Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy

• Main Authors: Yoshinori Okamoto, Hideto Jinno, Shinji Itoh, Shinya Shibutani
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: estrogen; chlorination; mammary tumor; uterotrophic activity; hormone replacement therapy; DNA damage
• Online Access: https://www.mdpi.com/1422-0067/22/13/7222
• ISSN: 1661-6596; 1422-0067

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.