Progestins initiate adverse events of menopausal estrogen therapy

Abstract

Objective: Recent reports, particularly the Women's Health Initiative, demonstrated that hormone therapy with combined estrogen plus progestin increased the incidence of heart attacks, stroke, blood clots, breast cancer and dementia in women over 65 years old. We investigated the role of synthetic progestins in initiating the adverse events associated with estrogen therapy. Methods: We used a fluorescence imaging technique, which allows video microscopic recordings of blood flow, blood vessel morphology and activities of various blood cells in a live animal. The acute peripheral and cerebrovascular responses were measured following intraperitoneal (5 or 10 mg) or intravenous (10 or 100 μg) administration of progesterone, synthetic progestins (medroxyprogesterone acetate and norethindrone) or estrogens (conjugated equine estrogens and 17β-estradiol). Results: In both peripheral and cerebral vasculature, synthetic progestins caused endothelial disruption, accumulation of monocytes in the vessel wall, platelet activation and clot formation, which are early events in atherosclerosis, inflammation and thrombosis. Natural progesterone or estrogens did not show such toxicity. Conclusions: The risks associated with combined estrogen plus progestin therapy may be a consequence of vascular actions of progestins. Using progestins with minimal vascular toxicity may lead to safer estrogen preparations for menopausal women.