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Raloxifene hydrochloride treatment leads to better outcomes than medroxyprogesterone acetate when paired with estrogen in ovariectomized cholesterol-fed rabbits.

The benefits of estrogen in cardiovascular system include a reduction in low-density lipoprotein cholesterol (LDL-C), decrease in LDL oxidation, and enhancement of vascular function [1]. Estrogen replacement therapy, however, has been linked to an increased risk of tissue-specific side effects including breast cancer and uterine cancer [2]. These issues have led to the development of hormone replacement therapy (HRT) which combines estrogen and progestin. Progestin can reverse endometrial hyperplasia induced by estrogen. The most commonly used progestin in HRT is medroxyprogesterone acetate (MPA), a synthetic progestin, although there is some evidence that the administration of MPA is not as beneficial as natural progesterone [3]. Findings from randomized placebo-controlled trials have demonstrated that the combination of estrogen and MPA does not confer cardiac protection and may increase the risk of coronary heart disease among healthy postmenopausal women, especially in the first year after initiation of hormone therapy. Furthermore, an increase in the risk of breast cancer was also found with this therapy [4]. Although the role of progestin remains poorly defined, it is possible that the coadministration of progestin could counteract the cardioprotective effects of estrogen [5]. In an effort to obtain the beneficial effects and reduce the risks associated with HRT, new replacement therapy formulations including selective estrogen receptor modulators (SERMs) have been developed. However, in a preclinical trial, treatment with bazedoxifene acetate (BZA), a new third-generation SERM, and conjugated equine estrogen (CEE) in combination did not show significant effects on plasma lipid profiles, and BZA treatment had no adverse