Metabolomic Effects of Hormone Therapy and Associations with Coronary Heart Disease among Postmenopausal Women.

Background - In the Women's Health Initiative hormone therapy (WHI-HT) trials, treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), while oral conjugated equine estrogens alone (CEE) did not. Methods - 481 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 change in metabolite profiles at 1-year was evaluated in linear models adjusting for age, BMI, 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 Observational Study (WHI-OS), 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 (FDR adjusted p value < 0.05) in multivariable models. Concerted increases in abundance were seen within various metabolite classes including triacylglycerols (TAG), phosphatidylethanolamines and phosphatidylcholines (PC); 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 LASSO 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 ). The findings of a subset of four metabolites including C58:11 TAG, C54:9 TAG, C36:1 PC and sucrose replicated in an independent dataset of 980 participants. Conclusions - Randomized treatment with oral HT resulted in large metabolome shifts. Discordant metabolite effects between HT regimens may partially mediate the differences in CHD risk between the two WHI-HT trials.