Effect of chronic estradiol plus progesterone treatment on experimental arterial and venous thrombosis in mouse

Postmenopausal hormone replacement therapy (HRT) with estrogen plus progestogens is the first line therapy to treat menopausal symptoms. The progestogen is added to estrogen to reduce or eliminate the excess risk of endometrial cancer due to the unopposed effect of estrogen. Whereas progestin clearly opposes the proliferative and deleterious long-term actions of estrogen on the endometrium, the interference of progestin on the other estrogen action remains unclear. We previously reported that chronic subcutaneous 17 alpha-estradiol (E2) in mice decreases platelet responsiveness, prolongs the tail-bleeding time and protects against acute thromboembolism. Here, we report the tissue-specific interference of progesterone (P4) on the action of E2 in ovariectomized mice. We first confirm that, in our experimental conditions, P4 attenuates the proliferative action of E2 on the uterus and the effects of E2 on vagina weight and lubrication. We then studied the effect of E2 combined with P4 on hemostasis and thrombosis in vivo in mice and found that P4 did not interfere with the main actions of E2 on platelets, bleeding time and arterial and venous thrombosis. Thus, whereas activation of progesterone receptor interferes with the action of E2 on its classic sex targets, P4 appears to have minimal effect on the hemostasis and thrombosis actions of E2, supporting the prominent role of estrogens and the accessory role of natural progestin on the extra-reproductive cells and tissues involved in thrombosis.