Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE₂) or 4-chloro-17β-estradiol (4-ClE₂) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E₂) frequently induced mammary tumors while both 2-ClE₂ and 4-ClE₂ did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE₂) nor 4-chloro-17α-ethinylestradiol (4-ClEE₂) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E₂ may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE₂ and 4-ClE₂ administered subcutaneously and 2-ClEE₂ and 4-ClEE₂ given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E₂. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.