OBJECTIVE

To determine whether measurement of baseline serum concentrations of total thyroxine (T4), and triiodothyronine (T3), free T4, and thyrotropin (thyroid-stimulating hormone; TSH) would aid in the diagnosis of hypothyroidism in dogs.

METHODS

Prospective case series.

METHODS

54 dogs with hypothyroidism, 54 euthyroid dogs with nonthyroidal disease initially suspected to have hypothyroidism, and 150 clinically normal dogs.

METHODS

In the 54 dogs with hypothyroidism, diagnosis was established on the basis of clinical signs, results of routine laboratory and TSH stimulation tests, exclusion of concurrent nonthyroidal disease, and a good clinical response to treatment with L-thyroxine. Blood samples were collected from all dogs and were tested for thyroid hormone and TSH concentrations. Reference ranges for hormone concentrations were established on the basis of results for the 150 clinically normal dogs.

RESULTS

Of the 54 hypothyroid dogs, 48 (89%) had low total T4 concentrations, 3 had low-normal concentrations, and 3 had high concentrations because of T4 autoantibodies. In contrast, only 10 (18%) euthyroid dogs had low total T4 concentrations. Only 3 of 31 (10%) hypothyroid dogs had low T3 concentrations; 23 had concentrations within the reference range, and 5 had high concentrations because of T3 autoantibodies. Only 3 of 38 euthyroid dogs had low T3 concentrations. Of the hypothyroid dogs, 53 (98%) had low free T4 concentrations and 1 had a low-normal concentration. Only 4 (7%) euthyroid dogs had low free T4 concentrations. Of the hypothyroid dogs, 41 (76%) had high TSH concentrations, and 13 had TSH concentrations within the reference range. Of the euthyroid dogs, only 4 (8%) had high TSH concentrations. Of all single hormone measurements evaluated, measurement of free T4 concentration had the highest sensitivity (0.98), specificity (0.93), and accuracy (0.95) as a test for hypothyroidism; measurement of total T4 concentration had a lower sensitivity (0.89), specificity (0.82), and accuracy (0.85). Compared with measurement of total or free T4 concentration, measurement of TSH concentration had a lower sensitivity (0.76) and accuracy (0.84) but specificity (0.93) equal to that for measurement of free T4 concentration. When T4 (total or free) and TSH concentrations were evaluated together, specificity was higher than when T4 or TSH concentration was evaluated alone. Only 1 euthyroid dog had low T4 (total and free) and high TSH concentrations.

CONCLUSIONS

Results indicate that measurement of serum free T4 and TSH concentrations is useful for diagnosis of hypothyroidism in dogs. About a quarter of the dogs with confirmed hypothyroidism, however, will have serum TSH concentrations within reference limits.

Although the normal thyroid gland secretes both levothyroxine (L-T4) and levotriiodothyronine (L-T3), normalization of serum TSH with L-T4-replacement therapy alone in hypothyroidism is generally believed to result in a normal serum L-T3 and to reflect a euthyroid state. However several recent studies suggest that this may not be the case. Accordingly, the relationship between serum free L-T4 and free L-T3 was examined in 20 normal individuals (group A) and in 53 patients with chronic autoimmune thyroiditis, 18 with normal TSH on no L-T4-replacement (group B), and 35 with normal TSH on L-T4-replacement therapy for hypothyroidism (group C). Data were analyzed by applying a one-way analysis of variance with correction for multiple comparisons. Serum TSH values were very similar among the 3 groups. In groups A and B, mean serum free T4 and free T3 were very similar. In group C, the mean free T4 (16+/-2 pmol/l) was significantly higher than the values in groups A (14+/-1) and B (14+/-2) (p<0.001) and the mean free T3 lower (4.0+/-0.5 pmol/l vs 4.2+/-0.5, NS and 4.4+/-0.5, p<0.02). Consequently, the mean molar ratio of free T4 to free T3 was significantly higher in group C than the ratios in groups A and B (p<0.0001), despite very similar TSH values. These findings indicate that in hypothyroid patients L-T4-replacement, that is sufficient to maintain a normal serum TSH, is accompanied by a serum free T4 that is higher than that in untreated euthyroid patients or normal individuals and may not result in an appropriately normal serum free T3 concentration.

We have retrospectively studied 41 patients with hypothalamic-pituitary disease and central hypothyroidism associated with hypopituitarism. Sixteen patients had nonsecreting pituitary macroadenoma, whereas different sellar and suprasellar pathologies affected all other patients. Pretreatment thyrotropin (TSH) level (mean +/- standard error of the mean [SEM]) was 2.04 +/- 0.25 mU/L (normal, 0.4-4), and gradually decreased to 0.51 +/- 0.19 mU/L (range, 0.009-3.38) by treatment with levothyroxine in a mean dose of 86 +/- 6 microg/d. TSH was suppressed by thyroid replacement to less than 0.5 mU/L in 80% of patients. Mean baseline free thyroxine (FT4) was 7.55 +/- 0.51 pmol/L (normal, 11.8-24.6) and gradually increased with thyroid hormone to 15.19 +/- 1.0 pmol/L, whereas total thyroxine (TT4) increased from 57.4 +/- 2.6 to 104.4 +/- 5.0 nmol/L (normal, 77-154). Mean pretreatment total triiodothyronine (TT3) was 1.44 +/- 0.09 nmol/L (normal, 1.1-2.7), and was not altered by treatment. Thyrotropin-releasing hormone (TRH) test was performed in 20 patients before thyroid replacement, and mean baseline and peak TSH levels were 1.33 +/- 0.3 and 7.14 +/- 1.62 mU/L, respectively. In 5 subjects TSH was stimulated to 6 mU/L or more, whereas in 5 others TSH was not affected. Based on linear regression of logarithm (Ln) TSH against FT4, a leftward shift of the TSH/FT4 ratio was demonstrated in patients with central hypothyroidism compared to 17 patients with primary hypothyroidism. Plotting measurements of TSH against FT4 for 6 individuals with central hypothyroidism showed different regression slope for each patient. Suppression of TSH by thyroid replacement to levels below 0.1 mU/L predicted euthyroidism in 92% of cases, compared to 34% when TSH was above 1 mU/L (p < 0.0001). In conclusion, in central hypothyroidism baseline TSH is usually within normal values, and is further suppressed by exogenous thyroid hormone as in primary hypothyroidism, but to lower levels. Thus, insufficient replacement may be reflected by inappropriately elevated TSH levels, and may lead to dosage increment.

BACKGROUND

Surgical management of symptomatic benign thyroid nodules in patients with previous lobectomy poses a dilemma for physicians. Radiofrequency (RF) ablation may provide a treatment option that avoids surgery and preserves thyroid function. We evaluated whether RF ablation of benign thyroid nodules affects thyroid function in patients with previous lobectomy.

METHODS

A total of 11 patients with 14 thyroid nodules were enrolled using the following criteria: (i) having a predominantly solid nodule; (ii) reporting pressure symptoms or cosmetic problems; (iii) cytological confirmation of benignancy; (iv) no malignant features detected using ultrasound; (v) serum thyroid hormone and thyrotropin (TSH) levels within normal limits; and (vi) refusal of or ineligibility for surgery. Thyroid function, nodule volumes, and clinical concerns were evaluated before RF ablation and during follow-up after RF ablation.

RESULTS

The mean follow-up duration after RF ablation was 43.7±30.7 months (range=7-92 months). The mean nodule volume was 9.7 mL (0.9-57.6 mL) before the procedure, and was significantly decreased at the last follow-up (p<0.001) with a mean volume reduction rate of 87.2%. The mean symptom score (p=0.003) and cosmetic score (p=0.003) were both significantly decreased at the last follow-up. Levels of TSH, free thyroxine, and triiodothyronine were not significantly different prior to treatment and at the last follow-up (p>0.05), and remained normal in all patients.

CONCLUSIONS

In patients with previous lobectomy, RF ablation should be considered as a first-line treatment for symptomatic benign thyroid nodules to preserve thyroid function.

Lower relative rates of energy expenditure (EE), increased energetic efficiency, and altered fuel utilization purportedly associated with obesity have not been demonstrated indisputably in overweight children. We hypothesized that differences in energy metabolism between nonoverweight and overweight children are attributable to differences in body size and composition, circulating thyroid hormones, sympathetic nervous system, and adrenomedullary activity. A total of 836 Hispanic children, 5-19 y old, participated in 24-h calorimetry, anthropometric, and dual-energy X-ray absorptiometry measurements. Biochemistries were determined by standard techniques. Absolute total EE (TEE) and its components (sleep EE, basal EE, sedentary EE, cycling EE, walking EE, activity EE, nonexercising activity thermogenesis) were higher in overweight children (P = 0.001). Net mechanical energetic efficiency of cycling was lower in overweight children (P = 0.001). Adjusting for body size and composition accounted for differences in TEE, its components, and energetic efficiency. Net carbohydrate and fat utilization did not differ between groups. TEE was independently influenced by sex, Tanner stage, fat free mass, fat mass (FM), fasting serum nonesterified fatty acids (NEFA), leptin, free thyroxine, triiodothyronine, and 24-h urinary norepinephrine and epinephrine. Fat utilization was independently associated with age2, sex, FM, fasting serum NEFA, triacylglycerol, adiponectin, leptin, total thyroxine, and free triiodothyronine. Higher EE in overweight children was largely explained by differences in body size and composition, with minor contributions of thyroid and sympathoadrenal systems. Alterations in EE, energetic efficiency, and substrate utilization were not evident in the overweight children.

As a prerequisite to studies of whether the plasma membrane of the rat thymocyte contains specific, saturable binding sites for the thyroid hormone 3,5,3'-triiodothyronine (T(3)), a method was developed for the isolation of a plasma membrane fraction from these cells. As judged from both electron microscopic and marker enzyme studies, the fraction was composed principally of plasma membrane vesicles, was free of nuclear contaminants, and was only slightly contaminated with other subcellular components. At 37 degrees C and pH 7.4, binding of [(125)I]T(3) by the fresh membrane preparation was rapid, reaching a maximum at 5 min and then declining with time, so that by 60 min binding was virtually nil. Decreased binding with time was due to a loss of functional binding sites, but did not reflect desensitization, since the decrease in binding activity with time was independent of the presence or absence of T(3). Scatchard analysis of saturation studies revealed the presence of two binding sites, one with an apparent dissociation constant (K(d)) of 0.95 nM and a maximum capacity of 5.3 x 10(10) sites/100 mug protein, and the other with an apparent K(d) of 25 nM and a binding capacity of 1.4 x 10(12) sites/100 mug protein. Measurement of the ability of several thyronine analogues to inhibit the binding of [(125)I]T(3) revealed the following rank order of potency: l-T(3)>> l-T(4)>> d-T(3) = d-T(4)>> l-3,5-T(2)>> rT(3)>> d,l-thyronine. Binding of T(3) was inhibited by the omission of calcium from the medium or by the addition of the beta adrenergic antagonist alprenolol. As judged from studies of the lower affinity binding site, these manipulations decreased the affinity, but not the number, of binding sites for T(3). The relative potencies of thyronine analogues to inhibit the binding of [(125)I]T(3) were generally parallel to their previously reported potencies in stimulating the uptake of the sugar analogue 2-deoxy-glucose (2-DG) in intact rat thymocytes in vitro. Further, the inhibition of T(3)-binding produced by l-alprenolol or by excluding calcium from the medium resembled the previously reported inhibition that these manipulations produce with respect to T(3)-induced enhancement of 2-DG uptake. These findings suggest that the binding sites for T(3) present in the plasma membrane of rat thymocytes act as functional receptors linked to the stimulation of 2-DG uptake that T(3) induces in these cells.

A 30% solution of a polychlorinated biphenyl (PCB) mixture or a microscope immersion oil containing 34% PCB, when applied to the skin of rats, led to substantial increases in the biliary excretion of intravenously injected [125I]thyroxine (T4) in bile: plasma 125I ratios, in the biliary clearance rate of plasma [125I]T4, and in bile flow. Both PCB preparations also elevated liver weight, thyroid 125I uptake, and Sephadex uptake of [125I]triiodothyronine (T3), and depressed serum T4 concentrations; serum T3 levels were unaltered by the PCB solution or by the immersion oil containing PCB. PCB, either in mineral or immersion oil, reduced the free T4 index (serum T4 X fraction Sephadex T3 uptake), indicating a probable reduction in the concentration of free T4 in serum; the free T3 index, on the other hand, was elevated in PCB-treated rats. The same type of immersion oil, in which the PCB was replaced by a hydrogenated terphenyl, was without effect on any of the indices studied. Thus, the effects of microscope immersion oil on T4 metabolism were due to its PCB content. In thyroidectomized, T4-maintained rats, PCB in mineral oil again increased Sephadex uptake of [125I]T3, greatly reduced serum T4, and moderately reduced serum T3 levels; the free T4 index was substantially reduced and the free T3 index moderately lowered in treated animals. These data indicate that in PCB-treated rats both the peripheral conversion of T4 to T3 and thyroid T3 secretion were enhanced. The metabolic impact of thyroid hormone in PCB-treated animals was unchanged, as shown by normal activity of hepatic mitochondrial L-alpha-glycerophosphate dehydrogenase.

Reported evidence regarding relationships between polychlorinated biphenyls (PCBs) and thyroid homeostasis in adults has been considered contradictory. The objective of this systematic review is to determine a possible association between PCB exposure and the circulating thyroid hormones and thyrotropin (TSH) levels in adults, by analyzing the quality of published studies. A systematic review of epidemiological papers was conducted using PubMed. An evaluation of the quality of 22 studies was performed, and the papers were classified into two tiers: Tier I for studies with higher quality scores (eight) and Tier II for studies with lower quality scores (14). It appears that PCBs can interfere with thyroid hormone homeostasis; however epidemiological evidence is not entirely clear. For triiodothyronine (T3) and thyroxine (T4), Tier I studies showed either an inverse (four cases for T3; five cases for T4) or no significant association (two cases for T3; five cases for T4) with PCBs. In the case of free thyroxine and TSH, the Tier I papers observed no clear association with PCB levels. Rigorous study design, assessment of potential confounding factors, and fuller reporting of methods and results in future studies will facilitate understanding of whether PCB exposure is associated with changes in thyroid function.

In order to evaluate the effects of some neuro-endocrine changes during aging we have studied adrenal, thyroid and pineal secretion in young, healthy old and centenarians. The number of subjects in each hormone group varied. The following parameters were evaluated: serum levels of cortisol, dehydroepiandrosterone-sulfate (DHEAS), free triiodothyronine (FT3), thyroxine (FT4), reverse triiodothyronine (rT3) and thyroid-stimulating hormone (TSH). Urinary 6-hydroxymelatonin sulfate (aMT6s) and free cortisol were measured twice daily. Centenarians exhibited significantly lower TSH levels together with slightly higher rT3 levels than old controls. These changes could be due to reduced 5'-deiodinase activity occurring also in absence of substantial changes of the nutritional pattern. Morning serum cortisol levels were found to be similar in the 3 age groups, whereas the decline of serum DHEAS levels was well evident also after the ninth decade of life. The cortisol/DHEAS molar ratio, which usually increases with age and considered to be an expression of a neurotoxic pattern of the steroidal milieu in the central nervous system, did not shown any further increase in centenarians. The urinary free cortisol and aMT6s excretion declined with age; however only in centenarians and in young controls aMT6s excretion was significantly higher at night than during the day. These findings suggest that the circadian rhythm of melatonin secretion is maintained in centenarians and, based on the limitations of this study, could be considered one factor in successful aging.

OBJECTIVE

In recognition of its primary role in pituitary-thyroid feedback, TSH determination has become a key parameter for clinical decision-making. This study examines the value of TSH as a measure of thyroid hormone homoeostasis under thyroxine (T(4)) therapy.

METHODS

We have examined the interrelationships between free triiodothyronine (FT(3)), free T(4) (FT(4)) and pituitary TSH by means of i) a retrospective analysis of a large clinical sample comprising 1994 patients either untreated or on varying doses of l-T(4) and ii) independent mathematical simulation applying a model of thyroid homoeostasis, together with a sensitivity analysis.

RESULTS

Over a euthyroid to mildly hyperthyroid functional range, we found markedly different correlation slopes of log TSH vs FT(3) and FT(4) between untreated patients and l-T(4) groups. Total deiodinase activity (G(D)) was positively correlated with TSH in untreated subjects. However, G(D) was significantly altered and the correlation was lost under increasing l-T(4) doses. Ninety-five per cent confidence intervals for FT(3) and FT(4), when assessed in defined TSH concentration bands, differed significantly for l-T(4)-treated compared with untreated patients. Higher doses were often needed to restore FT(3) levels within its reference range. Sensitivity analysis revealed the influence of various structural parameters on pituitary TSH secretion including an important role of pituitary deiodinase type 2.

CONCLUSIONS

The data reveal disjoints between FT(4)-TSH feedback and T(3) production that persist even when sufficient T(4) apparently restores euthyroidism. T(4) treatment displays a compensatory adaptation but does not completely re-enact normal euthyroid physiology. This invites a study of the clinical consequences of this disparity.

An increasing number of disorders that may cause hyperthyroxinemia without thyrotoxicosis have been recognized in recent years. These include acquired and inherited abnormalities of serum thyroid-hormone-binding proteins, peripheral resistance to thyroid hormones, acute nonthyroidal illness, acute psychiatric illness, and some drug-induced conditions associated with nonthyrotoxic elevations of serum thyroxine. In addition to the laboratory finding of elevated serum thyroxine levels, many of these syndromes are also accompanied by abnormalities in triiodothyronine and free thyroid hormone levels, as well as unresponsiveness of thyroid-stimulating hormone to thyrotropin-releasing hormone, all of which further erroneously indicate a diagnosis of thyrotoxicosis. An awareness of these syndromes and alterations in the results of thyroid function tests that accompany them is important to prevent a misdiagnosis of hyperthyroidism and inappropriate therapy.

OBJECTIVE

To determine whether nonthyroidal disease of various causes and severity is associated with abnormalities in baseline serum concentrations of total thyroxine (T4), triiodothyronine (T3), free T4, or thyrotropin (thyroid-stimulating hormone [TSH]) in dogs believed to be euthyroid.

METHODS

Case-control study.

METHODS

223 dogs with confirmed nonthyroidal diseases and presumptive normal thyroid function, and 150 clinically normal dogs.

METHODS

Serum total T4, total T3, free T4, and TSH concentrations were measured in dogs with confirmed nonthyroidal disease. Reference ranges for hormone concentrations were established on the basis of results from 150 clinically normal dogs.

RESULTS

In dogs with nonthyroidal disease, median serum concentrations of total T4, total T3, and free T4 were significantly lower than those in clinically normal dogs. Median serum TSH concentration in sick dogs was significantly greater than that of clinically normal dogs. When stratified by severity of disease (ie, mild, moderate, and severe), dogs with severe disease had low serum concentrations of total T4, total T3, or free T4 more commonly than did dogs with mild disease. In contrast, serum TSH concentrations were more likely to remain within the reference range regardless of severity of disease.

CONCLUSIONS

Results indicate that serum total T4, free T4, and total T3 concentrations may be low (ie, in the hypothyroid range) in dogs with moderate to severe nonthyroidal disease. Serum TSH concentrations are more likely to remain within the reference range in sick dogs.

BACKGROUND

Congenital hypothyroidism is known to be associated with mental retardation which, if recognized promptly, is largely prevented by thyroid hormone replacement. Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity, and is also associated with neurodevelopmental delay. Fetuses with IUGR have reduced circulating concentrations of free thyroxine (T4) and free triiodothyronine (T3), leading to the hypothesis that a reduction in the tissue effects of thyroid hormones in the central nervous system (CNS) may contribute to neurodevelopmental morbidity. Since thyroid hormone effects are mediated through binding to specific nuclear thyroid hormone receptors (TRs), we have defined the pattern of TR isoform expression in the CNS throughout normal human development and have compared TR expression in the CNS of normal fetuses with those affected by IUGR.

METHODS

Samples of normal human fetal brain from first and second trimesters were obtained at surgical termination of pregnancy. Appropriately grown and third trimester fetuses affected by Intrauterine growth restriction (IUGR) were also investigated after unexplained stillbirth at post mortem examination. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to examine the expression of TR isoform mRNAs in frozen cerebral cortex from 10 to 16 weeks gestation. TR protein expression in human fetal brains (both cerebral hemispheres and cerebellum) was also examined in formalin fixed sections and expression of TR alpha1, alpha2, beta1 and beta2 isoforms being defined using semiquantitative immunocytochemistry.

RESULTS

RT-PCR revealed the presence of mRNAs encoding TR alpha1, beta1 and beta2 isoforms and the nonfunctional TRalpha2 variant in the fetal cerebral cortex from week 10 of human pregnancy. Immunostaining of the fetal brain revealed TR alpha1 and alpha2 protein from week 11 of human gestation. Expression of all TR isoform proteins was largely confined to the pyramidal neurones of the cerebral cortex and the Purkinje cells of the cerebellum with increasing receptor expression evident with gestational age. Semiquantitative observer scoring showed that by the second trimester, there was a marked increase in the proportion of pyramidal and Purkinje cells expressing TR isoforms, while by the third trimester, all these cells immunostained. Comparison of TR immunostaining in the cerebral cortex and cerebellum from IUGR fetuses (n = 18) matched for gestational age to normal fetuses revealed a lower intensity of expression of all the TR isoforms confirmed by observer scoring and quantification using TR protein immunofluoresence (P<0.01).

CONCLUSIONS

Our findings indicate both pre- and post-translational expression of TR alpha and beta isoforms in the cerebral cortex of first trimester fetuses. These findings support the view that the transplacental passage of thyroid hormone in early gestation may be critical to neurological development. Our finding that in severe IUGR the expression of TR isoforms in the human fetal cerebral cortex and cerebellum was significantly reduced, in association with reduced circulating thyroid hormone concentrations indicate that changes in free ligand and receptors may affect CNS development. These findings should prompt further investigation of the potential therapeutic role of peripartum thyroid hormone treatment.

OBJECTIVE

Endocrine parameters have proven useful in the detection of early or low-level responses to pollutants. Although most of the studies on endocrine modulation have been focused on processes involving gonadal steroids, contaminants may target other parts of the endocrine system as well. In this study we examined the adrenocortical stress response and thyroid hormone status in free-living nestling white storks (Ciconia ciconia) in relation to heavy metals (zinc, lead, copper, cadmium) and arsenic levels in blood.

METHODS

Fieldwork was conducted in an area polluted by the Aznalcóllar mine accident (southwestern Spain) and in a reference site. We used a standardized capture, handling, and restraint protocol to determine both baseline and maximum plasma corticosterone. Circulating levels of thyroxine (T4) and triiodothyronine (T3) were also measured.

RESULTS

No effects of metals or As were found on baseline corticosterone, but maximum levels of corticosterone were positively related to Pb in both locations. This relationship was stronger in single nestlings than in birds from multiple-chick broods, which suggests a greater impact of Pb on more stressed individuals. Metal pollution did not affect plasma T4 or T3 levels, although thyroid status differed with location.

CONCLUSIONS

Because a compromised hypothalamus-pituitary-adrenal (HPA) function can have far-reaching consequences in terms of altered behavioral and metabolic processes necessary for survival, our results suggest that birds exposed to sublethal Pb levels may be at risk through an altered adrenocortical stress response, and further support the idea that HPA axis-related end points might be useful indicators of metal exposure and potential toxicity in wild animals.

Because of suggestions that thyroid hormones modulate serum lipoprotein(a) [Lp(a)] concentration, we evaluated prospectively the serial changes of serum Lp(a), measured as apolipoprotein(a) [apo(a)], and other lipoproteins in 40 subjects with hyperthyroidism treated with radioactive iodine (RAI) therapy. Hyperthyroid patients had lower (P < 0.001) concentrations of apo(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apo B, but higher apo A-I concentrations compared with age-matched controls [geometric mean (range)]; apo(a) 81 (17-614) vs 187 (17-1808 IU/L): TC 4.07 +/- 0.8 vs 5.22 +/- 1.00 mmol/L (mean +/- SD); LDL-C 2.47 +/- 0.89 vs 3.40 +/- 0.88 mmol/L; HDL-C 1.05 +/- 0.33 vs 1.24 +/- 0.34 mmol/L; apo B 0.66 +/- 0.23 vs 1.13 +/- 0.34 g/L, and apo A-I 2.07 +/- 0.42 vs 1.46 +/- 0.28 g/L, respectively. Euthyroidism was associated with normalization of serum TC, LDL-C, and apo B within 1 month of treatment. However, apo(a) required 4 months to normalize, and HDL-C and apo A-I were still abnormal 6 months after RAI. Serum apo(a), TC, LDL-C, and apo B were negatively correlated with serum thyroxine (T4), free thyroxine index, and triiodothyronine (T3) and positively correlated with thyrotropin during the transitional period from hyperthyroidism to euthyroidism. Parallel changes of these lipoproteins and thyroid hormones were also observed after treatment of hyperthyroidism. In conclusion, thyroid hormones do modulate lipoproteins, particularly Lp(a). The delay in normalization of apo(a) but not LDL suggests an effect on apo(a) production rather than on LDL removal.

Because the cutaneous permeability barrier develops late in gestation, prematurity may result in increased morbidity and mortality due to barrier incompetence. The purpose of the present study was to develop an in vitro model of barrier ontogenesis in order to identify those factors critical for fetal barrier formation. Skin explants from gestational day 17 fetal rats (term is 22 days) were incubated in hormone- and serum-free media. After 4 d in culture, a multi-layered stratum corneum (SC) developed that demonstrated a membrane pattern of fluorescence using the hydrophobic probe, nile red, and the deposition of mature lamellar unit structures throughout the SC interstices, ultrastructurally. Transepidermal water loss rates declined during explant culture such that after 4 d a competent barrier was present. Similarly, lanthanum permeation studies showed tracer penetration into all cell layers in 2-d explants, whereas it did not penetrate above the stratum granulosum in 4-d explants. Thus, the chronology of epidermal development in the explants precisely mirrored that observed in utero. Treatment with either 10 nM dexamethasone or 10 nM triiodothyronine accelerated SC development and barrier formation by 2 d. These results indicate that (i) the late events of fetal epidermal development progress in vitro under serum- and growth factor-free conditions, culminating in the formation of a functional barrier, and (ii) both dexamethasone and triiodothyronine accelerate barrier development.

Human skin fibroblasts synthesize and accumulate glycosaminoglycans (GAG). Recently, we reported that fibroblasts incubated in thyroid hormone-deficient media accumulate more GAG than do cultures incubated in the same media enriched with 0.1 muM triiodothyronine (T(3)) (1981. Endocrinology. 108: 2397). The current study characterizes that enhanced accumulation. Confluent cultures were maintained in thyroid hormone-deficient media without or with added T(3), labeled with [(3)H]acetate and analyzed for total [(3)H]GAG and [(3)H]hyaluronic acid content. Addition of T(3) to thyroid hormone-depleted media consistently inhibited the incorporation of [(3)H]acetate into GAG by 28-60% in fibroblast cultures from four different normal human donors. Maximal inhibitory effect was observed within 3 d after hormone addition at concentrations>> 1 nM. 73% of the maximal inhibitory effect was observed in the presence of physiologic concentrations of T(3) (0.16 nM total T(3) or 1.4 pM free T(3)). The following observations indicated that T(3) inhibition of [(3)H]GAG accumulation is most likely due to a decrease in GAG synthesis rather than to changes in the acetate pool or GAG degradation: (a) Addition of 0, 100, 500, and 2,500 muM unlabeled acetate progressively decreased [(3)H]acetate incorporation into GAG, up to 80%, without altering the further inhibitory effect of T(3) (35-40%); (b). A similar effect of T(3) on GAG (32% inhibition) was observed using [(3)H]glucosamine as substrate; (c) T(3) decreased hyaluronate synthetase activity by 32%; and (d) There was no effect of T(3) on GAG degradation in a pulse-chase experiment. The effect of T(3) on [(3)H]GAG accumulation appears to be quite specific, since the hormone had no effect on the incorporation of [(3)H]leucine into trichloroacetic acid-precipitable material.Thus, thyroid hormone inhibits GAG accumulation in a dose-, time-dependent, and reversible manner. This inhibition is apparently due to specific effects on the rate of macromolecular synthesis.

Serum thyroid hormone concentrations increase after radioiodine (RAI) therapy for Graves' disease. This phenomenon has been ascribed to either antithyroid drug withdrawal before RAI therapy or release of preformed thyroid hormones into the bloodstream from the RAI-damaged thyroid. Lithium blocks the release of iodine and thyroid hormones from the thyroid, thus enhancing the effectiveness of RAI therapy. Changes in serum-free thyroxine (FT4) and triiodothyronine (FT3) levels after methimazole (MMI) discontinuation and RAI therapy were evaluated in a prospective, randomized, control study of 36 patients with Graves' disease. After a 3- to 4-month course of MMI, patients were assigned to one of three groups: G1 (RAI alone); G2 (RAI plus lithium for 6 d starting on the day of RAI therapy); or G3 (RAI plus lithium for 19 d starting on the day of MMI withdrawal). G1-G2 patients had an increase in serum FT4 and FT3 levels from 13.5 +/- 6.5 to 19.8 +/- 9.2 pmol/liter and 5.0 +/- 2.0 to 8.0 +/- 4.8 pmol/liter, respectively (P < 0.0001), 2-5 d after MMI withdrawal, but G3 patients showed no changes. In the 30 d after RAI therapy, mean serum FT4 values increased in G1 patients (P = 0.02), peaking at 3-7 d (P < 0.05) but not in G2 and G3 patients. Serum FT3 levels decreased in G1, G2, and G3 (P = 0.03, P = 0.001, P = 0.02, respectively). Hyperthyroidism was cured in 8 of 12 G1 patients, 11 of 12 G2 patients, and 11 of 12 G3 patients (P = 0.31). Control of hyperthyroidism was prompter in G2 (P = 0.08) and G3 (P < 0.05) than in G1 patients. Patients in the three groups received a similar dose of RAI, but the committed radiation to the thyroid was higher in G3 (563 +/- 174 Gray) and G2 (588 +/- 347 Gray) than in G1 (429 +/- 204 Gray) (P < 0.03). In conclusion, the results of the present study demonstrate that: 1) MMI withdrawal is associated with a slight rise in serum thyroid hormone levels; 2) a further increase occurs after RAI therapy; 3) changes in serum thyroid hormone concentrations are prevented by lithium; and 4) the increased effectiveness of RAI therapy in lithium-treated patients is related to the increased RAI retention in the thyroid gland. Accordingly, a short course of lithium therapy can be considered a useful adjunct to RAI therapy to obtain a prompter control of thyrotoxicosis and avoid its transient exacerbation because of MMI withdrawal and RAI administration.

BACKGROUND

The hormonal factors involved in the regulation of peak bone mass (PBM) in men have not been fully investigated. Apart from gonadal steroids and somatotropic hormones, thyroid hormones are known to affect bone maturation and homeostasis and are additional candidate determinants of adult bone mass.

OBJECTIVE

We aimed to investigate between-subject physiological variation in free and total thyroid hormone concentrations, TSH, and thyroid binding globulin (TBG) in relation to parameters of bone mass, geometry, and mineral density in healthy men at the age of PBM.

METHODS

We recruited 677 healthy male siblings aged 25-45 years in a cross-sectional, population-based study. Areal and volumetric bone parameters were determined using dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Total and free thyroid hormones, TBG, and TSH were determined using immunoassays.

RESULTS

Free and total thyroid hormone concentrations were inversely associated with bone mineral density (BMD) and bone mineral content (BMC) at the hip and total body (free triiodothyronine (FT(3)), total T(3) (TT(3)), and total T(4) (TT(4))) and at the spine (FT(3)). TBG was negatively associated with BMC and areal BMD at all sites. At the radius, cortical bone area was inversely associated with TT(3), TT(4), and TBG, and trabecular bone density was inversely associated with free thyroxine, TT(4), and TBG. We observed inverse associations between cortical bone area at the mid-tibia and FT(3), TT(3), TT(4), and TBG. No associations between TSH and DXA or pQCT measurements were found.

CONCLUSIONS

In healthy men at the age of PBM, between-subject variation in thyroid hormone concentrations affects bone density, with higher levels of FT(3), TT(3), TT(4), and TBG being associated with less favorable bone density and content.

The symptomatology of the fibromyalgia syndrome (FMS) often resembles an alteration in central nervous set points at least in three systems. The patients suffer under chronic pain in the region of the locomotor system, presumably reflecting a disturbed central processing of pain. Anxiety and depression often characterizes the clinical picture. Almost all of the hormonal feedback mechanisms controlled by the hypothalamus are altered. Characteristic for FMS patients are the elevated basal values of ACTH, follicle-stimulating hormone (FSH), and cortisol as well as lowered basal values of insulin-like growth factor 1 (IGF-1, somatomedin C), free triiodothyronine (FT3), and oestrogen. In FMS patients, the systemic administration of the relevant releasing hormones of corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), thyreotropin-releasing hormone (TRH), and luteinizing hormone-releasing hormone (LHRH) leads to increased secretion of ACTH and prolactin, whereas the degree to which TSH can be stimulated is reduced. The stimulation of the hypophysis with LHRH in female FMS patients during their follicular phase results in a significantly reduced LH response. All in all, the typical alterations in set points of hormonal regulation that are typical for FMS patients can be explained as a primary stress activation of hypothalamic CRH neurons caused by the chronic pain. In addition to the stimulation of pituitary ACTH secretion, CRH activates somatostatin on the hypothalamic level, which in turn inhibits the release of GH and TSH on the hypophyseal level. The lowered oestrogen levels could be accounted for both via an inhibitory effect of the CRH on the hypothalamic release of LHRH or via a direct CRH-mediated inhibition of the FSH-stimulated oestrogen production in the ovary. Serotonin (5HT), precursors like tryptophan (5HTP), drugs which release 5HT or act directly on 5HT receptors stimulate HPA axis, indicating a stimulatory serotonergic influence on HPA axis function. Therefore activation of the HPA axis may reflect an elevated serotonergic tonus in the central nervous system of FMS patients.

BACKGROUND

Nanotechnology has enabled researchers to synthesize nanosize particles that possess increased surface areas. Compared to conventional microparticles, it has resulted in increased interactions with biological targets.

OBJECTIVE

The objective of this study was to determine the protective ability of selenium nanoparticles against hexavalent chromium-induced thyrotoxicity.

METHODS

Twenty male rats were used in the study, and arbitrarily assigned to four groups. Group 1 was the control group, and was given phosphate-buffered saline. Group 2 was the chromium-treated group and was given K2Cr2O7 60 μg/kg body weight intraperitoneally as a single dose on the third day of administration. Group 3 was the nano-selenium-treated group and was given selenium nanoparticles (size 3-20 nm) 0.5 mg/kg body weight intraperitoneally daily for 5 consecutive days. Group 4 was the nano-selenium chromium-treated group, which received selenium nanoparticles for 5 days and a single dose of K2Cr2O7 on the third day of administration.

METHODS

Blood samples were collected from rats for measuring thyroid hormones (free triiodothyronine [T3] and free thyroxine [T4]) and oxidative and antioxidant parameters (malondialdehyde [MDA], reduced glutathione [GSH], catalase, and superoxide dismutase [SOD]). Upon dissection, thyroid glands were taken for histopathological examination by using paraffin preparations stained with hematoxylin and eosin (H&E) and Masson's trichrome. Immunohistochemical staining was performed for detecting cellular proliferation using Ki67 antibodies.

RESULTS

The present study shows that K2Cr2O7 has a toxic effect on the thyroid gland as a result of inducing a marked oxidative damage and release of reactive oxygen species. This was shown by the significant decrease in free T3 and T4 and GSH levels, which was accompanied by significant increases in catalase, SOD, and MDA in the chromium-treated group compared to the control group. Se nanoparticles have a protective effect on K2Cr2O7-induced thyroid damage, as a result of correcting the free T3 and T4 levels and GSH, catalase, SOD, and MDA compared to the K2Cr2O7-treated group. Administration of nano-selenium alone in the nano-selenium-treated group had no toxic effect on rats' thyroid compared to the control group. The biochemical results were confirmed by histopathological, immunohistochemical and pathomorphological studies.

The role of thyroid hormone [L-3,5,3'-triiodothyronine (T3)] and the thyroid hormone receptor (TR) in regulating growth, development, and metabolic homeostasis is well established. It is also emerging that T3 is associated with oxidative stress through the regulation of the activity of superoxide dismutase-1 (SOD-1), a key enzyme in the metabolism of oxygen free radicals. We found that T3 reverses the activation of the SOD-1 promoter caused by the free radical generators paraquat and phorbol 12-myristate 13-acetate through the direct repression of the SOD-1 promoter by liganded TR. Conversely, the SOD-1 promoter is significantly stimulated by unliganded TRs. This regulation requires the DNA-binding domain of the TR, which is recruited to an inhibitory element between -157 and +17 of the SOD-1 promoter. TR mutations, which abolish recruitment of coactivator proteins, block repression of the SOD-1 promoter. Conversely, a mutation that inhibits corepressor binding to the TR prevents activation. Together, our findings suggest a mechanism of negative regulation in which TR binds to the SOD-1 promoter but coactivator and corepressor binding surfaces have an inverted function. This effect may be important in T3 induction of oxidative stress in thyroid hormone excess.

BACKGROUND

Subclinical hypothyroidism (SH) represents the mildest form of thyroid hormone deficiency and may be associated with adverse consequences [Subclinical hypothyroidism was defined as a TSH level>> 4.0 mIU/L and a normal free thyroxine level 0.6-1.8 ng/dL]. The identification of patients with subclinical hypothyroidism having an increased cardiovascular risk (CVR) is important. The aim of the study was to evaluate atherosclerotic risk factors in patients with subclinical hypothyroidism.

METHODS

Forty patients with subclinical hypothyroidism and forty healthy euthyroid controls, age and gender matched were included in the study. Serum total triiodothyronine (T3), thyroxine (T4), TSH, free T3 (FT3) and free T4 (FT4) were measured by enzyme linked immunosorbent assay (ELISA). Atherosclerotic risk factors measured were high sensitivity-CRP (hs-CRP), Lipoprotein (a) [Lp (a)] and lipid parameters. Lipid parameters (triglycerides, total cholesterol and high density lipoprotein cholesterol) were analysed by enzymatic colorimetric, endpoint method whereas the hs-CRP and Lp (a) were measured by quantitative latex turbidimetric method.

RESULTS

Patients with subclinical hypothyroidism had significantly higher levels of serum hs-CRP, Lp (a), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) when compared to same parameters of controls. Further, a significant positive correlation was observed between TSH and hs-CRP, Lp (a), LDL-C and TC in subjects with subclinical hypothyroidism. However, TG levels showed no significant correlation with TSH levels.

CONCLUSIONS

We concluded that the SH patients presented increased concentration of some CVR factors. The potential benefits of diagnosis and treatment of subclinical hypothyroidism may have possible advantages firstly by preventing the progression to overt hypothyroidism and secondly decrease the risk of death from cardiovascular disease (CVD) by starting appropriate therapy to improve lipid parameters. Further research is needed on subclinical hypothyroidism and the associated atherosclerotic risk factors.

BACKGROUND

Serum free triiodothyronine (fT3) level is suggested to be a risk factor for mortality in unselected dialysis patients. We investigated the prognostic value of serum fT3 levels and also low-T3 syndrome on overall survival in a large cohort of hemodialysis (HD) patients with normal thyroid-stimulating hormone levels.

METHODS

A total of 669 prevalent HD patients were enrolled in the study. Serum fT3 level was measured by enzyme immune assay in frozen sera samples at the time of enrollment. Overall mortality was assessed during 48 months of follow-up.

RESULTS

Baseline fT3 was 1.47 ± 0.43 (0.01-2.98) pg/ml, and low-T3 syndrome was present in 71.7% of the cases. During a mean follow-up of 34 ± 16 months, 165 (24.7%) patients died. fT3 level was a strong predictor for mortality in crude and adjusted Cox models including albumin or high-sensitivity C-reactive protein (hs-CRP). Further adjustment for both albumin and hs-CRP made the impact of fT3 on mortality disappear. The presence of low-T3 syndrome was associated with mortality in only the unadjusted model.

CONCLUSIONS

Low-T3 syndrome is a frequent finding among HD patients, but it does not predict outcome. However, serum fT3 level is a strong and inverse mortality predictor, in part explained by its underlying association with nutritional state and inflammation.