Distinct Sexual Dimorphism in the Effect of Hypothyroidism on the Expression of the Growth Hormone Receptor and Growth Hormone-Binding Protein Gene in Rat Liver

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Abstract
Impairment of growth is a hallmark of hypothyroidism in animals. The ability of the thyroid hormone-thyroid hormone receptor complex to regulate gene transcription may be relevant to the growth impairment associated with hypothyroidism. To study the role of thyroid hormone in the expression of the GH receptor (GHR) and GH-binding protein (GHBP) gene, we examined the serum and liver tissue of female and male hypothyroid (thyroidectomized), thyroxine-treated thyroidectomized and euthyroid control rats. Compared to the control and to the thyroxine-treated group, the hypothyroid rats had significantly lower serum levels of thyroxine, increased levels of TSH, and decreased rates of weight gain. GHR and GHBP mRNA levels in liver were estimated by ribonuclease protection assays. In female rats, the levels of hepatic GHR and GHBP mRNA were increased in the hypothyroid group compared to euthyroid controls (p < 0.001 for GHR and p < 0.05 for GHBP). In contrast, in males the hypothyroid state was associated with decreased levels of GHR (p < 0.001) and GHBP (p < 0.001) mRNA levels compared to euthyroid controls. In both females and males, administration of thyroxine for a period of 2 weeks to the thyroidectomized rats prevented these changes in GHR and GHBP mRNA levels in liver. The differences observed between females and males could not be attributed to differences in the circulating levels of GH at sacrifice (female vs. male, 9.9 ± 1.3 vs. 13.9 ± 6.5 ng/ml). We conclude that (1) thyroid hormone affects the transcription of the GHR/GHBP gene; (2) there is a distinct sexual dimorphism in the effect of hypothyroidism on the expression of the GHR/GHBP gene, and (3) this effect is reversible following amelioration of the hypothyroid state. We speculate that regulation of expression of the GHR/GHBP gene by thyroid hormones involves multiple thyroid response elements that have opposite effects depending on the status of other factors such as sex hormones.