Esterified Estrogens With and Without Methyltestosterone Decrease Arterial LDL Metabolism in Cynomolgus Monkeys

Abstract

Although both epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of coronary heart disease, the mechanisms for this beneficial effect are largely unknown. Furthermore, the addition of progestins or androgens to estrogen replacement therapy is of concern. The objective of this study was to examine the effects of esterified estrogens alone or in combination with an androgen on arterial LDL metabolism and early atherogenesis in ovariectomized female cynomolgus monkeys. Arterial LDL metabolism was assessed by using dual-labeled LDL that was injected 24 hours before necropsy. Arterial LDL degradation was reduced by 64% to 84% and cholesteryl ester content was decreased by approximately 50% in the thoracic aorta in both treatment groups compared with controls. In addition, aortic lipid peroxidation products, as assessed by thiobarbituric acid reaction, were significantly lower in animals treated with esterified estrogens, with a similar trend for combined estrogen-androgen treatment. Both treatments also reduced plasma concentrations of apoB-containing lipoproteins, reduced LDL particle size, and increased total-body LDL catabolism. The combination of decreased arterial LDL metabolism, decreased arterial lipid peroxidation, and improved plasma lipoprotein metabolism may explain some of the protective effects of estrogens on coronary heart disease and indicate that beneficial actions extend to a combination of estrogen and androgen.

17β-Estradiol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level

“…The protective effects of estradiol on the endothelium have been documented in hypercholesterolemic pigs and rabbits [22,23]. Others have reported that absence of estradiol induced by gonadectomy causes endothelial dysfunction in monkeys [24]. Our previous work showed that in vitro, 17h-estradiol attenuated inhibition of vasodilator responses to acetylcholine by ox-LDL or lysophosphatidylcholine in the isolated rabbit thoracic aortas [2].…”

“…Estradiol has a biochemical structure similar to a-tocopherol and is a natural antioxidant [38]. It has been reported that estrogen replacement therapy decreases arterial LDL metabolism in cynomolgus monkeys [24]. In cultured endothelial cells, estradiol has been shown to inhibit oxidative modification of LDL [39].…”

Modified LDL–Mediated Increases in Endothelial Layer Permeability Are Attenuated With 17β-Estradiol

“…5 To counteract oxidant stress effects on LDL and/or the artery wall, a number of potential antioxidants have been examined. In particular, some estrogens (eg, 17␤-estradiol) are known to reduce LDL accumulation in the artery wall 19,20 and to be potent antioxidants. [21][22][23] In addition, estrogens may protect endothelial cells from oxidative damage.…”

Dihydrotestosterone and estradiol-17β mutually neutralize their inhibitory effects on human vascular smooth muscle cell growth in vitro

“…The reaction mixture was incubated overnight at 4 • C and the labeled protein was purified by gel filtration on Sephadex G-25 M. The europium labeled antibody was eluted with 50 mM Tris-HCl buffer (pH 7.5) and stored at 4 • C until use [19,20].…”

“…RNA was extracted from cultured VSMC and was subjected to reverse transcription as previously described [19,20]. For ER(, we used 5 l of cDNA in the reaction mixture with the primers 5 -AA-TTCTGACAATCGACGCCAG-3 (forward) and 5 -GTGCTTCAACATTCT-CCCTCCTC-3 (reverse), for 30 cycles at 94 • C for 30 s, at 57 • C for 30 s and at 72 • C for 1 min.…”