Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy.

Yoshinori Okamoto,Shinya Shibutani,Shinji Itoh,Hideto Jinno

doi:10.3390/ijms22137222

Abstract

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.

Highlights

Human estrogens are used in hormone replacement therapy (HRT) to alleviate menopausal symptoms and protect against osteoporosis [1,2]
The mechanism underlying estrogen-induced carcinogenesis has not been fully explored, but both proliferative effects mediated through the estrogen receptor and/or DNA damage induced by human estrogen metabolites are significant factors in the process [9,10,11]
When dissected August Copenhagen Irish (ACI) rats treated with chlorinated estrogens at the end of experiment, no significant abnormality was observed in other organs including ovary and uterus

Summary

Introduction

Human estrogens are used in hormone replacement therapy (HRT) to alleviate menopausal symptoms and protect against osteoporosis [1,2]. Long-term HRT increases the incidence of breast [3,4,5,6] and endometrial cancers [7]. The risk of these cancers is correlated with the duration of HRT [4,5,6,8]. DNA damage has been detected in the tissues of rodents treated with human estrogens [12,13,14,15]. Human estrogens are primarily metabolized by cytochrome P450 enzymes to form 2- and 4-hydroxyestrogens (2- and 4-OHE) [16] (Figure 1). The catecholestrogens are oxidized further to 2,3-quinone and/or 3,4-quinone by P450 enzymes or peroxidase [16,17,18]

Methods

Results

Conclusion