The effect of oral hormone therapy on the metabolome of postmenopausal women is profound. Different hormone therapy regimens result in discordant metabolomic effects that impact the risk for coronary heart disease, reports a study led by Raji Balasubramanian, associate professor in the School of Public Health and Health Sciences, University of Massachusetts, Amherst.
The study, based on the assessment of 481 metabolites in 934 women who participated in the Women’s Health Initiative hormone therapy (WHI-HT) trials, is reported in the article “Metabolomic Effects of Hormone Therapy and Associations with Coronary Heart Disease among Postmenopausal Women,” published in the journal Circulation: Genomic and Precision Medicine.
Balasubramanian’s investigations build on earlier WHI-HT studies that report a 29% increase in the risk of coronary heart disease upon combined oral treatment with conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) but not upon treatment with CEE alone.
To explain this difference in outcomes of the WHI-HT regimens, Balasubramanian and colleagues asked whether hormone therapy alters small-molecule metabolites. “The answer is a resounding yes,” says Balasubramanian.
In addition to coronary heart disease, the CEE+MPA regimen also increased risk of invasive breast cancer, stroke, pulmonary embolism, dementia, gallbladder disease, and urinary incontinence, while it reduced hip fractures, colorectal cancer, and diabetes. Earlier studies on the trial also show an association of CEE alone with a higher risk of stroke, and a lower risk of hip fracture
“Our focus was on cardiovascular disease and understanding at a molecular level why these two hormone therapy regimens had disparate effects in regard to cardiovascular disease,” Balasubramanian says.
The study reports metabolite changes assessed using liquid chromatography mass spectrometry in 431 women on a combined regimen (CEE+MPA) and 503 women on CEE alone, with both randomized groups including 50% placebo treatments. These metabolite profiling studies are carried out at the beginning and end of the year-long trial.
62% metabolites were significantly changed upon treatment with CEE alone, and 52% with CEE+MPA. The findings reveal “profound changes in the metabolome, spanning a wide range of classes including lipids, amino acids and other small molecule metabolites,” Balasubramanian says.
While the types, degrees and directions of change were analogous for most metabolites investigated in the two hormone therapy regimens, 22 metabolites showed discordant effects. Of these, 12 metabolites were associated with increased risk for coronary heart disease in an independent WHI-HT study on 944 participants and a metabolomics dataset nested within the Prevención con Dieta Mediterránea (PREDIMED) trial. The 12 metabolites included seven triacylglycerols, and the amino acid lysine.
In the CEE regimen, the direction of the changes in all 12 metabolites provided protection against coronary heart disease. The amino acid lysine was significantly altered by both hormone therapies, but in opposite directions. CEE alone increased lysine levels, providing a protective effect, whereas CEE+MPA decreased lysine levels, increasing the risk for coronary heart disease. In the CEE+MPA regimen, 11 metabolites were unchanged.
“We believe that these disparate metabolomic effects between estrogen alone and estrogen in combination with medroxyprogesterone acetate may partially explain the differences in coronary heart disease risks observed in the original Women’s Health Initiative Hormone Therapy trials,” explains Balasubramanian.
The study sets the stage for identifying other hormone therapy-related metabolomic changes in women of a broader age range and investigations into associations with other diseases, such as breast cancer.
“Given the large changes in the metabolome with hormone therapy, we would like to see how these changes correlate with the impact of hormone therapy on a wide range of health outcomes. In addition, we hope to examine the impact of different hormone therapy formulations, such as transdermal estrogens, and different formulations of progestins. By better understanding the impact of hormone therapy on the metabolome we may advance understanding of hormones and health,” says Kathryn M. Rexrode, MD, MPH, Chief, Division of Women’s Health, Harvard Medical School, and senior author on the study.
“We’re excited to contribute to advancing research in women’s health,” Balasubramanian says.