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Executive Summary

LOW-DOSE ORAL ESTROGEN "FAVORABLY ALTERS" PLASMA LIPID LEVELS, researchers conclude in an article in the Oct. 24 New England Journal of Medicine. The article, by Brigham and Women's Hospital and Harvard Medical School researchers led by Brian Walsh, MD, presents the results of two studies of that looked at the effects on plasma lipoproteins of Wyeth-Ayerst's conjugated estrogens (Premarin), Bristol-Myers Squibb's oral micronized estradiol (Estrace) and Ciba-Geigy's transdermal estradiol (Estraderm). The studies were supported by grants from Bristol-Myers Squibb and the National Institutes of Health. The studies were conducted to establish whether "low doses of estrogen maintain the favorable effects on LDL [low-density lipoprotein] and HDL [high density lipoprotein], and whether the apparent protective effect of estrogen use against cardiovascular disease will continue," the researchers wrote. Walsh et al. noted that "the doses of postmenopausal estrogens commonly prescribed have been decreased to newly established levels that prevent osteoporosis and relieve menopausal symptoms in an effort to minimize adverse effects such as endometrial hyperplasia, thrombotic complications, and hypertriglyceridemia." "We found that a low daily dose of micronized estradiol (2 mg) or conjugated estrogens (.625 mg) lowered LDL cholesterol levels and raised HDL cholesterol levels by 14 to 16 percent," the article says. "A higher daily dose of conjugated estrogens (1.25 mg) did not substantially enhance this effect." In the first of the two trials conducted by the researchers, 31 women were given doses of placebo, Premarin .625 mg, and Premarin 1.25 mg for three months each. They were evaluated "to quantify precisely the effect of conjugated estrogens on plasma lipoprotein concentrations." The study showed that triglyceride levels increased "in stepwise fashion" related to dose (24% increase at the lower dose, 38% at the higher). Beneficial effects were found in the lower dose and were not substantially improved in the higher dose, the study showed. LDL levels decreased by 15% in the .625 mg dose and 19% in the 1.25 mg dose. HDL levels increased by 16% and 18%, respectively. The second study enrolled nine women who received six weeks each of placebo, Estrace (2 mg per day) and Estraderm (.1 mg twice a week). The goal of the study was "to identify the physiologic mechanisms by which estrogen treatment lowers plasma LDL levels and raises VLDL [very-low-density lipoproteins] and triglyceride levels." The study found that oral estradiol significantly increased large VLDL and triglycerides by increasing their production rates, but had no effect on small VLDL. Oral estradiol lowered LDL by increasing catabolism rates, the researchers said. "Transdermal estradiol had no significant effect on the concentrations or metabolic rates of VLDL or LDL," the researchers noted. The "near equivalence of the effects of the two doses may help explain why the incidence of cardiovascular disease and mortality due to all causes among women who take .625 mg of conjugated estrogens daily are similar to those among women who take 1.25 mg daily," the researchers noted. "In contrast to their effect on LDL and HDL cholesterol levels, conjugated estrogens increased triglyceride levels in a dose-dependent way," the article says, "thus providing an additional reason for using the lower dose." Estrogen replacement "could exacerbate preexisting hypertriglyceridemia and should be used with great care in patients with this disorder," the researchers concluded. The researchers concluded that "the increases in HDL levels and the decreases in LDL levels caused by estrogen may, if sustained over many years, protect against the development of cardiovascular disease." They predicted that "the risk of cardiovascular disease may decrease by more than 40%" based on experience with other lipid-lowering drugs; however, "a clinical trial would be necessary to demonstrate conclusively that oral estrogen use reduces the incidence of cardiovascular disease." A study in the Sept. 12 NEJM found that estrogen therapy halved the risk of cardiovascular disease ("The Pink Sheet" Sept. 16, T&G- 10). Neither Premarin nor Estrace currently carry any cardioprotective claims in labeling. FDA's Fertility & Maternal Health Drugs Advisory Committee in June 1990 recommended that Premarin add a cardioprotective claim for women without uteruses ("The Pink Sheet" June 18, 1990, p. 5). The committee considered the topic more generally this June ("The Pink Sheet" June 24, p. 11). A second study published in the Oct. 24 NEJM evaluated estrogen replacement therapy versus calcium supplementation in the prevention of postmenopausal osteoporosis. The Australian study of 120 women compared exercise therapy plus placebo to exercise plus calcium and exercise plus Upjohn's Depo-Provera (medroxyprogesterone acetate). The study found that calcium supplementation slowed the loss of bone density (measured at the distal forearm), while Depo-Provera helped patients recover bone density. Hormone therapy, however, had more side effects.

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