Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone.

Abstract

Although controversy continues, the preponderance of evidence indicates that estrogen replacement therapy favorably influences the risk of coronary heart disease in postmenopausal women. It remains uncertain how this effect is mediated and whether the cyclic addition of a progestin may influence adversely an estrogenrelated cardioprotective effect. We investigated the influence of sex hormone replacement therapy on diet-induced coronary artery atherosclerosis in estrogendeficient (ovariectomized) adult female cynomolgus monkeys. Monkeys were assigned randomly to one of three treatment groups: 1) no hormone replacement (n=17), 2) continuously administered 17-beta estradiol plus cyclically administered progesterone (n=20), and 3) continuously administered 17-beta estradiol (n=18). The physiologic patterns of plasma estradiol and progesterone concentrations were maintained by administering the hormones in sustained-release subcutaneous Silastic implants. The experiment lasted 30 months. At necropsy, coronary artery atherosclerosis was inhibited similarly (reduced by approximately one-half) in animals in both hormone replacement groups (p<0.05). Antiatherogenic effects of hormone replacement were independent of variation in total plasma cholesterol, lipoprotein cholesterol, apoprotein A-1 and B concentrations, high density lipoprotein subtraction heterogeneity, and low density lipoprotein molecular weight. We conclude that physiologic estrogen replacement therapy with or without added progesterone inhibits atherosclerosis progression in ovariectomized monkeys. This may explain why estrogen replacement therapy results in reduced risk of coronary heart disease in postmenopausal women. (Arteriosclerosis 10:1051-1057, November/December 1990) P remenopausal white women are at a low risk of coronary heart disease relative to age-matched white men. Although direct evidence is lacking, it is widely believed that ovarian estrogen is responsible for this gender-related protection. However, there is no direct evidence that endogenous estrogen or progesterone influences the pathogenesis of coronary heart disease or its underlying cause, coronary artery atherosclerosis. Furthermore, it remains uncertain whether coronary risk in women is influenced by physiologic conditions that affect endogenous sex steroid levels.1 While most studies have found evidence for increased severity of coronary artery atherosclerosis and increased coronary risk in postmenopausal women, others have found no relationship. 1 The results of studies of the effects of pregnancy, Received February 20,1990; revision accepted May 14,1990. that coronary risk increases with increasing number of pregnancies and half find no relationship. As regards exogenous estrogen, the preponderance of evidence indicates that estrogen replacement therapy favorably influences coronary risk in postmenopausal women.3 More controversial is whether the cyclic addition of a progestin to an estrogen replacement regimen may adversely influence an estrogen-related protective effect....

Effects of bazedoxifene alone and with conjugated equine estrogens on coronary and peripheral artery atherosclerosis in postmenopausal monkeys

“…Despite the lack of a beneficial effect of CEE treatment on the plasma lipid profiles of the monkeys, there was a robust inhibition of the atherosclerosis progression (extent) and plaque severity/complications in all three main epicardial coronary arteries and the common iliac artery. That finding is comparable to a number of studies we have reported previously finding that estrogen treatment initiated immediately after making the monkeys surgically menopausal results is an average inhibition of about 70% in the progression of coronary artery atherosclerosis 21,25-27 . Interestingly, a similar estimate was made for the beneficial effects of estrogen treatment on the progression of carotid artery intimal media thickness of postmenopausal women 28 .…”

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

“…The administration of estrogens for prolonged periods inhibits the deposition of cholesterol in the arteries and thickening of the intima in monkeys and rabbits fed an atherogenic diet 8 . However, the mechanisms determining the direct effects of estrogens on the arterial wall have not been completely elucidated.…”

Oral Contraceptives and Hormone Replacement Therapy Do Not Increase the Incidence of Arterial Thrombosis in a Nonhuman Primate Model

“…19,27,46 Postmenopausal cynomolgus monkeys, like women, have reduced plasma concentrations of HDL cholesterol and increased amounts of coronary atherosclerosis compared with premenopausal females fed the same atherosclerotic diet for the same length of time. 47 Thus, both premenopausal and postmenopausal (ovariectomized) female cynomolgus monkeys share with women many of the same risk factors for the development of coronary artery disease. Furthermore, estrogen replacement therapy inhibits progression of coronary artery atherosclerosis, 47 suggesting that, like postmenopausal women, ovariectomized cynomolgus females respond similarly to hormone treatment.…”

“…47 Thus, both premenopausal and postmenopausal (ovariectomized) female cynomolgus monkeys share with women many of the same risk factors for the development of coronary artery disease. Furthermore, estrogen replacement therapy inhibits progression of coronary artery atherosclerosis, 47 suggesting that, like postmenopausal women, ovariectomized cynomolgus females respond similarly to hormone treatment.…”