cautioned that there were too few women in the research group using this combination of the two drugs for conclusive results. He stated, "there simply aren't enough data to say whether taking the combined therapy has any effect on ovarian cancer."

An editorial about these two reports in the Journal of the American Medical Association (JAMA.2002;228:366-369) said "estrogen replacement therapy certainly is not the panacea it once appeared." Nevertheless, experts caution that the absolute risk is still low. Ovarian cancer is relatively rare, striking an estimated 23,000 U.S. women each year and killing 14,000. Too bad for Gilda Radner (one of my favorite comediennes), who happened to be one of these "statistics."

These Results Are Supported by Other Randomized Trials

The new National Institute of Cancer study is supported by the Postmenopausal Estrogen/Progestin Intervention Study (PEPI), February 1996, of healthy postmenopausal women. The findings were that taking estrogen alone increases the risk of uterine cancer. The use of the hormone progestin with estrogen offset the risk in that study.

In the HERS and HERS II studies, women assigned to placebo were more likely to use the statin drugs to lower their cholesterol levels than women assigned to hormone replacement therapy (HRT). Differences in statin use did not explain the lack of benefit of HRT for prevention of CHD events in women with coronary artery disease.

The finding of the WHI, and HERS and HERS II with regard to a lack of benefit of HRT in high-risk women are supported by findings from 2 randomized trials that assessed the effect of HRT on progression of atherosclerosis. The Estrogen Replacement Atherosclerosis Trial (N. England J. Med, 2000; 343:522-529.) randomized 309 postmenopausal women with angiographically verified coronary disease to receive placebo, estrogen replacement therapy (ERT) as 0.625mg/d of conjugated equine estrogen, or HRT as daily estrogen plus progestin as in HERS. After 3.2 years of follow-up, the mean minimal coronary artery diameter on repeat coronary angiograms was not significantly different among women assigned to placebo, ERT, or HRT.

In the Postmenopausal Hormone Replacement against Atherosclerosis Trial (Arterioscler Thromb Vasc Biol. 2001;21:262-268.) (Maturitas. 2002; 41:51-60.) 321 postmenopausal women with increased carotid intima-media thickness based on -mode ultrasound were randomly assigned to receive placebo or 1 of 2 HRT regimens (1mg/d of 17 -estradiol, with administration from day 17 through day 28 of 0.025mg of gestodene (a synthetic progestin) either every 4 weeks or every 12 weeks). After 48 weeks, there was no difference between placebo and active treatment groups in progression of atherosclerosis measured as a change in carotid (neck) or femoral (leg) artery intima-media thickness.

So, What's a Girl to Do? 

Millions of women in the U.S. have been on long-term regimens of estrogen, progestin since they were introduced in 1967 for contraception. Combination oral contraceptives are now being used to treat acne and estrogen is also sometimes useful in the treatment of menstrual migraine. It is well known that estrogen can increase the risk of venous thromboembolism (blood clots in veins). The risk is about 1 per 10,000 person-years in the general population of women of childbearing age, 3-4 with the newer third generation progestins (levonorgestrel) and 6-8 with desogestrel or gestadene, approaching 1 per 1,000 among new users of third generation progestins during the first year of use (BMJ 2000; 321:1190; N Engl J Med 2001:344:1527). A recent report (BMJ 2002; 324:869) mentioned 40 cases of venous thromboembolism with 2 fatalities in Europe in women taking a new oral contraceptive, Yasmin (ethinylestradol and drospirenone); about one million European women have taken Yasmin. The risks associated with these drugs must be weighted against their use for birth-control before considering alternative methods to be undesirable, or unacceptable.

Obviously, the verdict is in for postmenopausal women with coronary artery disease (CHD), or atherosclerotic arterial disease. HRT or ERT will increase their risk of disease, death or long-term disability. Is it possible that ERT or HRT might prevent CHD in women free of coronary artery disease or atherosclerosis? The Estrogen Prevention of Atherosclerosis Trial provides limited evidence. After 2 years of follow-up, the rate of atherosclerosis progression was less in the ERT-treated group than in the placebo group, but the benefit of ERT was limited to women who did not also need to take a lipid-lowering medication.

What Are the Benefits of HRT?

HRT has been beneficial for postmenopausal women for "quality of life" issues. It improves mood, skin tone, breast tissue mass, symptoms such as low libido, hot flushes, improved sleep, vaginal dryness, urinary incontinence and reduces the risk of osteoporosis. There are also reductions in the risk of colon cancer and fractures.

Prospective observational studies continued to suggest that ERT might protect against cognitive decline (Neurology, 2001;57:429-432). Data on ERT and HRT to prevent cognitive decline and dementia are not consistent however (Neuroscience 2000;101:485-512,JAMA, 2001;285:1489-1499, JAMA, 1998;279:688-695), and randomized trials of estrogen in the treatment of Alzheimer's disease show no evidence of benefit (Neurology, 2000;54:295-301, JAMA, 2000;283:1007-1015). Although the observational studies of HRT and CHD were consistent, randomized trials failed to confirm this benefit. This may eventually prove to be the case with cognitive decline and dementia.

The relationship between the use of estrogen replacement (ERT and cerebral magnetic resonance imaging (MRI) abnormalities in older women was recently compared in a population-based prospective study (Cardiovascular Health Study, J Amer Geriatrics Society, 2000; 48:467-472). Current ERT users had more clinically significant central atrophy of the brain than did non-users, but the implications remained unclear. These studies need to continue since there is some evidence showing the benefit of HRT only in the oldest old.

What Are the Evidence-Based Medicine Alternatives?

The new pessimism about HRT and ERT does not mean pessimism about disease prevention in postmenopausal women. Randomized trials that include women provide strong support for the use of -blockers (JAMA, 1193;270:1589-1595) and aspirin to prevent CHD events and ischemic stroke in women with coronary disease or a history of ischemic stroke or transient ischemic attack (BMJ, 1994;308:81-106). The Heart Outcomes Prevention Evaluation (HOPE) trial showed that angiotensin converting enzyme inhibitors prevent CHD events in women at high risk of cardiovascular disease (N ENG J Med, 2000; 342:145-153).Randomized trials show that blood pressure control prevents stroke and CHD in women with hypertension (Lancet,2000;356:1955-1964). Aspirin use has a favorable risk-benefit ratio for primary prevention of CHD in high risk women (N. Eng J Med. 2002,346:1468-1474). Randomized trials support screening and treatment of dyslipidemia to prevent first CHD events in women with average serum cholesterol levels (JAMA 1999;282:2340-2346, JAMA. 1998;279:1615-1622), and some lipid-lowering drugs may also prevent stroke (JAMA. 1997;278:313-321). Randomized trials show that bisphosphonates and raloxifene prevent fracture in women with low bone density or a history of fracture (J Clin Endocrinol Metab. 2000;85:4118-4124, JAMA.1999;282:637-645).

Be Aware of Alternative Health Issues

Alternative health proponents advocate the use of "natural hormones" with estrogen-like properties (herbs, soy based products, vegetables, legumes and cereals) high in isoflavones or phytoestrogen content. What they failed to mention are that risks are the same as prescription drugs. This may be well meant and they just do not know about them. However, estrogen or any estrogen-like substances, regardless of their source (synthetic, animal, or from plants), if taken in doses that can activate estrogen receptors, will necessarily have the same risk ratio for blood clots, strokes, heart attacks, cancer, and brain aging. (Obst Gynecol. 1998;91:6-11, N,Eng J, Med.1995;333:276-282. Archives of Internal Medicine.2001;161:1161-1172, Mayo Clinic Proceedings. Nov. 2000, J Am Col Nutrition. 2000;19:242-255, Am J Cardiol.2000;85:1297-1301).

Need to Focus on Preventive Interventions

An appropriate pessimistic view of HRT as an omnibus agent to prevent disease in postmenopausal women should focus more attention on these preventive interventions which have a strong evidence base. And, by the way, don't forget the old, tried and true techniques of keeping a low weight with a minimum of body fat (fat cells produce estrogen) by adhering to a regimen of frequent small feedings 6 times a day with a balanced, low-fat diet, rich in good quality proteins and high-fiber complex carbohydrates that do not raise your blood sugar/insulin levels, drink plenty of water, take my vitamin formulas morning and evening (twice a day), and don't forget to exercise regularly 3-4 times a week, both cardiovascular endurance exercise, as well as resistance weight training all of your life, or at least for as long as you want to stay as healthy as you can. Above all, keep in mind that it is never to late to become what you could have been!

Also see:
FDA Acts on Fraudulent Claims of Bioidentical Hormone Benefits

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