Combination of raloxifene, aspirin and estrogen as novel paradigm of hormone replacement therapy in rabbit model of menopause

Aim: To assess a novel hormone replacement therapy (HRT) paradigm using raloxifene, aspirin combined with estrogen in rabbit model of menopause. Methods: Female New Zealand white rabbits were ovariectomized or sham-operated. The ovariectomized rabbits were divided into 7 groups: estradiol valerate (E 2 ), raloxifene, aspirin, E 2 /raloxifene, E 2 /aspirin, E 2 /raloxifene/aspirin and vehicle. Two weeks after the operation, the rabbits were administered the above drugs for 12 weeks. Then, the mammary glands were examined histologically, uterus was weighted, and blood sample was collected for analyzing the levels of estrogen, serum lipids and monocyte chemoattractant protein (MCP)-1, and platelet aggregation. The aortic tissue was examined morphometrically. Results: Compared with E 2 0.1 mg·kg −1 ·d −1 treatment alone, the pairing of raloxifene 10 mg·kg −1 ·d −1 with E 2 significantly decreased the extent of mammary gland branches and ducts (5.53%±1.23% vs 15.4%±2.17%, P <0.01), as well as the uterine weight (2.16±0.35 g vs 4.91±0.75 g, P <0.01). However, E 2 /raloxifene or E 2 alone treatment significantly stimulated platelet aggregation relative to vehicle group. Addition of aspirin 5 mg·kg −1 ·d −1 reduced platelet aggregation to almost the same level as the vehicle group. E 2 treatment exerted a positive effect on serum lipids and MCP-1, and a regression in aortic intimal plaque size compared to the vehicle. Raloxifene reinforced the positive effects of E 2 . Conclusion: The combination of raloxifene, aspirin and E 2 exhibits positive lipid, MCP-1 and atherosclerotic responses with minimal stimulation of breast and uterine tissues as well as platelet aggregation in a rabbit model of the menopause.