The ‘sick euthyroid syndrome’ or ‘non-thyroidal illness syndrome’ (NTIS) occurs in a large proportion of hospitalized patients and comprises a variety of alterations in the hypothalamus–pituitary–thyroid (HPT) axis that are observed during illness. One of the hallmarks of NTIS is decreased thyroid hormone (TH) serum concentrations, often viewed as an adaptive mechanism to save energy. Downregulation of hypophysiotropic TRH neurons in the paraventricular nucleus of the hypothalamus and of TSH production in the pituitary gland points to disturbed negative feedback regulation during illness. In addition to these alterations in the central component of the HPT axis, changes in TH metabolism occur in a variety of TH target tissues during NTIS, dependent on the timing, nature and severity of the illness. Cytokines, released during illness, are known to affect a variety of genes involved in TH metabolism and are therefore considered a major determinant of NTIS. The availability of in vivo and in vitro models for NTIS has elucidated part of the mechanisms involved in the sometimes paradoxical changes in the HPT axis and TH responsive tissues. However, the pathogenesis of NTIS is still incompletely understood. This review focusses on the molecular mechanisms involved in the tissue changes in TH metabolism and discusses the gaps that still require further research.
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- Abstract: Thyroid* x
- Abstract: Digestion x
- Abstract: Thyroxine x
- Abstract: Thyroglobulin x
- Abstract: Thyroiditis x
- Abstract: Thyrotoxicosis x
- Abstract: Hypothyroidism x
- Abstract: Hyperthyroidism x
- Abstract: TSHR x
- Abstract: Metabolism x
Emmely M de Vries, Eric Fliers and Anita Boelen
JAN-ÅKE GUSTAFSSON and PAUL SKETT
The presence of ectopic pituitary tissue (derived from an adult rat) in prepubertal male and female rats caused the immature, masculine-type hepatic steroid metabolism to develop into female-type metabolism. It is concluded that the hypothalamus–pituitary system controls the ontogenesis of sex-dependent steroid metabolism in rat liver.
R. L. SUTHERLAND and M. W. SIMPSON-MORGAN
The concentration of circulating plasma thyroxine (T4) appears to have little effect on the maximal binding capacity of plasma thyroxine-binding globulin (TBG). Several studies in man have shown that thyrotoxicosis results in normal or slightly lowered levels of TBG, while hypothyroidism leads to a normal or slightly increased TBG binding capacity (Oppenheimer, Squef, Surks & Hauer, 1963; Inada & Sterling, 1967; Gordon, Kleinerman, Ehrenfeld & Ehrenfeld, 1971). In contrast the binding capacities of corticosteroid-binding globulin (CBG) and sex steroid-binding globulin (SBG) have been shown to be markedly affected by the level of circulating thyroid hormone. In the rat the binding capacity of CBG was markedly depressed by thyroid-ectomy and enhanced by chronic administration of T4 (Labrie, Raynaud & Fortier, 1965). Similarly, Dray, Mowszowicz, Ledru, Crépy, Delzant & Sebaoun (1969) administered T4 to normal human subjects and observed an increase of SBG concentration. Hyperthyroidism has been shown to
J A M Mattheij, J J M Swarts, P Lokerse, J T van Kampen and D Van der Heide
The pituitary-ovarian axis was studied after withdrawal of thyroid hormone in 131I-radiothyroidectomized adult female rats. Oestrous cycles became prolonged and irregular within 2 weeks after the supply of thyroid hormone was stopped. If an LH surge occurred in hypothyroid rats on the day of vaginal pro-oestrus it was significantly greater in rats which had been made hypothyroid for 4–5 weeks than in controls; in hypothyroid rats with an LH surge on pro-oestrus, plasma progesterone showed a rise similar to that in controls at pro-oestrus; the ovulation rate was decreased in hypothyroid rats. About half of the rats from which blood was sampled daily in the afternoon between 7 and 18 days after tri-iodothyronine (T3) withdrawal had 1 day of pro-oestrus; on this day the LH surge was higher than in controls. On days 2 and 1 before and days 1 and 2 after this pro-oestrus, plasma progesterone was similar to that of controls on days 2 and 1 before and days 1 and 2 after pro-oestrus respectively. However, progesterone was higher in the period before and after these days. The other hypothyroid rats showed no pro-oestrus and no LH surge during this period, while their plasma progesterone levels were high on all days. On the morning of day 10 after T3 withdrawal and 5 days after the preceding pro-oestrus, most hypothyroid rats had high progesterone and low oestradiol plasma levels. In these rats, injection of gonadotrophin-releasing hormone caused a relatively small increase in LH; it did not stimulate the secretion of oestradiol or progesterone, and it did not induce ovulation. It was concluded that hypothyroidism induces major changes in the secretion of steroids by corpora lutea and growing follicles. Whether the changed steroid metabolism is the primary cause of the observed prolongation of the oestrous cycles, the increased pro-oestrous LH surge and the reduced ovulation rate remains to be investigated.
Journal of Endocrinology (1995) 146, 87–94
Sangeeta Maity, Dipak Kar, Kakali De, Vivek Chander and Arun Bandyopadhyay
This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism. Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a peroxisome proliferator-activated receptor alpha agonist bezafibrate (Bzf; 30 μg/100 g BW, oral) and were found to improve in the Bzf co-treated condition. Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by Bzf co-administration. Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by Bzf. Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by Bzf co-treatment. In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction.
WB Minich and U Loos
We report a method for the purification and radioactive labeling of human TSH receptor (TSHR). The method is based on the construction of a fusion TSHR (TSHR-Xa-BIO) which consists of the N-terminal 725 amino acids of human TSHR linked to the 4-amino acid Xa protease cleavage site and the 87-amino acid C-terminal domain of the biotin carboxyl carrier protein subunit of Escherichia coli acetyl-CoA carboxylase (the C-terminal domain directs the efficient posttranslational biotinylation of the protein). TSHR-Xa-BIO was produced in HeLa cells using recombinant vaccinia virus. The expressed protein was fully functional and was biotinylated with an efficiency of about 90%. Streptavidin-agarose-immobilized TSHR-Xa-BIO was labeled with 125I using the chloramine T oxidation procedure and specifically eluted from the solid phase after cleavage with protease Xa. Isolated native radiochemically pure 125I-labeled TSHR specifically interacted with pathological autoantibodies in the sera of patients with Graves' disease, and thus could be useful for the detection of these autoantibodies by immunoprecipitation analysis.
Biological inactivation and metabolism of oestrogens in the normal liver of animals
Biological inactivation and metabolism of oestrogens in the damaged liver of animals
Biological inactivation and metabolism of oestrogens in the normal human liver
The role of conjugation of oestrogens in their biological inactivation
Role of the enterohepatic circulation in the biological inactivation and metabolism of oestrogens in human subjects
Oestrogen metabolism in human subjects with liver disease
Studies in vitro
Studies on urinary excretion of oestrogens using biological and chemical methods
Studies on the biological effects of oestrogens on the vaginal smear and urinary sediment in liver disease
Studies on the mechanism leading to increased oestrogen excretion and to symptoms of increased oestrogen activity in the organism
The relation of the disturbed metabolism of oestrogens to the clinical symptoms seen in liver disease
The nature of the changes in oestrogen metabolism in liver
U Leonhardt, U Ritzel, G Schafer, W Becker and G Ramadori
Leptin, the product of the ob gene, is an important circulating signal for the regulation of body weight. In the present study the role of immunoreactive leptin (leptin-IR) was investigated in functional thyroid disease. Serum leptin-IR levels of 23 hypothyroid and 19 hyperthyroid patients were compared with 21 controls. Leptin-IR was quantified by a specific RIA. In hyperthyroid patients, leptin-IR was not different from controls. Serum leptin-IR levels were significantly increased in hypothyroid patients (21.0 +/- 2.7 micrograms/l vs controls 10.8 +/- 2.1 micrograms/l, P = 0.0044). When serum leptin of hypothyroid patients was compared with euthyroid controls of the same body mass index the difference was still significant (P = 0.0333 by paired Student's t-test). This might indicate that elevation of the serum leptin level does not merely reflect changes in body weight secondary to hypothyroidism, but might be increased to overcome the gain of body weight caused by hypothyroidism.
R Vasilatos-Younken, Y Zhou, X Wang, JP McMurtry, RW Rosebrough, E Decuypere, N Buys, VM Darras, S Van Der Geyten and F Tomas
In contrast to most vertebrates, GH reportedly has no effect upon somatic growth of the chicken. However, previous studies employed only one to two dosages of the hormone, and limited evidence exists of a hyperthyroid response that may confound its anabolic potential. This study evaluated the effects of 0, 10, 50, 100 and 200 microgram/kg body weight per day chicken GH (cGH) (0-200 GH) infused i.v. for 7 days in a pulsatile pattern to immature, growing broiler chickens (9-10 birds/dosage). Comprehensive profiles of thyroid hormone metabolism and measures of somatic growth were obtained. Overall (average) body weight gain was reduced 25% by GH, with a curvilinear, dose-dependent decrease in skeletal (breast) muscle mass that was maximal (12%) at 100 GH. This profile mirrored GH dose-dependent decreases in hepatic type III deiodinase (DIII) activity and increases in plasma tri-iodothyronine (T(3)), with bot! h also maximal (74 and 108% respectively) at 100 GH. No effect on type I deiodinase was observed. At the maximally effective dosage, hepatic DIII gene expression was reduced 44% versus controls. Despite dose-dependent, fold-increases in hepatic IGF-I protein content, circulating IGF-I was not altered with GH infusion, suggesting impairment of hepatic IGF-I release. Significant, GH dose-dependent increases in plasma non-esterified fatty acid and glucose, and overall decreases in triacylglycerides were also observed. At 200 GH, feed intake was significantly reduced (19%; P<0.05) versus controls; however, additional control birds pair-fed to this level did not exhibit any responses observed for GH-treated birds. The results of this study support a pathway by which GH impacts on thyroid hormone metabolism beginning at a pretranslational level, with reduced hepatic DIII gene expression, translating to reduced protein (enzyme) ex! pression, and reflected in a reduced level of peripheral T(3)-degrading activity. This contributes to decreased conversion of T(3) to its inactive form, thereby elevating circulating T(3) levels. The hyper-T(3) state leads to reduced net skeletal muscle deposition, and may impair release of GH-enhanced, hepatic IGF-I. In conclusion, GH has significant biological effects in the chicken, but profound metabolic actions predominate that may confound positive, IGF-I-mediated skeletal muscle growth.
J. R. WALL, P. TWOHIG and B. CHARTIER
A possible effect of thyroid hormones on numbers of mononuclear cells and immune reactivity has been studied in hyperthyroid and hypothyroid guinea-pigs and rats. There were no major changes in populations of blood mononuclear cells in hyperthyroid or hypothyroid animals compared with populations in euthyroid animals. Although there was some evidence for depressed cell-mediated responses to an extract of Candida (monilia) albicans in hyperthyroid rats as assessed by skin tests, this was minor, and responses in tuberculin purified protein derivative (PPD) were normal in all groups, whilst production of macrophage migration inhibition factor in response to PPD and Candida was similar in the three groups of animals. Antibody responses to sheep red blood cells, a thymic-dependent antigen, tended to be depressed in hyperthyroid and hypothyroid rats and increased in hyperthyroid and hypothyroid guinea-pigs, although this was significant only for hyperthyroid guinea-pigs 16 days after immunization. Responses to trinitrophenol-Ficoll, a thymic-independent antigen, were similar to the three groups of guinea-pigs. Thus, a major effect of excess or deficiency of thyroid hormone on immune responses to foreign antigens has not been demonstrated, although it is possible that immune reactions against thyroid antigens may be more sensitive to the effect of thyroid hormones than responses to foreign antigens.