Paradoxically subnormal serum T4 and T3 in dogs after prolonged excessive TSH stimulation of the thyroid caused by post-cAMP refractoriness of thyroid hormone secretion

Several studies have demonstrated that excessive TSH stimulation of the thyroid for hours to days makes the thyroid gland less responsive to TSH. In this study we extended the period of excessive TSH stimulation of dog thyroids in vivo to 28 days. Serum T4 and T3 were considerably elevated initially but then gradually declined and became paradoxically subnormal after 3 weeks. This was not caused by production of TSH antibodies. At day 28 the thyroid lobes were perfused for measurements of T4 and T3 secretion. Both the basal secretion rate and the response to TSH were considerably lower after TSH pretreatment than in control dogs. This was not due to reduction of TSH receptors because the response to forskolin was similarly reduced. The cAMP response to TSH and forskolin was not blunted by TSH pretreatment. The total amount of thyroglobulin in the thyroid was not significantly altered by TSH pretreatment, but the T4, T3, and iodine content of thyroglobulin was reduced to 50% to 70% of control levels. Such a moderate reduction in hormone content could not explain the development of subnormal serum T4 and T3 during intensive TSH stimulation. Apparently one or more processes involved in thyroid hormone secretion after cAMP generation were made so refractory to TSH by the prolonged excessive stimulation, that a state of biochemical hypothyroidism developed.