Hormonal changes during menopause put women at risk of several comorbidities including cardiovascular disease (CVD), decreased bone density, diabetes, and metabolic dysfunction-associated fatty liver disease (MAFLD). It is not surprising that the loss of estrogen during menopause affects the body profoundly as it has been shown to play a fundamental role in bone health and metabolic regulation. As such, estrogen receptors are abundantly expressed throughout the body including in the liver, heart, brain, and bones. Furthermore, estrogen has been shown to regulate inflammation and its loss is generally associated with increased inflammation. In a recent study by Dr. Prarthana Guha and colleagues used ovariectomized (OVX) rats to examine the effects of estrogen loss on hepatic metabolism and inflammation.
In this study, they demonstrate that loss of estrogen is associated with weight gain, lower high-density lipoprotein (HDL) levels, and increased total cholesterol levels compared to control animals. Hormone therapy (estradiol; E2) reverses the changes in the lipoprotein profile for ovariectomized animals. Additionally, inflammatory cytokines, interleukin 6 and tumor necrosis factor 𝛼, were increased in the liver of animals with low estrogen. In a previous study, the authors determined that indoleamine-2,3,-dioxygenase 1 (IDO1) contributed to the increased cholesterol levels via the downregulation of scavenger receptor class B type 1 (SR-B1). Additionally, it is well known that inflammation can increase tryptophan catabolism via the kynurenine pathway. Therefore, they wanted to further investigate if estrogen loss modulates tryptophan catabolism. Both enzymes IDO1 and tryptophan 2,3-dioxygenase (TDO2), as well as kynurenine levels were significantly increased in OVX animals and with estradiol treatment the levels were greatly reduced. Additionally, using targeted metabolomics they determined that other kynurenine pathway (KP) metabolites are altered by the loss of estrogen (such as increased kynurenic acid levels and a decreased tryptophan/kynurenine ratio) and hormone replacement therapy reverses the alterations.
Taken together, this study demonstrates that estrogen loss is associated with increased hepatic inflammation, lipoprotein profile changes, and increased KP activation, all of which are correlated with an increased risk of cardiovascular disease. Importantly, with hormone replacement therapy the increases are diminished. In another recent study (E-Y Kim et al., 2024) that looked at the risk of MAFLD associated with different menopausal ages demonstrated that the younger a woman is at menopausal onset the greater the risk of developing MAFLD. While estrogen loss likely occurs at a similar rate during menopause across ages, estrogen receptor expression decreases with age, suggesting that estrogen signaling changes with age. Therefore, hormonal replacement therapy during menopause transition may reduce comorbidity risks, especially for high-risk ages.