Wagner J D, Thomas M J, Williams J K, Zhang L, Greaves K A, Cefalu W T
Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157-1040, USA.
J Clin Endocrinol Metab. 1998 Mar;83(3):896-901. doi: 10.1210/jcem.83.3.4628.
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 i.v. 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) microU(-1) mL; 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 F2alpha (PGF2alpha) isomer (a prostaglandin (PG) isomer formed by both autooxidation of arachidonate and cyclooxygenase activity). PGF2alpha 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.
我们之前已经表明，醋酸甲羟孕酮（MPA）单独使用或与结合马雌激素（CEE）联合使用时，与未治疗的对照组以及仅接受CEE治疗的组相比，显著降低了胰岛素敏感性（SI）。本研究的目的是确定雌二醇（E2）单独使用以及与醋酸诺美孕酮（NA；一种缺乏雄激素活性的强效孕激素）联合使用时，对SI和动脉抗氧化活性的影响，动脉抗氧化活性通过F2 - 异前列腺素测定。36只成年雌性食蟹猴（猕猴属）接受卵巢切除术，并喂食适度致动脉粥样硬化的饮食，在饮食中添加以下三种治疗方法之一，持续12周：1）不治疗（对照组）；2）E2；或3）持续联合使用E2 + NA（E2 + NA）。治疗10周后，通过频繁取样的静脉葡萄糖耐量试验并在第三阶段输注胰岛素来评估SI和葡萄糖有效性。治疗12周后，测量胸主动脉中的胆固醇含量和F2 - 异前列腺素。与对照组或接受E2 + NA治疗的猴子相比，E2治疗导致SI显著更高（分别为10.03±0.91与6.35和6.49×10⁻⁴ min⁻¹ microU⁻¹ mL；P < 0.05）。与我们对CEE和MPA的研究不同，E2 + NA治疗虽然使SI低于E2组，但并未使SI低于对照组猴子。正如预期的那样，短时间的治疗在主动脉胆固醇含量上没有产生显著差异。对总F2 - 异前列腺素（主要代表由自动氧化引起的F2 - 异前列腺素形成）没有治疗效果，表明抗氧化活性最小。然而，在前列腺素F2α（PGF2α）异构体（一种由花生四烯酸自动氧化和环氧化酶活性形成的前列腺素（PG）异构体）上存在治疗差异。与对照组相比，E2治疗使PGF2α浓度降低32%，与E2 + NA治疗相比降低36%（分别为0.48±0.08与0.71±0.12和0.75±0.06；P < 0.05），表明激素治疗之间PG合成存在差异。总之，NA，一种无雄激素活性的孕激素，可能仍然会以与仅雌激素治疗不同的方式影响一些心血管危险因素。然而，它似乎比MPA的危害小。
