The Bioidentical Hormone Debate: are Bioidentical Hormones (estradiol, estriol, and Progesterone) safer or More efficacious than Commonly used synthetic Versions in Hormone replacement therapy? Abstract Background: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective. Objective: This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the com- monly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease. Methods: Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected. Results: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clini- cal data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone. Conclusion: Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal- derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly. Keywords: bioidentical hormones; synthetic hormones; hormone replacement therapy; estriol; progesterone; conjugated equine estrogens; medroxyprogesterone acetate; breast cancer; cardiovascular disease.   Introduction The relative safety of bioidentical hormone replacement compared with traditional synthetic and animal-derived ver- sions, such as conjugated equine estrogens (CEE), medroxy- progesterone acetate (MPA), and other synthetic progestins is the subject of intense debate. According to The Endocrine Society Position Statement, there is little or no evidence to support the claim that bioidentical hormones are safer or more effective than the commonly used synthetic versions of hormone replacement therapy (HRT).1 Furthermore, the US Food and Drug Administration (FDA) has ordered pharmacies to stop providing estriol, stating that it is a new, unapproved drug with unknown safety and effectiveness. Nevertheless, estriol has been used for decades without reported safety concerns and is a component of medications approved for use worldwide. The FDA has acknowledged that it is unaware of any adverse events associated with the use of compounded medications containing estriol, and US Congress is considering a resolution (HR342) to reverse the FDA’s decision to restrict its use. 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