Conjugated Equine Estrogens Alone, but Not in Combination With Medroxyprogesterone Acetate, Inhibit Aortic Connective Tissue Remodeling After Plasma Lipid Lowering in Female Monkeys

From the Comparative Medicine Clinical Research Center and the Department of Comparative Medicine of the Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Thomas C. Register, PhD, Department of Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail tregister{at}cpm.wfubmc.edu

Abstract—The objective of this study was to determine the arterial responses to plasma lipid lowering alone or in combination with (1) estrogen replacement therapy or (2) hormone replacement therapy in surgically postmenopausal female monkeys with preexisting atherosclerosis. Eighty-eight female cynomolgus macaques were ovariectomized, fed an atherogenic diet for 24 months, and then assigned by randomized stratification into 4 groups. One group (baseline, n=20) was necropsied at the end of the atherogenic diet period; the remaining 3 groups were fed a plasma lipid–lowering diet (regression) for 30 months. These regression groups were control (diet only), CEE (receiving conjugated equine estrogens alone), and CEE+MPA (receiving CEE and continuous medroxyprogesterone acetate). A previous report described coronary artery functional and histological results; the present report describes biochemical and histological results from the abdominal aorta. Aortic plaque size was not different between groups, similar to previous findings in the coronary arteries. Aortic cholesterol content (milligrams per gram lipid-free dry weight) was lower in the regression groups compared with baseline, both for free cholesterol (mean, control=19.1, CEE=15.7, CEE+MPA=14.4, and baseline=32.7; P<0.001) and for esterified cholesterol (mean, control=18.9, CEE=15.4, CEE+MPA=14.2, and baseline=58.7; P<0.001). This cholesterol efflux could lead to increased plaque stability without changing the physical size of the lesion. Alterations in aortic connective tissue composition were observed in the regression groups. When expressed as a percentage of the lipid-free tissue weight, the aortic elastin content of the control (mean=14.9) and the CEE+MPA (mean=14.0) groups was lower than that of the baseline group (mean=19.0), which was not different from that of the CEE group (mean=15.8). Aortic collagen content, as estimated by hydroxyproline content per milligram of lipid-free tissue, was higher in the control group (mean=67.4) and the CEE+MPA group (mean=66.1) than in the baseline group (mean=56.2; P<0.05). Collagen content of the CEE group (mean=58.9) was not different from that of the baseline group. When the regression groups were considered separately, the aortic collagen content of the CEE group was lower than that of the control group (P<0.05) and tended to be lower than that of the CEE+MPA group (P=0.10), suggesting that CEE therapy (but not CEE+MPA) inhibits potentially detrimental connective tissue alterations that accompany lesion regression. These results have implications for combinations of lipid-lowering and hormone replacement therapies in relation to vascular remodeling and abdominal aortic aneurysm development.

Key Words: collagen • elastin • plaque stability • aortic aneurysm

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