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Thyroid Hormone and Growth Hormone Interact to Regulate Insulin-Like Growth Factor-I Messenger Ribonucleic Acid and Circulating Levels in the Rat^*

MATTHIAS WOLF, SIDNEY H. INGBAR and ALAN C. MOSES

Department of Medicine, Charles A. Dana Research Institute, and the Harvard-Thorndike Laboratory, Beth Israel Hospital, Harvard Medical School Boston, Massachusetts 02215

Address requests for reprints to: Dr. Alan C. Moses, Department of Medicine, SL436, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215.

Abstract

Thyroid hormones influence growth in part by altering the secretion and effects of GH. GH, in turn, mediates its effects by regulating the synthesis and secretion of insulinlike growth factor-I (IGF-I). IGF-I is a pleiotropic growth factor that is synthesized by many tissues and acts on many tissues to regulate both cellular replication and differentiated function. We have studied the direct effects of thyroid hormones and the combined effects of thyroid hormones and GH on the regulation of IGF-I synthesis and secretion in hypophysectomized (hypox) rats in viuo. All rats, except normal littermates and a hypox control group, received 100 ng hydrocortisone/100 g BW for 10 days. Circulating IGF-I was measured by specific RIA (normal rats, 1 U/ml), and hepatic IGF-I mRNA was measured by Northern blot hybridization with an antisense cRNA probe. 1) Hypox rats treated with hGH (75 ng, ip, twice daily) for 10 days gained 17 g BW vs. 70 g for normal littermates. GH markedly increased hepatic IGF-I mRNA and circulating IGF-I (0.52 ± 0.14 U/ml 12 h after the last GH injection vs. 0.03 ± 0.02 for hypox controls). 2) T₄ (1 Mg/100 g BW, ip) for 10 days increased neither weight, hepatic IGF-I mRNA, nor circulating IGF-I. 3) Rats treated with T₄ for 10 days followed by a single injection of 1 mg GH, ip, increased hepatic IGF-I mRNA and circulating IGF-I levels comparably as in rats receiving acute GH alone (IGF-I, 12 h, 0.31 ± 0.09 us. 0.36 ± 0.06 U/ml). 4) Hypox rats treated with a single injection of T₃ (1.5 Mg/100 g BW, ip) had slightly increased hepatic IGF-I mRNA, but showed no significant change in circulating IGF-I levels. 5) A single injection of T₃ plus GH to hypox rats increased IGF-I mRNA levels above those in rats injected with GH alone and increased serum IGFI levels to 0.48 ± 0.12 U/ml compared to 0.36 ± 0.06 U/ml for GH alone. 6) After 10 days of GH treatment, a single injection of T₃ lowered both hepatic IGF-I mRNA and circulating IGF-I (0.52 ± 0.14 to 0.16 ± 0.06 U/ml, 6 h after T₃). These studies demonstrate that thyroid hormones have relatively little direct effect on IGF-I synthesis but can have major effects on GHstimulated IGF-I synthesis and secretion. The pattern of these effects depends on the integrity of the pituitary gland, prior exposure of the liver to GH and/or thyroid hormones, and the temporal relationship between GH and thyroid hormone administration.

Footnotes

^* Presented in part at the Annual Meeting of The Endocrine Society, June 21–24, 1989, Seattle, WA. This work was supported by NIH Grants DK-18416 and DK-37663.

Current address: Medizinische Kern- und Poliklinik, Universitats- Krankenhaus Eppendorf, Martinistrasse 52, 2000 Hamburg 20, West Germany.

Deceased.

Received June 21, 1989.

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