Abstract: The past several years have been marked by confusion and controversy concerning whether estrogens are cardioprotective. The issue is of utmost public health importance because coronary heart disease (CHD) remains the leading cause of death among postmenopausal women. Fortunately, a unifying hypothesis has emerged that reproductive stage is a major determinant of the effect of estrogens on atherosclerosis progression, complications, and plaque vulnerability.
Premenopausal Years: Premenopausal atherosclerosis progression seems to be an important determinant of postmenopausal atherosclerosis and thus the risk for CHD. Clearly, plasma lipids/lipoproteins influence this progression; however, estradiol deficiency seems to be the major modulator. Both monkeys and women with premenopausal estrogen deficiency develop premature atherosclerosis, an effect that can be prevented in both species by estrogen-containing oral contraceptives.
Perimenopausal/Early Postmenopausal Years: During this stage, there are robust estrogen benefits. Monkeys given estrogens immediately after surgical menopause have a 70% inhibition in coronary atherosclerosis progression. Estrogen treatment prevented progression of atherosclerosis of women in the Estrogen in the Prevention of Atherosclerosis Trial. A meta-analysis of women younger than 60 years given hormone therapy had reduced total mortality (relative risk = 0.61, 95% CI: 0.39-0.95).
Late Postmenopausal Years: This stage is one in which there are no or possible deleterious estrogen effects. Monkeys lose CHD benefits of estrogens when treatment is delayed. The increase in CHD events associated with initiating hormone therapy 10 or more years after menopause seems to be related to up-regulation of the plaque inflammatory processes and plaque instability and may be down-regulated by statin pretreatment.
Both experimental and clinical data indicate that estrogens inhibit the progression of atherosclerosis during the premenopausal, perimenopausal, and early postmenopausal years. To the contrary, however, estrogens administered in the later postmenopausal years can result in complicated atherosclerotic plaques becoming unstable.