CONTROL OF GROWTH-HORMONE SYNTHESIS IN CULTURED GH1 CELLS BY 3,5,3'-TRIIODO-L-THYRONINE AND GLUCOCORTICOID AGONISTS AND ANTAGONISTS - STUDIES ON THE INDEPENDENT AND SYNERGISTIC REGULATION OF THE GROWTH-HORMONE RESPONSE

We have previously reported that the thyroid hormone induction of growth hormone synthesis and mRNA in cultured GH1 cells, a rat pituitary cell line, is modulated by the thyroid hormone nuclear receptor. In addition, the induction of growth hormone synthesis and mRNA by glucocorticoid in GH] cells is highly dependent on thyroid hormone. In this study, using serum free defined medium and glucocorticoid agonists, antagonists, and partial agonist-antagonists, we have further defined the multihormonal control of the growth hormone response. Without glucocorticoid, 3, 5, 3'-triiodo-L-thyronine (L-triiodothyronine) induced a four-to sixfold increase in growth hormone synthesis within 24 h of incubation, and this increased to 10- to 12-fold by 48 h. Without L-triiodothyronine, Cortisol or dexamethasone induced a small growth hormone response which was only observed after 24-48 h of incubation. In contrast, the growth hormone response of cells incubated with L-triiodothyronine plus Cortisol was two- to fivefold greater than L-triiodothyronine alone and demonstrated induction kinetics which paralleled that of thyroid hormone. With L-triiodothyronine a half-maximal increase in growth hormone induction occurred at 3.5 nM dexamethasone and 12 nM Cortisol. Progesterone alone induced no growth hormone response but inhibited the small glucocorticoid induced response observed after 48 h of incubation. With L-triiodothyronine, progesterone induced a partial submaximal response which was 1.5-fold greater than with L-triiodothyronine alone. In addition, increasing progesterone concentrations inhibited the growth hormone response induced by L-triiodothyronine plus Cortisol to that observed for L-triiodothyronine plus progesterone. 17a-Methyltestosterone, a pure glucocorticoid antagonist, inhibited the growth hormone response of cells incubated with L-triiodothyronine plus Cortisol to that of thyroid hormone alone. The relative response elicited by the glucocorticoid agonists and antagonists paralleled the relative affinity of these steroids for the glucocorticoid receptor. Quantitation of growth hormone mRNA indicated that 17a-methyltestosterone lowered the glucocorticoid component of the growth hormone response by controlling growth hormone mRNA levels. These results are compatible with a concerted pretranslational control mechanism in which the nuclear associated receptors for thyroid and glucocorticoid hormones act independently as well as synergistically to regulate the growth hormone response. © 1979, American Chemical Society. All rights reserved.