Rats treated during the first 5 days of life with pharmacologic doses of thyroxin (T 4 ) subsequently develop a variety of persistent endocrine abnormalities which are designated the "neo-T 4 syndrome." In the present experiments the rats treated neonatally were smaller and their pituitary, thyroid, adrenal, testicular and ventral prostate weights were decreased. Their plasma TSH concentration was reduced, the metabolic clearance rate of exogenous TSH was normal, and the calculated basal TSH secretion rate was reduced from 30.2 ± 3.3 /xU/min to 19.7 ± 1.4. In four different experiments to test the response to thyrotropin-releasing hormone (TRH) stimulation there was a subnormal secretion of TSH in rats with the neo-T 4 syndrome. The TRH content of the hypothalami from the neo-T 4 treated rats was measured by radioimmunoassay and found to be unexpectedly and significantly elevated from a mean control value of 5.58 ± 0.12 ng/ hypothalamus to 7.12 ± 0.39 ng. It is concluded that the reduction in circulating TSH in the neo-T 4 syndrome is not mediated by alterations in TSH metabolism but is secondary to subnormal pituitary responsiveness to TRH, possibly associated with a chronic deficiency of TRH secretion. (Endocrinology 95: 406, 1974)

Rats made thyrotoxic with large doses of thyroxine (T4) during the neonatal period (neo-T4) show many abnormalities as adults. These usually include impaired body, pituitary and thyroid growth, diminished pituitary and serum TSH concentrations, a diminished serum T4 and a diminished response to PTU challenge and to thyrotropin-releasing hormone (TRH) stimulation. Experiments are presented which show that these rats are hypersensitive to feedback regulation by T4 in a manner similar to that seen after bilateral anterior hypothalamic lesions. They show a subnormal response to PTU challenge and an excessive suppression of serum TSH and goiter growth after T4. Pituitary TSH was less depleted in neo-T4 rats when a small dose of T4 was given daily with PTU and pituitary TSH was more sensitive to suppression by a larger dose of T4 in the neo-T4 group. There was an impaired rebound increase in pituitary TSH following a single inhibitory dose of T4 injected into the adult hypothyroid rat. Although the hypothalamic TRH content is increased in the neo-T4 rat, the circulating concentration of TRH was found to be significantly decreased, supporting the theory that the defects observed in the neo-T4 rat may be the consequence of an impaired hypothalamic secretion of TRH.

When neonatal rats are made hyperthyroid with large doses of thyroxine during the first 5 days of life, they develop hypothalamopituitary, thyroidal and gonadal abnormalities that persist through life. When female rats, which have been treated neonatally, are subsequently mated to normal males, their offspring show unexpected gonadal and thyroidal defects, such as reduced weaning weight and delayed vaginal opening and first estrus in females; males show a significant increase in relative thyroid weight and a significant decrease in ventral prostate weight. Cross-fostering was done to separate prenatal from postnatal influences. Even more surprising was the finding that when the untreated female F₁ progeny were mated with normal males, the untreated F₂ progeny showed more defects and to a greater degree than those present in the maternal parent.

Propylthiouracil (PTU) administration to rats produced a progressive and parallel increase in the serum TSH concentration and the thyroid weight over a one year period, but the pituitary TSH content followed a biphasic curve declining markedly for 4 weeks, returning to the control level in 10 weeks and then continuing to rise until a level 5 times the control was achieved after 32 weeks. Either physiologic replacement doses or toxic doses of thyroxine (DL-T4) caused depression of serum TSH levels, significant as early as one hour after administration, followed by an increased pituitary TSH content to as much as 8 times the starting level after 10-60 hours. Thus, T4 did not appear to directly inhibit TSH synthesis during this interval. The reaction appeared to be independent of the duration of prior PTU administration or the initial size and TSH potency of the pituitary gland or the dose of T4 between 2.5 μg/100 g in one day and 40 μg/100 g daily for 4 days. PTU was not essential to this reaction because it also occurred in radiothyroidectomized rats which never received PTU. This rise in pituitary TSH during the period when TSH secretion was suppressed indicated a net pituitary TSH synthesis of as much as 61 mU/h. These values were compatible with those obtained by indirect calculations and consistent with the temporary persistence of the pre-existing TSH synthesis rate although the possibility of the stimulation of TSH synthesis by the T4 was not excluded.