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PubMed1998

Retinoic acid and thyroid hormone may function through similar and competitive pathways in regenerating axolotls.

The objective of this study was to determine whether thyroid hormone (TH) would interfere with retinoic acid (RA), which proximalizes axolotl larvae regenerate limb pattern. RA and TH are ligands for members of the steroid hormone thyroid hormone nuclear binding protein superfamily which form functional homodimers, but may also form stable heterodimers with the RXR protein and may recognize identical DNA sequences. TH alone does not affect limb pattern but induces metamorphosis in regenerating animals. Coinjected animals do not metamorphose, and when compared to RA controls regenerate more proximal and in some cases anteroposterior (AP) and dorsoventral (DV) duplicate limb structures. In addition, the tissues that are normally lost or changed during metamorphosis appear to be sensitized resulting in the formation of (1) new dorsal gill lamellae accompanied by bifurcation and broadening of the original gill lamellae, (2) partial resorption of the tail fin, and (3) changes in eye position and snout morphology. Bifurcation of gill lamellae tips, but not the formation of supernumerary gills, is also observed in animals treated with RA alone. These results indicate that the molecular mechanism of RA and TH function through similar and perhaps competitive pathways.

Ambystoma↗
PubMed1977

Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor?

High resolution X-ray analysis of the hormone-binding protein prealbumin has shown that it has a structural complementarity to double-helical DNA. The proposed binding site is composed of two symmetry-related beta-sheets containing a pair of helically disposed arms, which can interact with the bases in the wide groove of DNA. A palindromic target sequence is indicated by the symmetry of the protein. The two identical thyroid hormone binding sites on prealbumin are located in a channel that runs completely through the molecule. These two structural features suggest prealbumin as a model for the thyroid hormone nuclear receptor, providing a number of detailed predictions of its properties.

Amino Acid Sequence↗
PubMed1988

Transcriptional and posttranscriptional regulation of rat hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase by thyroid hormones.

The mechanisms by which thyroid hormones increase hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNA levels were investigated in hypophysectomized rats. Feeding these rats a diet supplemented with 0.5% desiccated porcine thyroid powder resulted in a 5-fold increase in the rate of transcription of the HMG-CoA reductase gene as measured by in vitro "run-on" transcription assays in isolated rat liver nuclei. Time courses of change in reductase mRNA, showing the kinetics of approach to new steady-state levels, indicate that reductase mRNA is also 4-6-fold more stable in thyroid hormone-treated animals than in non-treated animals. Reductase mRNA decayed with a half-life of 2.5 h when mevinolin, a potent inhibitor of HMG-CoA reductase, and colestipol, a bile acid sequesterant, were removed from the diet of hypophysectomized rats. When these drugs were removed from the diet of thyroid hormone-treated hypophysectomized rats, reductase mRNA decayed with a half-life of 15 h. Treating rats with only mevinolin and colestipol increased reductase mRNA levels without stabilizing the mRNA. Administration of cycloheximide to thyroid hormone treated rats rapidly decreased HMG-CoA reductase mRNA levels by destabilizing reductase mRNA and decreasing reductase gene transcription. Cycloheximide treatment had no effect on beta-actin gene transcription or steady state levels of beta-actin mRNA. These results suggest that a short-lived protein(s) may mediate the transcriptional and post-transcriptional effects of thyroid hormones on HMG-CoA reductase mRNA levels.

Actins↗
PubMed1981

Thyroid hormones in acute myocardial infarction.

Thyroid hormones were serially measured over a 2-week period in thirty-four consecutive patients with acute myocardial infarction (AMI). A transient increase in plasma rT3 and a decrease in plasma T3 was found, with the maximum changes occurring on the third day after the onset of AMI. The changes in plasma rT3 and T3 were greater in the seventeen patients with a complicated AMI (mean peak SGOT 145 mu/l) than in the seventeen patients with an uncomplicated AMI (mean peak SGOT 79 mu/l). A correlation was found between infarct size (as estimated by the peak SGOT value) and the following indices: delta r T3, delta T3, highest rT3/t3 and highest rT3/T4 ratios. A transient increase in plasma TSH (peak on days 4 and 5) and in plasma T4 and FT4 index (peak on days 6 and 7) was also observed, whereas T3 resin uptake (T3U) decreased. These findings suggest that the following sequence of events occurs in thyroid hormone metabolism during AMI: (1) inhibition of the 5'-deiodination of T4, resulting in increased plasma rT3 and decreased plasma T3 values, and in a lower metabolic clearance of T4. (2) Increased secretion of TSH (provoked by the lower T3 levels) resulting in increased thyroidal secretion of T4 and T3, which is then switched off by the negative feedback of thyroid hormones on the pituitary.

Acute Disease↗
PubMed2003

Thyroid hormone and blood pressure regulation.

Thyroid hormone has well-recognized effects on the cardiovascular system and blood pressure regulation. Blood pressure is altered across the entire spectrum of thyroid disease. The effects of hyperthyroidism include increased cardiac output, contractility, tachycardia, widened pulse pressure, decreased systemic vascular resistance, and increased basal metabolic rate. The manifestations of hypothyroidism are in marked contrast to those of hyperthyroidism and include decreased cardiac output, narrow pulse pressure, increased systemic vascular resistance, and decreased metabolic rate. Although thyroid hormone affects almost all tissues of the body and mediates changes in homeostasis, adaptations of the cardiovascular system can result in changes in blood pressure to accommodate the new demands on the system. In this paper, we review the direct and indirect thyroid hormone-mediated effects on blood pressure.

Blood Pressure↗
PubMed1992

Tissue-specific regulation of fatty acid synthesis by thyroid hormone.

It is generally agreed that thyroid hormone stimulates the hepatic synthesis of long chain fatty acids in the rat. However, there are conflicting data about its effects in white adipose tissue, while in brown adipose tissue, lipogenic rates are highest in hypothyroid animals. We have systematically examined the effect of thyroid state on lipogenesis in different rat tissues. Fatty acid synthesis was assessed in vivo, using the incorporation of tritiated water. Hepatic lipogenesis was induced 16-fold between hypothyroid (4.1 +/- 0.6 microns H incorporated/g.h) and hyperthyroid rats (66.5 +/- 13.2 microns H/g.h). Kidney and heart were much less lipogenically active, but also responded positively to thyroid hormone. Both hyper- and hypothyroidism diminished fatty acid synthesis in retroperitoneal fat and had similar, although not significant, effects in epididymal fat. However, epididymal adipocytes, taken from hyperthyroid rats and cultured in vitro, were 3 times more lipogenically active than cells from either hypo- or euthyroid animals. Lipogenesis in sc fat from hyperthyroid rats was enhanced when calculated per g tissue, but was not different when expressed per whole tissue. In brown adipose tissue, lipogenesis was inversely related to thyroid hormone status. Fatty acid synthesis in brain, lung, skin, and bone and muscle did not respond to changes in thyroid state. TLC confirmed that greater than 90% of the incorporated tritium was in fatty acids. Thus, in hypothyroid animals, lipogenesis primarily occurs in skin, bone, muscle, and other nonresponsive organs, whereas in hyperthyroid rats, the liver alone constitutes almost half of all fatty acid synthesis. The fatty acid synthetic pathway provides an excellent model for examining the tissue-specific regulation of gene expression by thyroid hormone.

Adipose Tissue↗
PubMed1998

Attenuation of kindling-induced decreases in NT-3 mRNA by thyroid hormone depletion.

The expression of neurotrophins is altered by amygdala kindled seizures. Because thyroid hormone can regulate the transcription of neurotrophins, we asked whether thyroid hormone regulates neurotrophin mRNA expression following amygdala kindling. Rats with electrodes implanted in the basolateral nucleus of the amygdala were either depleted of thyroid hormone or given excess thyroid hormone. The rats were then kindled daily until they had one generalized seizure. The brains were removed 4 h after the seizure and processed for in situ hybridization of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) mRNAs. In non-kindled rats, thyroid hormone depletion increased the levels of BDNF mRNA in the paraventricular nucleus of the hypothalamus and the pituitary gland. NGF and NT-3 mRNA expression was not altered. In addition, thyroid hormone manipulations had no effect on kindling or on kindling-induced BDNF and NGF mRNA. However, the kindling-induced decrease in NT-3 mRNA expression in the dentate gyrus granule cell layer was significantly attenuated by thyroid hormone depletion. These effects were reversed by thyroid hormone replacement. The results indicate that thyroid hormone plays a modulatory role in the seizure-induced changes of NT-3 mRNA expression found in the dentate gyrus.

Animals↗
PubMed1990

Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST.

The differential diagnosis of the various forms of inappropriate secretion of TSH (IST), i.e. generalized thyroid hormone resistance (GRTH), selective pituitary resistance [non-neoplastic IST (nnIST)], and tumoral pituitary TSH hypersecretion [neoplastic IST (nIST)], mainly rests on clinical observation, skull imaging, and measurement of several parameters assessing peripheral thyroid hormone effects. Clinically, patients with GRTH usually display compensated hypothyroidism, while those with nnIST or nIST are hyperthyroid. Since sex hormone-binding globulin (SHBG) measurement has been shown to be a reliable parameter in distinguishing between euthyroid and hyperthyroid states, we evaluated serum SHBG levels in 39 patients with IST (7 with GRTH, 15 with nnIST, and 17 with nIST). The results were compared to those in 68 normal subjects, 76 hyperthyroid patients, and 31 hypothyroid patients. SHBG levels in patients with either GRTH or nnIST were similar to those in controls or hypothyroid patients [GRTH, 40.5 +/- 11.8 (+/- SD) nmol/L (range, 26.4-57.5); nnIST, 29.7 +/- 12.8 nmol/L (range, 6.8-46.8); controls, 36.7 +/- 21.7 nmol/L (range, 5.4-96.5); hypothyroid, 30.8 +/- 14.4 nmol/L (range, 10.4-63.3)]. On the contrary, SHBG levels in patients with either overt hyperthyroidism or nIST were significantly higher than those in the above groups [hyperthyroid, 149 +/- 111 nmol/L (range, 48-557); nIST, 99.5 +/- 54.7 nmol/L (range, 21.6-259)]. The apparent overlap of SHBG values between hyperthyroid patients and controls almost completely disappeared when comparisons were made with control groups matched for age and sex. Additional indices of peripheral thyroid hormone action (basal metabolic rate, cardiac systolic time intervals, and Achilles' reflex time) were normal in patients with GRTH, while they were in the hyperthyroid range in patients with nnIST and nIST. After successful treatment of hyperthyroidism, SHBG levels normalized in patients with nIST, but they did not change in patients with nnIST. In conclusion, the measurement of SHBG in patients with IST is useful in differentiating the neoplastic form from that due to thyroid hormone resistance, but it fails to distinguish between generalized and pituitary resistance to thyroid hormone action. Moreover, the present data suggest that the resistance to thyroid hormone action in patients with nnIST is not selective at the thyrotroph cell level, but also involves the hepatic SHBG-synthesizing cells, thus supporting the view that the various forms of thyroid hormone resistance could represent a continuum of the same defect with variable expression in different tissues.

Adenoma↗
PubMed1989

Thyroid hormone response elements in pituitary genes.

Thyroid hormones regulate the transcription of a number of genes in the anterior pituitary gland. A thyroid hormone response element in the regulatory region of the rat growth hormone gene has previously been shown to mediate the effects of thyroid hormones on growth hormone gene transcription. The 5' flanking regions of the thyrotrophin alpha and beta subunit and prolactin genes have now been examined for the presence of sequences similar to this response element. Southern blotting reveals that no such sequences are present in the regions of the thyrotrophin subunit and prolactin genes examined, suggesting that the thyroid response elements of these genes differ from that of the rat growth hormone gene.

Animals↗
PubMed1994

Consequences of thyroid hormone deficiency induced by the specific ablation of thyroid follicle cells in adult transgenic mice.

The herpes simplex type 1 virus thymidine kinase (HSV1-TK) reporter gene was coupled to a bovine thyroglobulin promoter (TG-tk construct). Within the thyroid glands of transgenic mice expression was confined to thyroid follicle cells. Infusion of Ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl]guanine) to 8 to 12 week transgenic females led to the complete loss of thyroid HSV1-TK activity (at 3 to 4 days) and thyroid follicles (between 7 and 14 days). During the first 5 days of treatment a single reciprocal oscillation in circulating thyroxine (T4) and TSH levels occurred. By 14 days the circulating tri-iodothyronine (T3) and T4 levels of all treated animals were below the detection limits of the assays, while TSH levels were elevated ten-fold and continued to increase thereafter. During 14 days of treatment the thyroids regressed, protein content fell by 80-90% and the C cells, normally dispersed within the central region of each gland, came together in aggregates. Pituitary GH levels in females rose and fell back to normal within 14 days and between 14 and 28 days fell to a level comparable with that of GH-deficient lit/lit mice. The levels of hepatic GH receptor mRNA and the predominant 6.6 kb T3 receptor mRNA were unaffected by thyrocyte ablation. Thyrocyte ablation had no effect on the level of prolactin (Prl) receptor mRNA in females, but increased Prl receptor mRNA levels in males and eliminated group 1 major urinary protein (MUP).mRNA in females. T4 replacement reversed the effects of thyrocyte ablation on MUP mRNA in females and on Prl receptor mRNA in males.2+ Despite the many physiological changes induced by thyrocyte ablation, ablated mice have been maintained for up to 1 year without thyroid hormone supplementation. T4-deficient females were normally fertile and carried pups to term. Although transgenic males expressed HSV1-TK ectopically in spermatids and spermatozoa at levels similar to thyrocyte levels, a rate of Ganciclovir infusion which successfully ablated the thyrocytes did not affect the testis. As an alternative to infusion by minipump, thyrocyte ablation could be achieved by 6 twice-daily injections of Ganciclovir, at a level of 112 micrograms Ganciclovir/g body weight per day, and fetuses in utero could be thyrocyte ablated by administering 50 or 15 micrograms/g body weight per day to pregnant females between days 14 and 18 of gestation. These data demonstrate the potential value of transgenic thyrocyte ablation in the study of the effects of thyroid hormone deprivation.

Animals↗
PubMed1994

[Diagnosis of thyroid hormone resistance by molecular biology].

The syndrome of thyroid hormone resistance is an inherited disease characterized by reduced thyroid hormone actions in the tissue. Clinically it is classified into two types: generalized resistance to thyroid hormone (GRTH) and pituitary resistance (PRTH). Recent advances in molecular biology have revealed a number of genetic abnormalities of thyroid hormone receptor beta (TR beta) in this disorder. The mutations of TR beta localized to two "hot spots" in the ligand binding domain. This article describes the basic procedures how to analyze TR beta genes and the functions of mutant TRs. Single stranded conformation polymorphism method is useful for screening and DNA sequencing is important to identify a TR gene mutation in patients. It is also necessary to construct the expression vector containing the mutant TR beta 1 gene to evaluate the mutant receptor functions.

DNA↗
PubMed2003

Control of thyroid hormone action in the developing rat brain.

Thyroid hormones play important roles in brain development. The physiologic function of thyroid hormones in the developing brain is to provide a timing signal that leads to the induction of differentiation and maturation programs during precise stages of development. Inappropriate initiation of these timing events leads to asynchrony in developmental processes and a deleterious outcome. The developing brain is protected from premature thyroid hormone signaling through a variety of measures. Firstly, local brain levels of both thyroxine and triiodothyronine are controlled by ontogenically regulated patterns of production and metabolism. Secondly, developmentally regulated expression of nuclear proteins involved with the nuclear TH response apparatus control the temporal response of brain genes to thyroid hormone. Finally, developmental regulation of TH action modulating transcription factor expression also controls TH action in the developing brain. Together these molecular mechanisms cooperatively act to temporally control TH action during brain development. A description of these controlling mechanisms is the subject of this review.

Aging↗
PubMed1992

Variations in thyroid hormone transport proteins and their clinical implications.

Variations in major thyroid hormone transport proteins may be inherited or acquired and may be associated with changes in serum concentration of the proteins or their affinity for thyroid hormones. These variations most frequently involve thyroxine-binding globulin (TBG), but changes in transthyretin and albumin are also observed. The consequent alteration of thyroid hormone-binding capacity in serum is associated with variations in total thyroid hormone concentration. Increased serum total thyroid hormone levels are found in subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia, and transthyretin-associated hyperthyroxinemia. Conversely, diminished serum thyroid hormone values are observed in subjects with TBG deficiency, and decreased concentration or affinity of transthyretin and albumin is not associated with variations in serum concentrations of thyroid hormones. The transport protein-associated variations in serum total thyroid hormone concentrations do not reflect a change in thyroid status. Euthyroidism can be easily established in subjects with transport protein abnormalities by the normal free thyroid hormone and TSH concentrations. It is, however, crucial to select methods for free thyroid hormone measurement that are not affected by abnormalities of transport proteins. Some assays, such as the analog method, often provide artifactual and misleading results, which may lead to inappropriate and even detrimental treatments. The evolutionary advantage of TBG (and albumin) in terms of thyroid homeostasis still remains to be elucidated.

Acquired Immunodeficiency Syndrome↗
PubMed1975

Augmentation of thyrotropin responses to thyrotropin-releasing hormone following small decreases in serum thyroid hormone concentrations.

To determine whether slight decreases in serum thyroid hormone concentrations resulted in augmentation of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), TSH responses to TRH were determined before and after 13 days of iodide treatment in 20 normal subjects. Slight reductions in serum thyroxine (t4) and/or triiodothyronine (T3) concentrations and slight increases in basal serum TSH concentrations occurred in normal subjects treated with 50 or 250 mg iodide daily, though serum T4, T3 and TSH concentrations remained within their respective normal range. In contrast, TSH responses to TRH were significantly greater at the end of the iodide treatment period. In the subjects who received 50 mg iodide daily, mean basal serum TSH concentrations were 3.1 and 3.2 muU/ml before and 4.9 and 4.6 muU/ml after iodide. Post-TRH mean peak serum TSH concentrations were 14.2 muU/ml before and 27.4 muU/ml after iodide (P smaller than 0.01). A very similar augmentation of peak serum TSH was found in the subjects who received 250 mg iodide daily (before iodide, peak TSH 17.2 muU/ml; after iodide, peak TSH 28.7 muU/ml). No changes in serum T4, T3 or TSH concentrations or TSH responses to TRH followed iodide administration in 4 thyroxine-treated hypothyroid patients. These results indicate that slight reductions in serum T4 AND T3 concentrations result in increased pituitary sensitivity to TRH, just as small increases in serum T4 and T3 concentrations decrease sensitivity to TRH.

Adolescent↗
PubMed1986

Sex hormone-binding protein in hyperthyroxinemic patients: a discriminator for thyroid status in thyroid hormone resistance and familial dysalbuminemic hyperthyroxinemia.

Sex hormone-binding globulin (SHBG) levels in serum are affected by thyroid status; hyperthyroidism is associated with high SHBG levels, whereas hypothyroid patients have low or normal SHBG levels. This study was undertaken to test the usefulness of SHBG determinations to define the thyroid status in two hyperthyroxinemic states: thyroid hormone resistance (THR) and familial dysalbuminemic hyperthyroxinemia (FDH). Serum SHBG levels were determined in 193 patients and 26 normal subjects using an IRMA-type RIA. In the control group, the mean values in women (58.9 nmol/liter) and men (32.7 nmol/liter) were significantly different (P less than 0.001). In adult subjects with THR, SHBG levels were within the normal range, with mean values of 54.8 nmol/liter (range, 28.7-82.5 nmol/liter) in women and 18 and 20 nmol/liter in two men. In FDH subjects, the mean SHBG levels did not differ from the normal values; they averaged 60.7 nmol/liter in women and 42.3 nmol/liter in men. From these data we conclude that in THR and FDH, free T4 levels elicit an appropriate hepatic response corresponding to the euthyroid status of these subjects. SHBG determination may, therefore, serve as an in vitro test for end-organ sensitivity to thyroid hormones.

Drug Resistance↗
PubMed1994

Identification of iodinated proteins in cultured thyrocytes and their possible significance for thyroid hormone formation.

The thyroid gland is known to generate the iodinated hormones T3 and T4 from the prohormone thyroglobulin. In this report we examined whether polypeptides other than thyroglobulin are iodinated and hormonogenic in thyrocytes and the prerequisites for their iodination. In primary cultures of porcine thyrocytes, a substantial portion of organified radioiodine was incorporated into cellular proteins other than thyroglobulin. Some of these were identified by immunoprecipitation. They included proteins of the extracellular matrix, plasma membrane proteins, and lysosomal enzymes, which follow in part a secretion and recapture pathway. All of these proteins come into contact with the iodinating system of thyrocytes located on the apical plasma membrane and possess iodination consensus sequences. Immunoprecipitation with T3- or T4-specific antibodies showed that thyroid hormones were detectable only within thyroglobulin. This was confirmed by an analysis of the iodoamino acids of thyroglobulin, cathepsin-D (representing a secretory protein), and aminopeptidase-N (a membrane-integrated protein) by two-dimensional TLC, which revealed the presence of T3 and T4 only within the polypeptide chain of thyroglobulin. These results indicate that iodoproteins other than thyroglobulin do not participate in the generation of thyroid hormones in situ.

Antibodies↗