Hypothyroidism leads to a decreased activity of the low-density lipoprotein (LDL) receptor, which contributes to the hypercholesterolemia frequently seen during hypothyroidism. It is not known whether the decreased activity of the LDL receptor is directly due to the absence of thyroid hormone, or secondary to a deficiency of growth hormone (GH). Therefore, the effect of GH administration on LDL receptor activity was studied in hypothyroid rats. Following induction of hypothyroidism, the level of LDL receptor mRNA was significantly decreased in liver homogenates to 31 % +/- 6% of the control value. LDL binding to liver cell membranes and plasma membranes decreased during hypothyroidism to approximately 65% of the control value. The effect of hypothyroidism on the hepatic LDL receptor was reflected in a significantly increased half-life of (125)I-LDL of 29 hours in controls versus 48 hours in hypothyroid rats. Treatment of hypothyroid rats with human GH (hGH) resulted in normalization of both the amount of hepatic LDL receptor mRNA and LDL binding on liver cell membranes. The plasma half-life of human (125)I-labeled LDL decreased during GH substitution but did not normalize. GH treatment significantly reduced plasma LDL cholesterol levels by 36% (P < .05, n = 8), to levels that were still higher than in control animals. These data indicate that at least part of the decreased LDL receptor activity during hypothyroidism is secondary to GH deficiency.