Background:In the WHI-HT trials (Women’s Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not.Methods:Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes. Metabolites with discordant effects by HT type were evaluated for association with incident CHD in 944 participants (472 CHD cases) in the WHI-OS (Women’s Health Initiative Observational Study), with replication in an independent cohort of 980 men and women at high risk for cardiovascular disease.Results:HT effects on the metabolome were profound; 62% of metabolites significantly changed with randomized CEE and 52% with CEE+MPA (false discovery rate–adjusted P value<0.05) in multivariable models. Concerted increases in abundance were seen within various metabolite classes including triacylglycerols, phosphatidylethanolamines, and phosphatidylcholines; decreases in abundance was observed for acylcarnitines, lysophosphatidylcholines, quaternary amines, and cholesteryl/cholesteryl esters. Twelve metabolites had discordant effects by HT type and were associated with incident CHD in the WHI-OS; a metabolite score estimated in a Least Absolute Shrinkage and Selection Operator regression was associated with CHD risk with an odds ratio of 1.47 per SD increase (95% CI, 1.27–1.70, P<10^-6). All twelve metabolites were altered in the CHD protective direction by CEE treatment. One metabolite (lysine) was significantly altered in the direction of increased CHD risk by CEE+MPA; the remaining 11 metabolites were not significantly changed by CEE+MPA. The CHD associations of a subset of 4 metabolites including C58:11 triacylglycerol, C54:9 triacylglycerol, C36:1 phosphatidylcholine and sucrose replicated in an independent dataset of 980 participants in the PREDIMED trial (Prevención con Dieta Mediterránea).Conclusions:Randomized treatment with oral HT resulted in large metabolome shifts that generally favored CEE alone over CEE+MPA in term of CHD risk. Discordant metabolite effects between HT regimens may partially mediate the differences in CHD risk between the 2 WHI-HT trials.

中文翻译：

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绝经后妇女激素治疗的代谢组学效应及其与冠心病的关系

背景：在 WHI-HT 试验（女性健康倡议激素疗法）中，口服结合马雌激素和醋酸甲羟孕酮 (CEE+MPA) 治疗导致冠心病 (CHD) 风险增加，而口服结合马雌激素 (CEE)没有。方法：分别在 WHI CEE 和 CEE+MPA 试验的 503 名和 431 名参与者中在基线和 1 年时测量了 481 种代谢物。在线性模型中评估了随机 HT 对 1 年代谢物谱的影响，调整了基线代谢物水平、年龄、体重指数、种族、冠心病事件、普遍的高血压和糖尿病。在 WHI-OS（妇女健康倡议观察研究）中，对 944 名参与者（472 例 CHD 病例）中 HT 类型具有不一致影响的代谢物与冠心病事件的关联进行了评估，在一个由 980 名心血管疾病高危男性和女性组成的独立队列中进行了复制。结果：HT 对代谢组的影响是深远的；随机 CEE 组 62% 的代谢物发生显着变化，CEE+MPA 组 52% 的代谢物发生显着变化（错误发现率调整P值<0.05）在多变量模型中。在包括三酰基甘油、磷脂酰乙醇胺和磷脂酰胆碱在内的各种代谢物类别中都观察到丰度的一致增加；观察到酰基肉碱、溶血磷脂酰胆碱、季胺和胆固醇/胆固醇酯的丰度降低。12 种代谢物对 HT 类型的影响不一致，并且与 WHI-OS 中的 CHD 事件相关；在最小绝对收缩和选择算子回归中估计的代谢物评分与 CHD 风险相关，比值比为每 SD 增加 1.47（95% CI，1.27–1.70，P <10 ^-6）。通过 CEE 治疗，所有 12 种代谢物都在 CHD 保护方向上发生了改变。CEE+MPA 在增加 CHD 风险的方向上显着改变了一种代谢物（赖氨酸）；CEE+MPA 未显着改变其余 11 种代谢物。在 PREDIMED 试验 (Prevención con Dieta Mediterránea) 的 980 名参与者的独立数据集中复制了 4 种代谢物子集的 CHD 关联，包括 C58:11 三酰基甘油、C54:9 三酰基甘油、C36:1 磷脂酰胆碱和蔗糖。结论：随机治疗口服 HT 导致大的代谢组变化，就 CHD 风险而言，单独使用 CEE 优于 CEE + MPA。HT 方案之间不一致的代谢物效应可能部分调节了 2 项 WHI-HT 试验之间 CHD 风险的差异。