SEVERE BUT NOT MILD ALTERATIONS OF THYROID-FUNCTION MODULATE THE DENSITY OF THYROID-STIMULATING HORMONE RECEPTORS IN THE RAT-THYROID GLAND

TSH initiates its action by binding to specific membrane receptors thyroid cells and induces activation of the adenylate cyclase-cAMP cascade. The factors involved in the regulation of TSH receptors are poorly known, except for the TSH dose-dependent regulatory effect. The fact that the thyroid gland of Graves' patients has a normal density of TSH receptors with suppressed TSH and high T-4 and T-3 levels suggests a modulatory role of thyroid hormones on TSH receptors. To evaluate this hypothesis, the density of TSH receptors and the activity of adenylate cyclase were determined in the thyroid membranes from hyperthyroid and hypothyroid adult male rats; they were rendered hyperthyroid either with bovine TSK, TRH, or T-3 for 7 days and hypothyroid by propylthiouracil treatment or by hypophysectomy. NaCl was given to the control group. Plasma T-4, T-3, and TSH were also quantified. Bovine TSH and TRH treatments induced mild hyperthyroidism with a small goiter and a 50% reduction in the density of TSH receptors due to hyperstimulation of the gland by either exogenous or endogenous high TSH levels. Severe hyperthyroidism caused by T-3 treatment resulted in low T-4, high T-3, and suppressed TSH thyrocyte stimulation; it was associated with a significant increase in the number of TSH receptors (29.6 +/- 2.3 vs. control 17.9 +/- 1.7 mU TSH/mg protein). These last results suggest a putative positive effect of T-3 on TSH receptors. To confirm this effect, hypothyroid rats were investigated. Severe primary hypothyroidism due to propylthiouracil treatment was associated with a large goiter, high plasma TSH levels (11.8 +/- 1.2 vs. control 1.5 +/- 0.1 mU TSH/ml), low plasma T-4 and T-3, and a 70% reduction in TSH receptors, confirming the down-regulatory effect of high TSH on the thyroid cell. However, in hypophysectomized rats, a 45% reduction in the density of TSH receptors was also observed in the absence of TSH. Injections of either TSH or T-3 to these hypophysectomized rats restored a normal number of TSH-binding sites, and simultaneous TSH and T-3 treatments resulted in a mildly additive effect in the number of TSH receptors, which was slightly greater than that of the controls. No important changes were found in the adenylate cyclase activity in the thyroid membrane preparations from hyperthyroid and hypothyroid rats despite variations in the density of TSH receptors. In conclusion, the present data show that: 1) when T-3 is in excess and TSH secretion is suppressed, there is a positive modulatory role of T-3 on the expression of TSH receptors; and 2) TSH has either a positive or a negative modulatory role on its own receptors, according to both its concentration and thyroid gland activity.