The National Heart, Lung, and Blood Institute published results of the first major clinical trial to test the effects of estrogen replacement therapy on factors affecting a woman's risk of heart disease:HDL-cholesterol, systolic blood pressure, fibrinogen and insulin In the first major clinical trial to examine the effects of sex hormones on heart disease risk factors in postmenopausal women, scientists supported by the National Heart, Lung, and Blood Institute (NHLBI) found that all four of the hormonal regimens tested produced significant increases in the levels of HDL or good cholesterol. Estrogen taken alone and estrogen combined with micronized (natural) progesterone produced the most favorable increases in HDL levels. The two other estrogen/progestin combinations tested also produced significantly greater increases in HDL-cholesterol levels than a placebo (an inactive substance). None of the three estrogen/progestin combinations tested in the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial caused hyperplasia--cell overgrowth in the uterine lining--a potentially harmful condition which sometimes develops into cancer. However, estrogen taken alone significantly increased the occurrence of severe hyperplasia in women with a uterus. The PEPI study was reported today at the annual meeting of the American Heart Association in Dallas. "The results of this landmark study provide the best available guide for postmenopausal women and their physicians as they seek safe hormonal regimens that will improve their heart disease risk factors," said Dr. Claude Lenfant, NHLBI director. Coronary heart disease is the number one killer of American women. Each year, 250,000 women die of this disease. The PEPI study tested the effects of estrogen replacement therapy on these factors which affect a woman's risk of heart disease:HDL-cholesterol, systolic blood pressure, fibrinogen (a blood clotting factor predictive of stroke and heart attack), and insulin. Estrogen and progestin are female hormones produced by a woman's ovaries until menopause. Estrogen use in postmenopausal women has been associated with decreased LDL or bad cholesterol and increased HDL. For women, a high level of HDL-cholesterol is believed to strongly protect against coronary heart disease. Hormone therapy in which estrogen is combined with progestin has been shown to reduce the risk of estrogen-induced uterine changes, which are thought to lead to cancer in some women. However, there had been contradictory opinions as to whether adding progestin interferes with estrogen's positive effect on HDL-cholesterol levels. The 3-year PEPI study involved 875 healthy postmenopausal women aged 45 to 64 years at seven clinical centers in the U.S. Thirty-two percent of the women had previously had a hysterectomy. The women were randomly assigned to one of five treatment groups: (1) placebo, (2) daily estrogen use, (3) daily estrogen plus a synthetic progestin taken daily for 12 days per month, (4) daily estrogen plus daily synthetic progestin, and (5) daily estrogen plus a natural (micronized) progesterone (MP) taken daily for 12 days per month. All of the estrogen/progestin combinations produced significantly greater increases in HDL- cholesterol levels than the placebo. Even small increases in HDL have a potentially large impact on the risk of heart disease, said Dr. Lenfant. He cautioned, however, that there is a distinction between risk factors for heart disease and actual heart disease. "We must wait for the result of large clinical trials such as the Women's Health Initiative to determine whether increasing HDL ultimately reduces a woman's chance of developing or dying from heart disease. Until then, the PEPI results are a significant step forward in our understanding of hormone therapy," he said. In addition to the HDL findings, the PEPI study also found that, compared to the placebo, all of the active treatments caused significant decreases in LDL-cholesterol and fibrinogen. Furthermore, neither estrogen/progestin combinations increased blood pressure as had been previously believed. The PEPI investigators reported that one-third of the women with a uterus assigned to unopposed estrogen developed severe endometrial changes, diagnosed as adenomatous or atypical hyperplasias. These conditions are potentially precancerous. By the third year of the study, over half of the women with a uterus taking unopposed estrogen had to discontinue this regimen because of these endometrial changes, a requirement of the PEPI protocol. Annual endometrial biopsies to detect such changes were obtained from women with a uterus. "These results provide the strongest evidence to date that estrogen given alone produces the best effect on HDL-cholesterol. However, the high rate of potentially harmful endometrial changes makes combination hormone therapy advisable for most women with a uterus," said Dr. Elizabeth Barrett-Connor, professor and chair, Department of Family and Preventive Medicine, University of California, San Diego, and PEPI Steering Committee chair. "Because the endometrial hyperplasia is reversible with early diagnosis and treatment, the PEPI study shows the value of regular endometrial biopsy for its detection, particularly for women with a uterus who are taking unopposed estrogen," added Dr. Barrett-Connor. Dr. Barrett-Connor also commented on the finding that the fibrinogen levels of the PEPI participants on active treatment did not rise as they did in the placebo group. "This is the most convincing evidence so far that hormone replacement may prevent the rise in fibrinogen that occurs with age," she said. "The Framingham Heart Study found that the women with high fibrinogen levels had twice the risk of heart disease as women with low fibrinogen." The PEPI study was administered and primarily funded by the NHLBI. Co-funding for PEPI was provided by four other institutes of the National Institutes of Health: the National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute on Aging. Reprinted by permission. National Heart, Lung, and Blood Institute, Bethesda, MD.