2-Methoxyestradiol, an endogenous estrogen metabolite, induces thyroid cell apoptosis.
The etiology of autoimmune thyroid diseases is unclear; however, the extreme female predominance suggests that sex hormones may have a pathogenic role. 2-Methoxyestradiol (2-ME) is present in the serum of women during the ovulatory and luteal phases of the menstrual cycle, and during pregnancy. We investigated the actions of 2-ME and estrogen on thyroid follicular cells. 2-ME induced dramatic changes in cell morphology and decreased the viability of the cells, as well as disrupted the structural integrity of cultured thyroid follicles. Flow cytometric analysis showed that 2-ME halted cell proliferation by arresting the cells in the G2/M cell-cycle compartment. Prolonged exposure to 2-ME led to apoptosis and to increased release of the autoantigen thyroid peroxidase (TPO). 17beta-estradiol failed to produce a similar effect even in 40-fold molar excess to 2-ME. Co-treatment with estrogen receptor antagonists did not alter the 2-ME effect, indicating that 2-ME was not operating through a classic nuclear estrogen receptor. In conclusion, this study indicates that 2-ME induces G2/M cycle arrest, apoptosis and the disruption of thyroid follicles. This process results in the release of thyroid antigens that may play a role in high incidence of thyroid autoantibodies and autoimmune thyroid disease in women.
Department of Internal Medicine, University of Michigan Medical School, 9240 MSRB III, Ann Arbor, MI 48109-0666, USA.
S H
SH
Wang
A
A
Myc
R J
RJ
Koenig
J D
JD
Bretz
P L
PL
Arscott
J R
JR
Baker
D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D051381:Rats; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects*; D013967:Thyroiditis, Autoimmune / Q000209:etiology
D001324:Autoantigens; D004967:Estrogens; D004958:Estradiol; D000077584:2-Methoxyestradiol; D007453:Iodide Peroxidase