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Insulin Sensitivity and Cardiovascular Risk Factors in Ovariectomized Monkeys with Estradiol Alone or Combined with Nomegestrol Acetate¹

Departments of Comparative Medicine (J.D.W., J.K.W., L.Z., K.A.G.), Biochemistry (M.J.T.), and Internal Medicine (J.D.W., W.T.C.), Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157-1040

Address all correspondence and requests for reprints to: Janice D. Wagner, D.V.M., Ph.D., Department of Comparative Medicine, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1040. E-mail: jwagner{at}cpm.bgsm.edu

We have previously shown that medroxyprogesterone acetate (MPA), either alone or combined with conjugated equine estrogens (CEE), significantly decreased insulin sensitivity (SI), compared with both untreated controls and those treated with CEE alone. The purpose of this study was to determine the effects of estradiol (E₂), with and without nomegestrol acetate (NA; a potent progestin that lacks androgenic activity), on SI and arterial antioxidant activity, as determined by F₂-isoprostanes. Thirty-six adult female cynomolgus monkeys (Macaca fascicularis) were ovariectomized and fed a moderately atherogenic diet, with one of the following three treatments added to the diet, for 12 weeks: 1) no treatment (control); 2) E₂; or 3) continuous combined E₂ + NA (E₂+NA). SI and glucose effectiveness were assessed by the frequently sampled iv glucose tolerance test using a third-phase insulin infusion after 10 weeks of treatment. Cholesterol content and F₂-isoprostanes were measured in the thoracic aorta after 12 weeks of treatment. E₂ treatment resulted in a significantly greater SI, compared with control or E₂+NA-treated monkeys (10.03 ± 0.91 vs. 6.35 and 6.49 x 10^-4 min^-1 µU^-1mL; P < 0.05). In contrast to our studies of CEE and MPA, E₂+NA treatment, though reducing the SI below that of the E₂ group, did not reduce the SI below that of control monkeys. As expected, the short period of treatment resulted in no significant differences in aortic cholesterol content. There was no treatment effect on total F₂-isoprostanes (representing F₂-isoprostane formation caused primarily by autooxidation), suggesting minimal antioxidant activity. However, there was a treatment difference in the prostaglandin F₂ (PGF₂) isomer (a prostaglandin (PG) isomer formed by both autooxidation of arachidonate and cyclooxygenase activity). PGF₂ concentrations were 32% lower with E₂ treatment, compared with controls, and 36% lower, compared with E₂+NA treatment (0.48 ± 0.08 vs. 0.71 ± 0.12 and 0.75 ± 0.06; P < 0.05), suggesting differences in PG synthesis between hormone treatments. In conclusion, NA, a progestin without androgenic activity, may still affect some cardiovascular risk factors differently than estrogen-only therapy. However, it seems to be less detrimental than MPA.

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