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Thyroid Hormone Signaling in Human Ovarian Surface Epithelial Cells

Centre for Reproductive Biology, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Stephen G. Hillier Ph.D., The Queen’s Medical Research Institute, Centre for Reproductive Biology, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: s.hillier{at}ed.ac.uk.

Context: Ovarian surface epithelial (OSE) cells express multiple nuclear hormone receptor genes, including those encoding thyroid hormone and estrogen receptors (TR and ER, respectively). Ovarian cancer is hormone-dependent, and epidemiological evidence links hyperthyroidism, inflammation of the ovarian surface, and increased risk of ovarian cancer.

Objective: The objective of this study was to assess T₃ action on human OSE cells in vitro, asking 1) is there evidence for (pre)receptor control, 2) is T₃ inflammatory, and 3) does T₃ affect ER expression?

Design: Immunohistochemical analysis of fixed human ovaries and in vitro analysis of human OSE primary cell cultures were performed.

Patients: Twelve women aged 29–50 yr (median, 41 yr) undergoing elective gynecological surgery for nonmalignant conditions were studied.

Results: Messenger RNA transcripts for TR1, TR2, TRß1, and T₃ activating deiodinase 2 and inactivating deiodinase 3 were present in primary OSE cell cultures by RT-PCR. TR and TRß proteins were also localized to intact OSE by immunohistochemistry. Treatment of OSE cell cultures for 24 h with T₃ caused dose-dependent mRNA expression of inflammation-associated genes: cyclooxygenase-2, matrix metalloproteinase-9, and 11ßhydroxysteroid dehydrogenase type 1, determined by quantitative RT-PCR. Finally, treatment with T₃ dose dependently stimulated ER mRNA expression without affecting ERß1 or ERß2.

Conclusion: The ovarian surface is a potential T₃ target. T₃ exerts direct inflammatory effects on OSE cell function in vitro. OSE cell responses to T₃ include increased expression of ER mRNA, which encodes the ER isoform most strongly associated with ovarian cancer. This could help explain suggested epidemiological links between hyperthyroidism and ovarian cancer.

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