Evidence that the Major Physiological Role of TRH in the Hypothalamic Paraventricular Nuclei May Be to Regulate the Set-Point for Thyroid Hormone Negative Feedback on the Pituitary Thyrotroph

Abstract

If a primary physiologic action of TRH is to regulate the set-point for negative feedback, a sudden drop in plasma thyroid hormone concentration should stimulate the same rate of in vivo increase in TSH secretion from normal and TRH-deprived thyrotrophs. To test this hypothesis, 3 experiments were performed in which young adult female rats were divided into 3 groups of 6-10 rats each: intact controls, hypothalamic paraventricular nuclei ablation (PVN) and sham-ablated (Sham). Sham and PVN rats were thyroparathyroidectomized 2-4 weeks after brain lesions and serial blood samples taken in all groups at frequent intervals from 0 to 58 days post-thyroidectomy. Plasma TSH was significantly higher than in intact controls by 3 days post-thyroidectomy in both the Sham and PVN groups (p < 0.05). At 14 days PVN plasma TSH was 4 × higher and at 30 days 8 × higher than in intact controls and remained consistently at 50% of that of the Sham group. There was no statistical difference between PVN and Sham in the rate of increase in TSH. Plasma T4 was 40% lower in PVN than in Sham at the time of thyroidectomy and became undetectable in both by day 3. The prompt parallel rate of rise of plasma TSH in Sham and PVN groups following thyroidectomy indicates that a primary physiologic action of TRH in the thyrotroph is to control the set-point for thyroid hormone negative feedback on TSH secretion. However, this does not appear to be the sole mechanism by which TRH influences TSH secretion since even by 2 months post-thyroidectomy, when plasma TSH concentration had plateaued, plasma TSH was 50% lower in PVN than in Sham rats.

Hypothalamic thyrotropin-releasing hormone mRNA responses to hypothyroxinemia induced by sleep deprivation

“…Serum TSH concentrations in PVN-lesioned animals show only 30% of the increase seen in thyroidectomized rats with intact PVN (30,57). This is associated with a dramatically blunted increase in TSH subunit mRNA levels in anterior pituitary in response to hypothyroidism of 2-4 wk duration (57).…”

“…Many days also are required to observe increased prepro-TRH mRNA in experimental models of thyroid hormone depletion. T 4 is diminished after chemical or surgical thyroidectomy to a concentration much lower than that observed in sleep-deprived rats within 3-6 days (29,30,38) without an appreciable increase in TRH transcript levels in the PVN (38). Thereafter, prepro-TRH mRNA begins to rise (38), concurrent with TRH depletion in the median eminence and much of the hypothalamus (63).…”

“…Modest declines of serum T 4 by 11-24% during 4 days of low-dose methylmercaptoimidazole or propylthiouracil treatment, with little or no change in serum T 3 , are associated with three-to fourfold increases in serum TSH (40). Severalfold increases in TSH occur by 4-6 days after thyroidectomy treatments (29,30,38), before any detectable change in prepro-TRH mRNA expression (38). As experimental hypothyroidism is prolonged beyond this initial period, TSH levels increase progressively to more than 10-fold euthyroid levels (29,30,38).…”

“…Severalfold increases in TSH occur by 4-6 days after thyroidectomy treatments (29,30,38), before any detectable change in prepro-TRH mRNA expression (38). As experimental hypothyroidism is prolonged beyond this initial period, TSH levels increase progressively to more than 10-fold euthyroid levels (29,30,38). Maintenance of 50% of normal plasma T 4 in thyroidectomized animals by supplementary T 4 administration for 14 days is associated with an eight-to ninefold elevation of plasma TSH concentration (16).…”

Congenital Hypothyroidism (Cretinism) in neuroD2-Deficient Mice

“…TSH is transported in the bloodstream to the thyroid gland, where it positively regulates thyroglobulin, the precursor of thyroxine. Thyroxine binds to thyroid hormone receptors to control basal metabolic rate, growth, and maturation and affects almost every organ in the body (6,11). Thyroxine also negatively regulates TRH.…”