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

Abstract

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 17α-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.

Effects of Estrogens on Platelets and Megakaryocytes

“…Our team has reported that a three-week E2 treatment of ovariectomized mice (200 μg/kg/day) slightly reduced the platelet count [24]. In mice treated by a chronic subcutaneous administration of E2 (80 μg/kg/day) alone or in addition to progesterone (P4, pellet of 10 mg) during the three weeks, platelet count was not significantly affected in comparison to ovariectomized mice [25]. In addition, thrombocytopenia was induced after a three-week treatment by intraperitoneal injection of antimouse GPIbαantibody.…”

“…The platelet count recovery was measured fifteen days after this immune-induced thrombocytopenia and was similar in ovariectomized mice, E2, and E2 + P4 treated-mice. In conclusion, platelet production did not appear to be impacted by the treatments [25].…”

Effects of conjugated estrogen and bazedoxifene on hemostasis and thrombosis in mice

“…The Vevo2100 high-frequency ultrasound system (HFUS) (Visualsonics, Toronto, Canada) was used to monitor thrombus formation in the right carotid artery of mice as previously described (26). This micro imaging system consists of a single element probe of 18-38 MHz frequency.…”

“…We recently attempted to investigate the complexity of sex hormones actions on hemostasis and thrombosis in mice (24, 25, 26). We reported that chronic E2 (estradiol-17β) treatment administered subcutaneously increased tail-bleeding times and protected animals against collagen/epinephrine-induced thromboembolism and carotid artery thrombosis in comparison to ovariectomized or sham-operated mice (24).…”

Herpes Simplex Virus Type 2 Infection-Induced Expression of CXCR3 Ligands Promotes CD4+ T Cell Migration and Is Regulated by the Viral Immediate-Early Protein ICP4

“…In brief, female BALB/c mice (6–8 wk old) were purchased from Beijing HFK Biotechnology (Beijing, China) and maintained in specific pathogen–free conditions with food and water supplied. Seven days prior to challenge, each mouse was injected with 2 mg progesterone in intraperitoneal, subcutaneous, and intramuscular sites to ensure that each mouse rapidly entered the estrous cycle (23). After the estrous cycle, the mouse vaginal mucosal epithelia became thinner and were more susceptible to HSV-2.…”