I. Introduction IN classical physiology, the main regulation of the thyroid gland involves a positive control by pituitary TSH. The pituitary thyrotrophs that synthesize and secrete TSH are submitted to tonic stimulation by the hypothalamic TRH and to negative feedback by T3, which is generated in these cells from plasma T4 (1, 2). The predominant role of TSH in thyroid regulation is exemplified by physiological experiments and pathological situations. Hypophysectomy, or treatment with thyroid hormones that reduces plasma TSH levels without interfering with other pituitary functions, almost abolishes thyroid function and greatly reduces the weight and cell mass of the gland. Conversely, chronic inhibition of the synthesis of thyroid hormones, and thus of their secretion, which greatly enhances TSH plasma levels, enhances thyroid growth and iodine metabolism upstream from the inhibited step. In pathology, hyperthyrotropinemia caused by pituitary adenomas induces hyperthyroidism and goiter. Hypopituitarism ...

The thyrotropin receptor and the regulation of thyrocyte function and growth.

Thyroid nodules continue to be a source of concern to patients, and their management remains a controversy among physicians. Several diagnostic techniques have been proposed to distinguish benign nodules (the majority) from malignant lesions (the minority). The trend in the management of thyroid nodular disease has been to use these diagnostic techniques with increasing frequency. The past decade has seen widespread application of fine-needle aspiration biopsy, new radionuclide scanning agents, and sensitive ultrasonography for diagnosing thyroid nodular disease. The diagnostic techniques used to distinguish benign from malignant nodules, however, vary in reliability. Furthermore, technological improvements have introduced new problems — . . .

Nodular thyroid disease. Evaluation and management.

Thyroid Follicular Cell Carcinogenesis

This chapter has outlined the complex process required for thyroid growth and function. Both events are regulated by TSHR via a multiplicity of signals, with the aid of and requirement for a multiplicity of hormones that regulate the TSHR via receptor cross-talk: insulin, IGF-I, adrenergic receptors, and purinergic receptors. Cross-talk appears to regulate G-protein interactions or activities induced by TSH as well as TSHR gene expression. The TSHR structure and its mechanism of signal transduction is being rapidly unraveled in several laboratories, since the recent cloning of the receptor. In addition, the epitopes for autoantibodies against the receptor that can subvert the normal regulated synthesis and secretion of thyroid hormones, causing hyper- or hypofunction, have been defined. Studies of regulation of the TSHR minimal promotor have uncovered a better understanding of the mechanisms by which TSH regulates both growth and function of the thyroid cell. A key novel component of this phenomenon involves TSH AMP positive and negative regulation of the TSHR. Negative transcriptional regulation is a common feature of MHC class I genes in the thyroid. Subversion of negative regulation or too little negative regulation is suggested to result in autoimmune disease. Methimazole and iodide at autoregulatory levels may be important in reversing this process and returning thyroid function to normal. Their action appears to involve factors that react with the IREs on both the TSHR and the TG promoter. Too much negative regulation, as in the case of ras transformation, results in abnormal growth without function. TTF-1 is implicated as a critical autoregulatory component in both positive and negative regulation of the TSHR and appears to be the link between TSH, the TSHR, TSHR-mediated signals, TG and TPO biosynthesis, and thyroid hormone formation. Differentially regulated expression of the TSHR and TG by cAMP and insulin depend on differences in the specificity of the TTF-1 site, that is, the lack of Pax-8 interactions with the TSHR, and the IRE sites. Single-strand binding proteins will become important in determining how TSHR transcription is controlled mechanistically.

The thyrotropin receptor.

Solitary thyroid nodule: diagnosis and management.

Effects of TSH on the adenylate cyclase-cAMP system and some parameters of intermediary metabolism were investigated in human thyroid carcinoma and adjacent normal thyroid tissue. Basal adenylate cyclase activity and cAMP concentrations were significantly higher in carcinomatous tissue. Basal [1-l4C]glucose oxidation, 32Pi incorporation into phospholipids, and organification of iodide were similar in both tissues. Stimulation of cAMP by TSH was significantly greater in normal compared to carcinomatous tissue. In neither tissue was there a good correlation between TSH stimulation of adenylate cyclase activity and cAMP concentrations. The TSH stimulation of 32Pi incorporation into phospholipids by TSH was significantly greater in normal tissue. The mean effect of TSH on iodide organification and glucose oxidation was similar in normal and carcinomatous tissue. Although specific binding of TSH was demonstrated in both normal and carcinomatous tissue, it did not correlate very well with stimulation of adenyla...

Effects of Thyroid-Stimulating Hormone on Human Thyroid Carcinoma and Adjacent Normal Tissue*

Prior exposure of thyroid slices to thyrotropin (TSH) induced refractoriness to subsequent stimulation of the cyclic AMP system by the hormone. Although the inhibition is incomplete, we examined whether the reduction in cyclic AMP was sufficient to alter other metabolic effects of TSH. Bovine or dog thyroid slices were incubated with or without 5-100 mU/ml TSH for 1-2h, washed, and then incubated without hormone for 1-2h. Half of the slices not exposed to TSH initially were then incubated with buffer and half were exposed to 5-100 mU/ml TSH. Slices initially incubated with TSH were also incubated with or without TSH in the third incubation. During the refractory period, TSH activation of protein kinase was inhibited even though the hormone still caused some increase in cyclic AMP concentrations. However, protein kinase activity was fully responsive to dibutyryl cyclic AMP when slices were incubated with it during the third incubation. Stimulation of glucose oxidation by TSH was significantly decreased in thyroid slices previously incubated with the hormone. During refractoriness, stimulation of glucose oxidation caused by prostaglandin E1 and dibutyryl cyclic AMP was also significantly diminished but that due to acetylcholine was not. Thus even though dibutyryl cyclic AMP could fully activate protein kinase activity during refractoriness, its effect on glucose oxidation was still inhibited, suggesting that the metabolic block responsible for this refractoriness was distal to activation of protein kinase. Stimulation of 32Pi incorporation into phospholipid by TSH and acetylcholine was also inhibited during refractoriness. Despite reduction of the stimulatory effect of TSH, binding of 125ITSH was not modified by prior incubation of thyroid slices with TSH. These results indicate that changes in the TSH receptor are not responsible for the development of refractoriness and other metabolic sites besides activation of adenylate cyclase appear to be involved.

/pdf/inhibition-of-thyroid-stimulating-hormone-stimulation-of-3wyswcb4w6.pdf

Inhibition of thyroid-stimulating hormone stimulation of protein kinase, glucose oxidation, and phospholipid synthesis in thyroid slices previously exposed to the hormone.

A B S T RA C T Earlier studies indicated that initial exposure of thyroid slices to thyrotropin diminished responsiveness of the adenylate cyclase-cyclic AMP system, glucose oxidation, and 32Pi incorporation into phospholipids upon readdition of the hormone. The present studies demonstrate that slices from dog, beef, and human thyroid glands initially incubated with thyrotropin (TSH) were less responsive to subsequent addition of the hormone when organification of iodide was examined. Increasing the amount of TSH did not overcome the refractoriness induced by the initial exposure to the hormone. Furthermore, the stimulatory effects of dibutyryl cyclic AMP and prostagladin E1 were abolished in slices previously incubated with TSH. Development of such refractoriness did not depend upon new protein synthesis and was not abolished by 1 mM prophylthiouracil in the first incubation. Addition of 0.1 ,uM thyroxine or triiodothyronine or 1.5 ,M iodide during all three incubations did not modify the response to TSH, added for the first time in the third incubation. However, 1mM iodide in the buffer during all three incubations inhibited the response toTSH during the third incubation. During the refractory period, effects ofTSH on colloid droplet formation were also diminished. The in vivo effect ofTSH on serum 1- triiodothyronine in rats was significantly reduced when the rats had been injected with TSH 8 h earlier. These studies demonstrate that TSH-induced refractoriness also includes effects on organification of iodine and secretion of thyroid hormone. The results cannot be adequately explained by

https://dm5migu4zj3pb.cloudfront.net/manuscripts/109000/109447/JCI79109447.pdf

In Vitro and In Vivo Refractoriness to Thyrotropin Stimulation of Iodine Organification and Thyroid Hormone Secretion

We previously reported that LH increased cyclic AMP concentrations in dog thyroid slices and that this effect could not be accounted for on the basis of the stated TSH contamination of the preparation (1). This conclusion now appears incorrect since anti-² subunit LH antibody did not inhibit the effect of 2 μg LH on the thyroid. An equivalent amount of the antibody completely abolished the effect of 2 μg LH on cyclic AMP concentrations in slices of pig corpus luteum. Therefore, the action of LH on the thyroid represented TSH contamination and LH does not have any intrinsic activity to increase cyclic AMP in the thyroid. The TSH contamination of LH appears to be underestimated on the basis of a bioassay dependent upon 32P incorporation into phospholipids in chick thyroid. Bioassay based on cyclic AMP accumulation in thyroid slices indicated a TSH contamination tenfold greater than that reported using 32P incorporation into phospholipids. Two other LH preparations also had greater TSH contamination based on...

Mary E. Kerins

Papers

Effects of Thyroid-Stimulating Hormone on Human Thyroid Carcinoma and Adjacent Normal Tissue*

Inhibition of thyroid-stimulating hormone stimulation of protein kinase, glucose oxidation, and phospholipid synthesis in thyroid slices previously exposed to the hormone.

In Vitro and In Vivo Refractoriness to Thyrotropin Stimulation of Iodine Organification and Thyroid Hormone Secretion

LH Does Not Increase Cyclic AMP in the Thyroid