Irilone, a Red Clover Isoflavone, Combined with Progesterone Enhances PR Signaling through the Estrogen and Glucocorticoid Receptors

Abstract

Trifolium pratense L. (red clover) is a popular botanical supplement used for women’s health. Irilone isolated from red clover previously demonstrated progestogenic potentiation activity. In this study, irilone enhanced progesterone signaling was determined to not occur due to post-translational phosphorylation or by reducing progesterone receptor (PR) protein levels but instead increased PR protein levels in T47D breast cancer cells, which could be blocked by estrogen receptor (ER) antagonists, suggesting an ER dependent effect. Further, irilone increased luciferase activity from a hormone responsive element in a cell line that lacked ER and PR but expressed the glucocorticoid receptor (GR). A siRNA knockdown of GR in Ishikawa PR-B endometrial cancer cells reduced irilone’s ability to enhance progesterone signaling. In an ovariectomized CD-1 mouse model, irilone did not induce uterine epithelial cell proliferation. The mechanism of action of irilone gives insight into PR crosstalk with other steroid hormone receptors, which can be important for understanding botanicals that are used for women’s health.

Targeted and untargeted metabolomic profiles in wild rabbit does (Oryctolagus cuniculus) of different breeding states (pregnant and lactating)

“…According to our data, food consumption is similar in pregnant and lactating females, so the higher levels of irilone in the lactating does could be a consequence of a lower use of this compound by lactating females (increasing its excretion). In this context, more interesting is the oestrogenic potential (Lutter et al, 2014) and recent progestogenic activity found of this metabolite, which can enhance the progesterone signalling (Austin et al, 2021). It is suggested that the irilone has a synergic effect on progesterone and is capable of binding to the receptors of this hormone, enhancing its effects.…”