Biological evidence for extrathyroidal thyroxine formation.

The efficacy of iodide and thyroxine in ameliorating the several deficiencies occasioned by thyroidectomy in male and female rats was compared in order to obtain indirect evidence for extrathyroidal thyroxine formation. More direct refutation of the opposing concept that iodide simulates the action of thyroxine was also sought in experiments with propylthiouracil (PTU) and tribromothyronine. In all indices of thyroxine action examined in thyroidectomized rats, namely, growth, metabolic rate, heart rate, and pituitary, adrenal and reproductive function, the restorative or maintenance activities of large quantities of iodide were identical with those of minute quantities of thyroxine. Effective doses of iodide presumably resulted in the formation of thyroxine in quantities equivalent to the daily injection of 0.25-0.5 ng. PTU abolished most of the growth response to iodide, while not interfering with the action of thyroxine, which provided even more cogent evidence that the responses obtained were due to the formation of thyroxine. To further support the inference that the inhibitory influence of PTU was exercised through interference with iodothyronine formation rather than interference with the extrathyroidal intracellular oxidation of iodide to the potentially active substance iodine, it was necessary to analogize with the effects of tribromothyronine and bromide. Since tribromothyronine possessed high biological activity in thyroidectomized rats while bromide was inactive, it was concluded that the iodothyronine molecule functions in some manner other than that of a simple transmembrane transport system for oxidizable iodide. Although the results strongly suggest that extrathyroidal thyroxine formation does occur in the rat, these lines of evidence are still circumstantial. (Endocrinology 78: 983,1966) E has been presented that large quantities of iodide promote skeletal growth and maturation (1, 2), repair and maintain anterior pituitary acidophils (3-5) and repair testicular function in thyroidectomized rats (1). Failure to demonstrate thyroxine formation under these conditions (1) suggested that iodide in itself simulates the action of thyroxine. Nevertheless, comparisons of the biological effects of iodide with those of thyroxine in thyroidectomized rats were continued in an effort to demonstrate, indirectly, that the responses obtained with large doses of iodide were due to the formation of small quantities of thyroxine. Renewed efforts Received October 25,1965. Aided by grants from the USPHS (AM-03150 and AM-3612) and the Research Committee of the University of California. were also made to demonstrate extrathyroidal thyroxine formation by initiating the search for thyroxine during the first several weeks of iodide treatment and by using improved chromatographic procedures. The purpose of this paper is to present the biological studies and thereby provide further information on growth and pituitary function and new data on the maintenance of adrenal and ovarian function, metabolic rate and heart rate. In addition, experiments with propylthiouracil and tribromothyronine are reported which cast doubt on the conception that the striking biological effects observed are attributable to a direct action of the iodide ion. Finally, a report in preparation by two of the authors (AT and ESE) will demonstrate that significant quantities of thyroxine are present in the plasma of thyroidectomized rats treated with iodide.