Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis

Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver, and the physiological role of this hormone is unknown. Interestingly, E4 was recently evaluated in preclinical and phase II-III clinical studies in combination with a progestin, with the advantage to not increase the circulating level of coagulation factors, at variance to oral estradiol or ethinylestradiol. Here, we evaluated the effect of E4 on hemostasis and thrombosis in mouse. Following chronic E4 treatment, mice exhibited a prolonged tail-bleeding time and were protected from arterial and also venous thrombosis in vivo. In addition, E4 treatment decreased ex vivo thrombus growth on collagen under arterial flow conditions. We recently showed that E4 activates uterine epithelial proliferation through nuclear estrogen receptor (ER) alpha. To analyze the impact of nuclear ER alpha actions on hemostasis and thrombosis, we generated hematopoietic chimera with bone marrow cells deficient for nuclear ER alpha. E4-induced protection against thromboembolism was significantly reduced in the absence of hematopoietic nuclear ER alpha activation, while the increased tail-bleeding time was not impacted by this deletion. In addition to its liver friendly profile described in women, our data shows that E4 has anti-thrombotic properties in various mouse models. Altogether, the natural fetal estrogen E4 could represent an attractive alternative to classic estrogens in oral contraception and treatment of menopause.