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[Thyroid hormones and thyroid reserve in preclinical hypothyroidism].

Preclinical hypothyroidism (i.e. basal thyroxine within the normal laboratory range, basal TSH normal or elevated and exaggerated TSH response to TRH) is a biochemical constellation of uncertain clinical relevance. The oral TRH test with simultaneous measurements of TSH and thyroid hormones before and 3 h after 40 mg TRH provides information about both pituitary and thyroid reserve. In a group of female patients with preclinical hypothyroidism, basal thyroxine but not triiodothyronine was found to be clearly diminished compared with a group of healthy female controls, indicating a slight thyroid hormone deficiency. Furthermore, a progressively reduced thyroid reserve of T4 and especially of T3 was seen to be closely related to elevation of basal TSH as an expression of thyroid cell insufficiency. These data emphasize the clinical importance of TSH elevation despite normal thyroxine levels as a better individual sign of impending primary hypothyroidism.

Female↗

Free thyroid hormone index, thyroid hormone/thyroxin-binding globulin ratio, triiodothyronine uptake, and thyroxin-binding globulin compared for diagnostic value regarding thyroid function.

The thyroid hormone/thyroxin-binding globulin (TBG) ratio and the free thyroid hormone index (FTI) were compared in 372 subjects classified according to age, sex, and biochemical and clinical findings. Age-related variations in thyroid function tests were investigated, as was the relationship between triiodothyronine uptake and TBG. Men, but not women, showed significant age-dependent changes in concentrations of thyroid hormones. FTI was as good as the thyroid hormone/TBG ratio in hyperthyroidism and was a better index of thyroid status in pregnancy, TBG deficiency, and hypothyroidism. In addition, the triiodothyronine uptake correlated extremely well with TBG (r = -0.95, p less than 0.001) and was very efficient in detecting decreased and significantly increased concentrations of TBG. I conclude that FTI is a better discriminator of functional status of the thyroid over a wider range of TBG values than is the thyroid hormone/TBG ratio. Further, the triiodothyronine uptake test produced diagnostic information equivalent to that of TBG estimation and thus should not be replaced in routine use.

Adolescent↗

Acute or chronic immunoneutralization of somatostatin does not affect growth hormone or thyroid hormone secretion in sheep.

The effect of acute or chronic immunoneutralization of somatostatin (SRIF) on plasma GH, thyrotrophin (TSH) and thyroid hormones was examined. Acute responses to SRIF immunoneutralization were examined using 30 intact male lambs (19.8 +/- 0.6 kg) assigned to one of five treatment groups such that control (C) lambs received no anti-SRIF immunoglobulin and SRIF-immunized (SI) lambs received 2 mg (SI2), 10 mg (SI10), 20 mg (SI20) or 100 mg (SI100) anti-SRIF immunoglobulin/kg body weight (BW). Control immunoglobulin was administered such that all lambs received 100 mg total immunoglobulin protein/kg BW. Effects of chronic SRIF immunoneutralization were examined using C and SI100 lambs which received additional (40 mg/kg BW) control and anti-SRIF immunoglobulin respectively, 4 and 8 days following the initial dose. Blood samples were collected from all lambs, at 10-min intervals, for 5 h immediately following initial immunoglobulin infusion and, from C and SI100 lambs, at 10-min intervals, for 5 h at 11 days following initial immunoglobulin infusion. At the end of each 5-h sampling period, pituitary and thyroid function was examined by i.v. challenge with thyrotrophin-releasing hormone (TRH; 0.33 microgram/kg BW). Basal plasma GH and thyroxine (T4) and the GH, TSH, T4 and tri-iodothyronine (T3) responses to TRH were not influenced by acute or chronic immunoneutralization of SRIF. Acute, but not chronic, immunoneutralization of SRIF elevated basal plasma T3 in SI100 lambs only. The results suggest that SRIF, under physiological conditions, does not influence GH or thyroid hormone secretion in sheep but may influence thyroid hormone metabolism acutely.

Animals↗

Pituitary-thyroid interaction: effects of thyroid hormone, non thyroidal illness and various agents on TSH secretion.

Recent developments in thyroid hormone metabolism have helped to understand the complex events which characterize the regulation of TSH secretion. Plasma T3 concentration as well as intrapituitary T3 generation from T4, exert a profound effect on TSH synthesis and release. Pituitary Type II deiodinase differs from Type I deiodinase found in other tissue such as liver and kidney, and in fact different conditions such as hypothyroidism and hyperthyroidism affect these enzymes in opposite direction. Thyroid hormones exert other effects on the pituitary such as increased synthesis of substance P, increased synthesis of GH, and decreased TRH receptors, TRH also modifies its own receptors in the pituitary and exerts modulatory effects on TSH molecule. Patients with non thyroidal illness may display TSH molecules with decreased biological activity. Various agents used in every day praxis may alter TSH and thyroid secretion. The physician must be aware of changes in order to avoid diagnostic pitfalls.

Animals↗

Inhibition by immunoglobulin G of synthesis of thyroid hormone in thyroid cultures from hypothyroid patients with goitrous Hashimoto's thyroiditis.

Recently, thyroid microsomal antigen was identified as thyroid peroxidase, and thyroid microsomal antibody was found to inhibit thyroid peroxidase activity in vitro. We investigated the possibility that anti-microsomal antibody inhibits the iodination of tyrosine, in vivo. Immunoglobulin G with or without anti-microsomal antibody from hypothyroid patients with goitrous Hashimoto's thyroiditis inhibited thyroid hormone synthesis in cultured slices of normal human thyroid tissue. IgGs with anti-microsomal antibody inhibited 125I thyroidal uptake and thyroid hormone synthesis stimulated by TSH more than normal IgG did. However, the same results were obtained with IgGs without anti-microsomal antibody. This effect did not involve anti-microsomal antibody, anti-thyroglobulin antibody, TSH-binding inhibitor immunoglobulin, thyroid stimulation-blocking immunoglobulin, or the cAMP level of the thyroid tissue. The ratio of organic I to inorganic I with stimulation by TSH in slices incubated with IgG from hypothyroid patients with goitrous Hashimoto's thyroiditis or normal IgG was not significantly different, but was significantly higher in slices incubated with methylmercaptoimidazole. Therefore, IgG from hypothyroid patients with goitrous Hashimoto's thyroiditis mainly suppressed 125I thyroidal uptake, rather than inhibiting thyroid peroxidase activity. In addition, this IgG was present in the serum of 11 of the 12 hypothyroid patients with Hashimoto's thyroiditis studied. This IgG may be involved in the mechanism that causes hypothyroidism in some patients with goitrous Hashimoto's disease.

Adult↗

Evidence for a negative feedback in the control of eel growth hormone by thyroid hormones.

The regulation of growth hormone (GH) by thyroid hormones (THs) has been shown to present species variation. We investigated the regulation of GH in the eel, a representative of an ancient group of teleosts. In vivo administration of triiodothyronine (T(3)) or thyroxine (T(4)) significantly reduced pituitary and serum GH levels, as measured by homologous RIA. In order to investigate the ability of THs to regulate GH production directly at the pituitary level, we used a long-term, serum-free primary culture of eel pituitary cells. Both T(3) and T(4) inhibited GH release in a concentration-dependent manner, producing up to 50% inhibition at 10 nM, with an ED(50) of <0.2 nM, within the range of their physiological circulating levels. Other hormones also acting via the nuclear receptor superfamily, such as sex steroids (testosterone, estradiol and progesterone) and corticosteroid (cortisol), had no effect on GH release in vitro, underlining the specificity of the regulatory effect of THs on GH. Measurement of both GH release and cellular content for calculation of GH production in vitro indicated that THs not only inhibited GH release but also GH synthesis. Dot-blot assay of GH messenger RNA (mRNA) using an homologous eel cDNA probe showed a decrease in GH mRNA levels in cells cultured in the presence of T(3), as compared with control cells. This demonstrated that the inhibition of T(3) on GH synthesis was mediated by a decrease in GH mRNA steady state levels. In conclusion, we demonstrate inhibitory regulation of eel GH synthesis and release by THs, exerted directly at the pituitary level. These data contrast with the rat, where THs are known to have a stimulatory effect and suggest that the pattern observed here in an early vertebrate and also found in birds, reptiles and some mammals including humans, may represent an ancestral and more generalized vertebrate pattern of TH regulation of pituitary GH.

Analysis of Variance↗

[Functional interrelations of monoamines, thyrotropic hormone and thyroid hormones in hyperprolactinemia].

Functional interrelationships of serotonin, dopamine, prolactin, TRH and thyroid hormones in patients with hyperprolactinemia were studied. Altogether 26 patients with amenorrhea in hyperprolactinemia without clinical signs of disorder of thyroid function were examined. The levels of serotonin and dopamine were determined by spectrofluorimetry, the level of hormones was determined by a radioimmunoassay. An increase in the level of serotonin and a decrease in the level of dopamine in all the patients, a decrease in TRH and T4, and an increase in T3 were noted. The levels of monoamines, TRH and thyroid hormones showed correlation. It has been concluded that disorder of the monoaminergic mechanisms of regulation creates conditions for the rearrangement of hormonal interrelationships in the neuroendocrine functional system and determines the involvement of the hypophyseothyroid system in the pathological process. Therefore patients with hyperprolactinemia are at risk of developing thyroid functional disorders.

Adult↗

Serum thyroid hormone and thyroid gland weight measurements in protein-energy malnutrition.

Protein-energy malnutrition (PEM) is a problem which concerns about half the world's children. We investigated the effects of malnutrition on thyroid gland weight and thyroid hormone levels. 22 children suffering from malnutrition (14 children suffering from marasmus and 8 children suffering from kwashiorkor) and 7 healthy controls were studied. Malnutrition was confirmed clinically and according to the Wellcome classification definition of malnutrition. Serum thyroid hormone concentrations were measured by radioimmunoassay and the weights of the thyroid gland were evaluated scintigraphically. In the groups with marasmus and kwashiorkor the mean TT4, TT3 and FT3 levels were significantly lower, and TSH levels were significantly higher, compared to controls. FT4 was not influenced by PEM. The mean thyroid gland weights of the groups with marasmus and kwashiorkor were higher than that of the control group. We found no significant differences in all these parameters between groups with marasmus and kwashiorkor. In each of the three groups, the most marked positive correlation was between thyroid gland weight and ratio of thyroid gland weight to body surface area.

Body Surface Area↗

A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition.

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin (TSH) from the anterior pituitary in association with abnormal peripheral tissue responses to thyroid hormone. Whether TR-beta mutations cause a selective form of RTH, which only leads to abnormal pituitary TSH secretion (PRTH), is unclear. In a patient with PRTH, a novel mutation of a conserved arginine residue adjacent to the ninth heptad of TR-beta selectively disrupts TR homodimer formation. The mutant TR displays normal or enhanced function on stimulatory thyroid hormone response elements found in peripheral tissues, but has defective function on inhibitory thyroid hormone response elements found in the TRH and TSH subunit genes and explains the PRTH phenotype. This is the first report of a mutation in a member of the nuclear receptor superfamily that selectively abolishes hormone-dependent inhibition and localizes a novel C-terminal domain necessary for this property.

Amino Acid Sequence↗

Epidermal growth factor decreases thyroid hormone receptors and attenuates thyroid hormone responses in GH4C1 cells.

The present study was undertaken to examine the effect of long term exposure to epidermal growth factor (EGF) on thyroid hormone responses as well as the concentration of specific nuclear thyroid hormone receptors in GH4C1 rat pituitary tumor cells. GH4C1 cells were first incubated for 48 h in medium with 5% fetal calf serum depleted of thyroid hormones by ion exchange resin. EGF had no effect on thyroid hormone receptors after 2 h, but decreased [125I]T3 binding to 56% of control values at 24 h and 68% at 48 h. L-T3 (0.5 nM) caused down-regulation of thyroid hormone receptors, and addition of EGF caused a further decrease. T3 alone (0.5 nM) caused a 2- to 3-fold induction of GH after 48 h, and GH induction was significantly inhibited by the addition of 10 nM EGF. Scatchard analysis of specific nuclear [125I]T3 binding showed that 48-h incubation with 10 nM EGF decreased T3 receptors from a Bmax of 2.35 to 1.26 pmol/mg DNA in thyroid hormone-depleted medium without affecting receptor affinity (Kd, 80 pM). The decrease in nuclear thyroid hormone receptors caused by EGF was dose dependent, with half-maximal inhibition at 0.10 nM EGF. EGF attenuated the GH response to T3 with similar dose-response characteristics. When cells were incubated for 48 h with different concentrations of T3, EGF (10 nM) decreased thyroid hormone receptors to 56-72% of control values regardless of the dose of T3, and EGF shifted the ED50 for T3 stimulation of GH from 0.1 to 1.2 nM. EGF also reduced from 5- to 1.8-fold the increase in cell number caused by thyroid hormone over 2 weeks. In contrast, EGF stimulation of PRL synthesis was changed only slightly by thyroid hormone at all times. In conclusion, we demonstrate that low concentrations of EGF decrease nuclear thyroid hormone receptors and thyroid hormone responses; this may be the mechanism by which EGF suppresses T3-induced GH production in GH4C1 cells.

Animals↗

Dominant inhibition of thyroid hormone action selectively in the pituitary of thyroid hormone receptor-beta null mice abolishes the regulation of thyrotropin by thyroid hormone.

Thyroid hormones, T4 and T3, regulate their own production by feedback inhibition of TSH and TRH synthesis in the pituitary and hypothalamus when T3 binds to thyroid hormone receptors (TRs) that interact with the promoters of the genes for the TSH subunit and TRH. All TR isoforms are believed to be involved in the regulation of this endocrine axis, as evidenced by the massive dysregulation of TSH production in mice lacking all TR isoforms. However, the relative contributions of TR isoforms in the pituitary vs. the hypothalamus remain to be completely elucidated. Thus, to determine the relative contribution of pituitary expression of TR-alpha in the regulation of the hypothalamic-pituitary-thyroid axis, we selectively impaired TR-alpha function in TR-beta null mice (TR-beta-/-) by pituitary restricted expression of a dominant negative TR-beta transgene harboring a delta337T mutation. These animals exhibited 10-fold and 32-fold increase in T4 and TSH concentrations, respectively. Moreover, the negative regulation of TSH by exogenous T3 was completely absent and a paradoxical increase in TSH concentrations and TSH-beta mRNA was observed. In contrast, prepro-TRH expression levels in T3-treated TR-beta-/- were similar to levels observed in the delta337/TR-beta-/- mice, and ligand-independent activation of TSH in hypothyroid mice was equivalently impaired. Thus, isolated TR-beta deficiency in TRH paraventricular hypothalamic nucleus neurons and impaired function of all TRs in the pituitary recapitulate the baseline hormonal disturbances that characterize mice with complete absence of all TRs.

Animals↗

A thyroid hormone antagonist that inhibits thyroid hormone action in vivo.

We have characterized the newly developed thyroid hormone antagonist NH-3 in both cell culture and in vivo model systems. NH-3 binds Xenopus laevis thyroid hormone receptors directly in vitro and induces a conformation distinct from agonist-bound receptors. Transcriptional activation of a thyroid hormone response element-containing reporter gene is strongly inhibited by NH-3 in a dose-dependent manner. In addition, NH-3 prevents X. laevis thyroid hormone receptors from binding to the p160 family of co-activators GRIP-1 and SRC-1 in a two-hybrid assay. To assess the potency of the compound in vivo, we used induced and spontaneous X. laevis tadpole metamorphosis, a thyroid hormone-dependent developmental process. NH-3 inhibits thyroid hormone-induced morphological changes in a dose-dependent manner and inhibits the up-regulation of endogenous thyroid hormone-responsive genes. Spontaneous metamorphosis is efficiently and reversibly arrested by NH-3 with at least the same effectiveness as the thyroid hormone synthesis inhibitor methimazole. Therefore, NH-3 is the first thyroid hormone antagonist to demonstrate potent inhibition of thyroid hormone action in both cell culture- and whole animal-based assays.

Acetates↗

Mild resistance to thyroid hormone with a truncated thyroid hormone receptor beta.

Recent studies have revealed mutations in the thyroid hormone receptor beta (TR beta) gene as a cause of the most cases of the thyroid hormone resistance syndrome. We have identified a novel nonsense mutation in codon 449 in the 3' end of exon 10 in the TR beta gene in a 16-year-old male patient with generalized resistance to thyroid hormone who also had familial thyroxine binding globulin deficiency. Receptor protein generated from this gene is thought to be 13 amino acid deficient at carboxy-terminus. Resistance to thyroid hormone was mild at least when the patient was evaluated. The patient was eumetabolic in the presence of elevated plasma-free thyroid hormone levels, and both thyrotrope and peripheral tissues responded to triiodothyronine (T3) administration. This mildness of resistance is in contrast to severe resistance to thyroid hormone in two previously reported cases with truncated receptors in which 16 amino acids or 11 amino acids were deficient at C-terminus. Thus, truncation of C-terminus of thyroid hormone receptor beta does not uniformly produce sever resistance.

Adolescent↗

Regular moderate intensity physical activity and blood concentrations of endogenous anabolic hormones and thyroid hormones in aging men.

BACKGROUND: Physical activity has been reported to affect endocrine function in elderly men. OBJECTIVE: To establish an association between regular moderate physical activity and endogenous anabolic hormone levels in healthy aging men. PARTICIPANTS: Twenty four middle-aged (57.4+/-4.7 years) and 24 elderly (68.3+/-2.6 years) physically active men who in the past 10 years had been regularly bicycling during leisure time were compared with 24 middle-aged (57.9+/-4.0 years) and 24 elderly (67.2+/-1.7 years) sedentary men. Groups did not differ for body composition. MEASUREMENTS: Serum dehydroepiandrosterone sulfate (DHEAS), insulin-like growth factor-I (IGF-1), free testosterone (FT), and thyroid hormone levels were assessed. RESULTS: In general, elderly men had lower IGF-1 (P<0.001), DHEAS (P=0.013), and triodothyronine levels (P<0.001) than their middle-aged counterparts. Independently of age, however, physically active men had on average higher IGF-1 (P=0.031), DHEAS (P=0.001), and triodothyronine serum levels (P<0.001) than sedentary men. FT and thyroid stimulating hormone (TSH) serum concentrations did not differ across age groups, but physically active men had lower TSH values than sedentary men (P=0.021). CONCLUSIONS: Our results suggest that, in aging men, regular moderate physical activity is associated with higher levels of IGF-1 and DHEAS levels and with thyroid function alterations.

Aged↗

Search for genetic variants in the retinoid X receptor-gamma-gene by polymerase chain reaction-single-strand conformation polymorphism in patients with resistance to thyroid hormone without mutations in thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is an inherited disease characterized by reduced tissue sensitivity to thyroid hormone. Approximately 90% of subjects with RTH have mutation in the thyroid hormone receptor beta (TRbeta) gene. Approximately 10% of subjects diagnosed as having RTH do not carry mutation in the TRbeta gene. A possible linkage was reported with the retinoid X receptor-gamma (RXR-gamma) gene in two families. The aim of this study is to search for mutation within the RXR-gamma gene in unrelated subjects with diagnosed RTH without mutations in the TRbeta gene. Four subjects with RTH were studied, and sequence variants in the RXR-gamma gene were searched by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Analysis of all the 10 exons of the RXR-gamma gene, including intron-exon boundaries, promoter region and 3' untranslated region (UTR) reveled two variant bands in subjects II and III. Sequencing of these variants showed two single nucleotide polymorphisms (SNPs): 447C > T in exon 3 for patients II and IVS9 + 6A > G for patient III. Both SNPs were also present at high frequency in a group of normal subjects and in nonaffected relatives of subject III. In conclusion, in patients with RTH we have found two SNPs in the RXR-gamma gene; these SNPS are common in the general population, thus excluding a role for the RXR-gamma gene in these patients.

Adult↗

Nuclear thyroid hormone receptors: ontogeny and thyroid hormone effects in sheep.

To investigate the mechanism(s) responsible for the paucity of fetal thyroid hormone effects, thyroid hormone nuclear receptor (T3NR) binding characteristics were quantified in liver and brain of fetal and neonatal sheep. Maximal binding capacities [MBC; mean +/- SE fmol 3,5,3'-triiodothyronine (T3)/mg DNA] in liver increased from values of 68 +/- 14 at 80 days gestation to 684 +/- 152 at term. Liver T3NR MBC in newborn and adult sheep were comparable to values in term fetuses. Liver T3NR binding affinities were similar in all animals, averaging 1.68 +/- 0.05 X 10(9) M-1. Brain T3NR MBC were comparable at all fetal ages studied (410 +/- 55 fmol T3/mg DNA), increasing to 1,517 +/- 315 fmol T3/mg DNA during the 1st postnatal week and returning to comparable fetal values (368 +/- 37 fmol T3/mg DNA) in the 3rd week after birth. Brain T3NR binding affinities were comparable in all animals studied (7.5 +/- 2.1 X 10(9) M-1), and the mean value was significantly greater than mean liver T3NR affinity. T3NR binding of T3 analogues in six term fetal animals were qualitatively similar for both brain and liver and showed T3 = triiodothyroacetic acid greater than thyroxine greater than reverse T3. Like T3 binding affinity, T3NR analogue binding affinities in brain tissue were five- to sevenfold greater than those in liver. Fetal hypothyroidism induced by thyroidectomy at either 99-107 or 129-132 days of gestation was not associated with changes in brain or liver T3NR binding characteristics. The heterogenous ontogeny and binding characteristics of brain and liver T3NR is compatible with the hypothesis that different thyroid hormone receptors are expressed in these tissues.

Animals↗

Human spot 14 glucose and thyroid hormone response: characterization and thyroid hormone response element identification.

Spot 14 is a 17-kDa protein expressed in lipogenic tissues and is postulated to play a role in thyroid hormone stimulation of lipogenesis. To further our understanding of Spot 14 regulation in humans, our laboratory recently cloned the human Spot 14 gene. The gene is highly homologous to the rat Spot 14 ortholog and located on a chromosomal region implicated in human obesity. Because our understanding of Spot 14 transcriptional regulation is derived from rat promoter studies, we assessed the thyroid hormone responsivity of the human Spot 14 promoter. These studies revealed a significantly greater thyroid hormone response for the human promoter, compared with the rat. Deletional studies of the human Spot 14 promoter reveal a 774-bp region at approximately position -2700, which is both necessary and sufficient for the thyroid hormone response. EMSAs with subfragments from this region identify a 146-bp DNA fragment capable of binding a TRbeta1-retinoid X receptor heterodimer. Site-directed mutagenesis confirmed the identity of a candidate DR-4 thyroid hormone response element within this fragment that is similar, but not identical, to the two rat Spot 14 thyroid hormone response elements. We hypothesize that the difference in thyroid hormone response between the orthologous promoters may allow a selective advantage to each species based on their different nutritional and physiological niches.

Animals↗