Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats

Abstract

Objective Progesterone (P4) plays a central role in women's health. Synthetic progestins are used clinically in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Unfortunately, synthetic progestins are associated with side effects, including cardiovascular disease and breast cancer. Botanical dietary supplements are widely consumed for the alleviation of a variety of gynecological issues, but very few studies have characterized natural compounds in terms of their ability to bind to and activate progesterone receptors (PR). Kaempferol is a flavonoid that functions as a non-steroidal selective progesterone receptor modulator (SPRM) in vitro. This study investigated the molecular and physiological effects of kaempferol in the ovariectomized rat uteri. Methods Since genistein is a phytoestrogen that was previously demonstrated to increase uterine weight and proliferation, the ability of kaempferol to block genistein action in the uterus was investigated. Analyses of proliferation, steroid receptor expression, and induction of well-established PR-regulated targets Areg and Hand2 were completed using histological analysis and qPCR gene induction experiments. In addition, kaempferol in silico binding analysis was completed for PR. The activation of estrogen and androgen receptor signalling was determined in vitro. Results Molecular docking analysis confirmed that kaempferol adopts poses that are consistent with occupying the ligand-binding pocket of PRA. Kaempferol induced expression of PR regulated transcriptional targets in the ovariectomized rat uteri, including Hand2 and Areg. Consistent with progesterone-l ke activity, kaempferol attenuated genistein-induced uterine luminal epithelial proliferation without increasing uterine weight. Kaempferol signalled without down regulating PR expression in vitro and in vivo and without activating estrogen and androgen receptors. Conclusion Taken together, these data suggest that kaempferol is a unique natural PR modulator that activates PR signaling in vitro and in vivo without triggering PR degradation.

Irilone from Red Clover (Trifolium pratense) Potentiates Progesterone Signaling

“…This was a surprising finding, as previous studies found natural products that interacted with the PR had antagonist activity or no activity when tested in the presence of other PR ligands. 7,8,14,15 Only one other natural product study reported synergistic activity with steroid signaling. 16 In that study, extracts from Eucommia ulmoides synergistically increased androgen signaling, even in the presence of saturating concentrations of testosterone, but the compound responsible for this action was not isolated or further characterized.…”

“…6 We previously reported that the red clover constituent, kaempferol, exhibited progestogenic effects in ovariectomized rats, though its abundance and potency profile did not account for all of the progesterone activity observed in the crude extract. 7,8 This suggested that other progesterone-like compounds were present in red clover. In the current study, we employed a progesterone response element (PRE)-luciferase (Luc) reporter assay in Ishikawa cells to characterize the agonist and antagonist effects of red clover extracts, and to identify molecules responsible for the activity.…”

Roles of Dietary Phytoestrogens on the Regulation of Epithelial-Mesenchymal Transition in Diverse Cancer Metastasis

“…Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4 H -1-benzopyran-4-one) is one of the flavonoids found in many edible plants, like tea, broccoli, cabbage, beans and tomato, and its name was derived due to its specific source of the rhizome of Kaempferi galangal L., known as a popular traditional aromatic plant [ 115 , 116 ]. As one of the phytoestrogens due to its polyphenolic structure, kaempferol also exerts anti-proliferative and anti-carcinogenic actions though ER, AR, the aryl hydrocarbon receptor (AhR) and the progesterone receptor (PR) signaling pathways in many types of cancer [ 117 , 118 , 119 ].…”

Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products

“…In the uterine stroma, genistein increased PR expression, as expected for an estrogenic compound. Interestingly, kaempferol did not reduce PR levels, as might be expected for a progestin (Toh et al, 2014). Kaempferol also increased amphiregulin A, a well-established progesterone stimulated gene.…”

“…However, in the presence of progesterone, both compounds acted as antagonists, and reduced progesterone-stimulated PRE/luciferase activity by >50% (Toh et al, 2012). In a follow up study, kaempferol failed to induce ERE/luciferase or PSA/luciferase activity, showing its specificity toward PR (Toh et al, 2014). In vivo genistein (a phytoestrogen) increased proliferation of the uterine epithelium as measured by Ki67 immunostaining, and kaempferol reduced the effect.…”