Growth hormone response to thyrotropin-releasing hormone in the urethane-anesthetized rat: effect of thyroid status

To evaluate the role of thyroid hormones in regulation of the GH-stimulatory effects of TRH and human pancreatic GH-releasing factor (hpGRF-40), we studied the plasma GH responses to these secretagogues under conditions of thyroid hormone deprivation and replacement in the urethane-anesthetized rat. In euthyroid control rats, TRH (1 microgram/kg) elicited a small transient rise in plasma GH, which peaked at 2-5 min and returned to basal by 20 min. In chronically hypothyroid rats (10 weeks after thyroidectomy), intrapituitary GH was markedly depleted to less than 0.1% of normal, and TRH was completely ineffective in eliciting a plasma GH response to TRH. In chronically hypothyroid rats given T4 (20 micrograms/kg daily) for 4 days, intrapituitary GH was partially repleted, and the GH response to TRH was markedly enhanced compared to that in euthyroid rats. The extent to which the GH response to TRH was enhanced by chronic hypothyroidism, followed by short term T4 treatment, depended on the duration of T4 administration. The plasma GH response was greatest after 1-3 days of T4 treatment; treatment for 7 days, on the other hand, suppressed the GH response to below that of euthyroid rats. The minimal duration of hypothyroidism which, in combination with short term (2 days) T4 treatment, enhanced the plasma GH response to TRH, was 6 weeks, with 8 weeks or longer being optimal. The effect of TRH on plasma GH was dose dependent in thyroidectomized rats given T4 for 2 days; the lowest maximally stimulatory dose was 10 times less than that in the euthyroid rat (1 vs. 10 micrograms/kg). The GH-stimulatory effect of TRH in thyroidectomized rats given T4 for 2 days was abolished by the simultaneous administration of SRIF (40 micrograms/kg). That the failure of TRH to stimulate GH release in the chronically hypothyroid rat may have been the consequence of a depletion of intrapituitary GH available for release was suggested by the finding that in parallel studies, hpGRF-40, a more potent stimulator of GH release in the euthyroid rat, was also without effect. In contrast to the GH response to TRH, the GH response to hpGRF-40 was only partially restored by T4 treatment of chronically hypothyroid rats for 2 days. We conclude that chronic thyroid hormone deficiency selectively sensitizes the somatotroph to TRH. Short term thyroid hormone replacement is needed to replete intrapituitary GH and allow the expression of this enhanced GH secretory response to TRH. More prolonged treatment with T4, on the other hand, appears to desensitize the somatotroph to TRH.