Estetrol prevents Western diet–induced obesity and atheroma independently of hepatic estrogen receptor α

Abstract

Estetrol (E4), a natural estrogen synthesized by the human fetal liver, is currently evaluated in phase III clinical studies as a new menopause hormone therapy. Indeed, E4 significantly improves vasomotor and genito-urinary menopausal symptoms and prevents bone demineralization. Compared to other estrogens, E4 was found to have limited effects on coagulation factors in the liver of women allowing to expect less thrombotic events. To fully delineate its clinical potential, the aim of this study was to assess the effect of E4 on metabolic disorders. Here, we studied the pathophysiological consequences of a western diet (42% kcal fat, 0.2% cholesterol) in ovariectomized female mice under chronic E4 treatment. We showed that E4 reduces body weight gain and improves glucose tolerance in both C57Bl/6 and LDLR-/- mice. To evaluate the role of hepatic ERα in the preventive effect of E4 against obesity and associated disorders such as atherosclerosis and steatosis, mice harbouring a hepatocyte-specific ERα deletion (LERKO) were crossed with LDLR-/- mice. Our results demonstrated that, whereas liver ERα is dispensable for the E4 beneficial actions on obesity and atheroma, it is necessary to prevent steatosis in mice. Overall, these findings suggest that E4 could prevent metabolic, hepatic and vascular disorders occurring at menopause, extending the potential medical interest of this natural estrogen as a new hormonal treatment.

Estrogen Receptor and Vascular Aging

“…In mice, E4 was found to confer protection against atherosclerosis ( Abot et al, 2014 ; Buscato et al, 2021 ), AngII-induced hypertension, and to promote FMR ( Guivarc’h et al, 2018 ). Interestingly, E4 selectively modulates nuclear ERα ( Abot et al, 2014 ) and was found associated to a unique transcriptional signature in female mice liver, different from E2 ( Buscato et al, 2021 ), suggesting that this estrogen shares common properties with SERMs. Because nuclear ERα actions may be preserved during aging compared to membrane signaling ( Guivarc’h et al, 2020 ), selective modulation by E4 could represent an attractive option for the prevention of CVD in postmenopausal women.…”

“…In addition to SERMs, estetrol (E4), a natural estrogen produced during pregnancy, has been authorized by the FDA for commercial distribution for contraception and is in phase III clinical trial for MHT. In mice, E4 was found to confer protection against atherosclerosis ( Abot et al, 2014 ; Buscato et al, 2021 ), AngII-induced hypertension, and to promote FMR ( Guivarc’h et al, 2018 ). Interestingly, E4 selectively modulates nuclear ERα ( Abot et al, 2014 ) and was found associated to a unique transcriptional signature in female mice liver, different from E2 ( Buscato et al, 2021 ), suggesting that this estrogen shares common properties with SERMs.…”

Estrogen Receptor Functions and Pathways at the Vascular Immune Interface

“…Another pharmacological challenge in the ER field is the development of agents that uncouple nuclear and membrane ERα activation. Estetrol (E4) has shown such a pattern [118]: this agent is less potent than E2 and shows some tissue selectivity as it induces limited effects on the liver [119]. E4 is under clinical development for a few indications including contraception and breast cancer [120,121].…”

Nuclear Receptors and Clock Components in Cardiovascular Diseases

“…Interestingly, this effect may be explained by an increase in circulating pro-atherogenic lipoproteins rather than by an impaired immune function [ 96 ]. As mentioned above, the estrogen receptor ERα is not only an important regulator of the clock machinery but also a critical atheroprotective factor [ 97 , 98 , 99 , 100 , 101 , 102 ], which may account for this gender-specific defense against circadian desynchronization-mediated atherogenesis. Furthermore, an increase in serum cholesterol levels was observed in ApoE −/− mice exposed to constant light, demonstrating here the impact of a severe clock disruption on cholesterol homeostasis [ 96 ].…”