Oral hormone therapy may increase risk of coronary heart disease in postmenopausal women

The metabolic functioning of menopause is still poorly understood by the scientific community. Since the 1990s, a vast study has been launched to understand what were the profound changes initiated by this hormonal transition in the lives of women. According to a study by biostatisticians from the University of Massachusetts Amherst (USA), oral hormone therapy significantly alters the metabolome of postmenopausal women. The results of this study have been published in the journal Circulation: Genomics and Precision Medicine.

A phenomenon that affects all women

Menopause is a natural phenomenon that affects all women and occurs with age when the ovaries stop working. Scientifically, we speak of menopause when a woman has not had a menstrual cycle for more than 12 months. With the cessation of menstrual cycles also occurs the end of secretions of female hormones that are estrogen and progesterone. Menopause is accompanied by more or less accentuated symptoms depending on the woman (vaginal dryness, hot flashes, sleep disturbances, night sweats). To remedy this, it is possible to use hormone replacement therapy to compensate for the cessation of hormones. As for the metabolome, it corresponds to all the molecules and metabolic interactions present in an organism, a cell or a biological sample.

In 1990, the Women’s Health Initiative was a study to examine blood samples from millions of women around the world to better understand how menopause works. The Women’s Health Initiative hormone therapy trials in the 1990s examined the effects on coronary heart disease, breast cancer and other conditions of two hormone therapies – estrogen alone and a combination of estrogen and of progestin.

At that time, researchers had found that the combination therapy significantly increased the risk of coronary artery disease by 29%. For its part, estrogen alone reduced the risk of coronary artery disease by 9%, although this effect was not statistically significant.

Disease markers present in the metabolome

Using new technologies, including liquid chromatography-mass spectrometry (LC-MS) techniques, researchers measured 481 metabolites in blood samples from participants in the Women’s Health Initiative hormone therapy trial. Thus, 503 metabolites were found in women in the estrogen-only group, half of them on placebo, and 431 in the estrogen plus progestin group, half of them on placebo.

Most changes in metabolites corresponded to a particular type of hormone therapy, and the researchers identified 22 metabolites that had discordant effects. Twelve of them were associated with a risk of coronary artery disease in an evaluation of an independent dataset from the Women’s Health Initiative.

However, when treated with estrogen alone, changes in all 12 metabolites were protective against coronary heart disease. With the estrogen-progestin combination, 11 metabolites remained unchanged. Finally, estrogen therapy alone increases lysine levels, which has a protective effect, and estrogen plus progestogen combination decreases lysine levels, which increases the risk of coronary heart disease.

According to the researchers, this reveals “profound changes in the metabolome, spanning a wide range of classes, including lipids, amino acids, and other small molecule metabolites”, points out Raji Balasubramanian, associate professor at the School of Public Health and Health Sciences at the University of Massachusetts Amherst. Put simply, 62% of metabolites were significantly changed with estrogen-only treatment, and 52% with estrogen plus progestogen treatment.

Further research is currently underway to identify other changes in the metabolome that may be related to hormone therapy in a larger group of women. This will help to better understand the changes and health risks associated with this period of women’s lives.