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The late effects of neonatal hyperthyroidism upon the feedback regulation of TSH secretion in rats
Insights
Neonatal thyroxine exposure in rats leads to adult thyroid dysfunction and hypersensitivity to T4 feedback. Impaired hypothalamic thyrotropin-releasing hormone (TRH) secretion may explain these thyroid abnormalities.
Area of Science:
- Endocrinology
- Neuroendocrinology
- Developmental Biology
Background:
- Neonatal exposure to excessive thyroxine (T4) induces lasting abnormalities in rat thyroid function.
- Adult rats exposed to thyroxine neonatally (neo-T4) exhibit impaired growth, pituitary, and thyroid function, with altered TSH and T4 levels.
- These neo-T4 rats show diminished responses to propylthiouracil (PTU) challenge and thyrotropin-releasing hormone (TRH) stimulation.
Purpose of the Study:
- To investigate the hypersensitivity to T4 feedback regulation in adult rats neonatally exposed to thyroxine.
- To explore the role of hypothalamic TRH secretion in the observed thyroid abnormalities.
- To characterize the pituitary and serum thyroid-stimulating hormone (TSH) responses to T4 and PTU in neo-T4 rats.
Main Methods:
- Induction of thyrotoxicosis in neonatal rats using large doses of thyroxine (T4).
- Assessment of adult neo-T4 rats' response to PTU challenge and TRH stimulation.
- Evaluation of pituitary TSH depletion and sensitivity to T4 suppression.
- Measurement of hypothalamic TRH content and circulating TRH concentrations.
Main Results:
- Neo-T4 rats demonstrated hypersensitivity to T4 feedback, mimicking effects of anterior hypothalamic lesions.
- Subnormal response to PTU challenge and exaggerated TSH suppression and goiter growth inhibition by T4 were observed.
- Pituitary TSH was less depleted with combined T4 and PTU treatment, and more sensitive to T4 suppression in neo-T4 rats.
- Impaired pituitary TSH rebound increase after T4 inhibition was noted in adult hypothyroid neo-T4 rats.
- Increased hypothalamic TRH content contrasted with significantly decreased circulating TRH levels in neo-T4 rats.
Conclusions:
- Neonatal thyroxine exposure results in adult rats hypersensitive to T4 feedback regulation.
- The observed thyroid and pituitary dysfunctions in neo-T4 rats are likely linked to impaired hypothalamic TRH secretion.
- These findings suggest a critical role for neonatal thyroid hormone levels in programming hypothalamic control of the thyroid axis.
Abstract:
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.