GENE-EXPRESSION OF HYPOTHALAMIC SOMATOSTATIN, GROWTH-HORMONE RELEASING-FACTOR, AND THEIR PITUITARY RECEPTORS IN HYPOTHYROIDISM

Thyroid hormones are important to growth in mammals and have been show n to rapidly stimulate the rate of GH gene transcription. In this stud y, we investigated whether thyroid hormones modulate GH secretion thro ugh their effects on the gene expression of GRF, somatostatin (SS), GR F receptor, and receptor subtype 2 for SS (SSTR(2)). Male adult Spragu e-Dawley rats were rendered hypothyroid with a single injection of pro pylthiouracil followed by methimazole in drinking water (0.02%) for 1 day to 12 weeks. Total RNA extracted from the anterior pituitary and h ypothalamus was analyzed by Northern hybridization. GH messenger RNA ( mRNA) level in the anterior pituitary was significantly reduced in the hypothyroid animals (P < 0.0001 vs. controls for all treatment durati on greater than or equal to 1 week). An increase in hypothalamic GRF m RNA level, by 2- and 4-fold, respectively, was seen after 3 and 12 wee ks of antithyroid treatment (both P < 0.001 vs. controls). Hypothalami c GRF content, studied in 12-week hypothyroid rats only, was decreased compared with controls (P < 0.05). A reduction in pituitary GRF recep tor mRNA. level was observed after 1 week of antithyroid treatment (P < 0.01 after 1 week, P < 0.001 after 3 weeks). Total hypothalamic SS c ontent and SS mRNA level in hypothalamic fragments consisting predomin antly of the paraventricular and periventricular nuclei became signifi cantly decreased (P < 0.05 and P < 0.005 respectively) after 12 weeks of antithyroid treatment. The reduction in SS gene expression in the p eriventricular nuclei was confirmed by in situ hybridization. No signi ficant change in the mRNA level of pituitary SSTR2 was observed up to 12 weeks of antithyroid treatment. In conclusion, we have demonstrated a reduction in the gene expression of GRF receptor and SS in the hypo thyroid rat. Our results suggest that the changes in hypothalamic GRF and SS gene expression in hypothyroid rats may be compensatory in natu re and are likely to be secondary to the reduction in GH synthesis and secretion in these animals. The reduction in basal and GRF-stimulated GH secretion in hypothyroidism can be explained by the observed reduc tion in GH and GRF receptor gene expression.