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Triiodothyronine and Follicle-Stimulating Hormone, Alone and Additively Together, Stimulate Production of the Tissue Inhibitor of Metalloproteinases-1 in Cultured Human Luteinized Granulosa Cells

Endocrine Research Unit (S.G., Z.K.) and Department of Obstetrics and Gynecology (M.D., H.A.), Carmel Medical Center; and the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology (H.A., Z.K.), Haifa, Israel

Address all correspondence and requests for reprints to: Z. Kraiem, Endocrine Research Unit, Carmel Medical Center, 7 Michal Street, Haifa 34362, Israel.

Thyroid disorders have been frequently associated with menstrual disturbances and impaired fertility. To characterize the nature of thyroid hormone action in the ovary, the direct effects of T₃-gonadotropin interactions were investigated in vitro using a culture system of human luteinized granulosa cells in serum-free medium. Although FSH alone was devoid of any significant effect on cell proliferation, it inhibited T₃-stimulated cell growth. The electrophoretic profiles of the radiolabeled proteins induced by the different hormonal treatments revealed similarity in overall protein patterns but differences in intensity of labeling. Human CG, alone or combined with T₃, had no major influence on the total intensity of labeling compared with control, whereas T₃ or FSH alone reduced total labeling intensity but a 30,000 Da protein band was increased. FSH combined with T₃ augmented the total intensity of labeling, including the 30,000-Da protein band. Western blot analysis revealed the presence of the tissue inhibitor of metalloproteinases-1 (TIMP-1), mol wt 30,000, known to play a key role in ovarian function. TIMP-1 was dose dependently stimulated by T₃ and FSH, and an additive effect was obtained when both hormones were combined.

This is the first report of TIMP-1 modulation by FSH in ovarian cells and of an effect by thyroid hormone on TIMP-1 levels. The study shows TIMP-1 induction in human ovarian cells not only by FSH, i.e. via a probable protein kinase A mechanism, but also demonstrates an additional mode of TIMP-1 hormonal induction: via thyroid hormone stimulation, acting by modulation of gene transcription. The present study provides novel data on TIMP-1 hormonal modulation and of direct T₃ in vitro ovarian effects that may account for the in vivo indications of a thyroid-ovarian connection.

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