Transthyretin (TTR) is the principal carrier of thyroid hormones in rodent plasma and the major protein synthesized by the choroid plexus. Mice lacking TTR generated by targeted disruption (Episkopou, V., Maeda, S., Nishiguchi, S., Shimada, K., Gaitanaris, G. A., Gottesman, M. E., and Robertson, E. J. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2375-2379) had a 50% decrease in total thyroxine (T4) plasma levels but had normal free hormone levels as compared to wild-type mice. In the mutant serum there was increased T4 binding to thyroxine-binding globulin. Thyroxine-binding globulin mRNA levels were the same in mutant and wild-type animals. Wild-type serum depleted of TTR also presented increased T4 binding to thyroxine-binding globulin, suggesting that TTR competes with thyroxine-binding globulin for T4 binding. Total and free triiodothyronine and thyrotoropin-stimulating hormone levels were not affected by the absence of TTR. Liver deiodinase-I activity, mRNA levels, and brain deiodinase-II activity were normal in the mutant mice, suggesting that the absence of TTR does not affect tissue thyroid hormone content. The low T4 levels found in the mutant mice sera cannot be accounted for by increased glucuronidation because the liver activity of UDP-glucuronosyltransferase was not affected in the TTR-deficient mice. We concluded that transthyretin-deficient mice are euthyroid in the absence of the major plasma T4 carrier. We ascribed this to the normal free hormone levels in the serum of the mutant mice. Our data, therefore, strongly supported the free hormone hypothesis for thyroxine uptake (Mendel, C. M. (1989) Endocr. Rev. 10, 232-274).

OBJECTIVE

A low triiodothyronine (T3) state is highly prevalent and is associated with a poor prognosis in critically ill patients. The authors investigated, in patients undergoing brain tumor surgery, the direct association of a perioperative low T3 syndrome with clinical outcomes and also with symptoms of depression and anxiety.

METHODS

Ninety consecutive patients (71% women, median age 55 years), on admission for brain tumor surgery, were evaluated for sociodemographic and clinical characteristics. Their thyroid function profile was assessed on the morning of brain tumor surgery and on the morning after brain tumor surgery. Patients with free T3 concentrations of 3.1 pmol/L or less were considered to have low T3 syndrome. The patients were evaluated for symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) before and after surgery and for clinical outcomes using the Glasgow Outcome Scale (GOS) at discharge.

RESULTS

After brain tumor surgery, free T3 concentrations decreased (p < 0.001) and the proportion of patients with low T3 levels increased from 38% to 54% (p = 0.02). Lower preoperative (rho = 0.30, p = 0.004) and postoperative (rho = 0.33, p = 0.002) free T3 concentrations correlated with low GOS scores at discharge. Preoperative low T3 syndrome (OR 5.49, 95% CI 1.27-23.69, p = 0.02) and postoperative low T3 syndrome (OR 8.73, 95% CI 1.49-51.21, p = 0.02) both increased risk for unfavorable clinical outcomes (GOS scores < 5) at discharge, after adjusting for age, sex, histological diagnosis of brain tumor, preoperative functional impairment, previous treatment for brain tumor, and depressive symptoms. Preoperative low T3 syndrome increased the risk for preoperative (HADS-depression subscale score ≥ 11; OR 4.12, 95% CI 1.16-14.58, p = 0.03) but not postoperative depressive symptoms independently from sociodemographic and clinical factors.

CONCLUSIONS

Low T3 syndrome is a strong independent predictor of unfavorable clinical outcomes and depressive symptoms, and its diagnosis and preoperative management should be considered in patients undergoing neurosurgery for the treatment of brain tumors.

Total cellular creatine content is an important bioenergetic parameter in skeletal muscle. To understand its regulation we investigated creatine transport and accumulation in the G8 cultured skeletal myoblast line. Like other cell types, these contain a creatine transporter, whose activity, measured using a radiolabelling technique, was saturable (Km = 110 +/- 25 microM) and largely dependent on extracellular [Na+]. To study sustained influences on steady state creatine concentration we measured total cellular creatine content using a fluorimetric method in 48 h incubations. We found that the total cellular creatine content was relatively independent of extracellular creatine concentration, consistent with high affinity sodium-dependent uptake balanced by slow passive efflux. Accordingly, in creatine-free incubations net creatine efflux was slow (5 +/- 1% of basal creatine content per day over 6 days), while creatine content in 48 h incubations was reduced by 28 +/- 13% of control by the Na+, K(+)-ATPase inhibitor ouabain. Creatine accumulation after 48 h was stimulated by treatment with the mixed alpha- and beta-adrenergic agonist noradrenaline, the beta-adrenergic agonist isoproterenol, the beta 2-agonist clenbuterol and the cAMP analogue N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate, but was unaffected by the alpha 1 adrenergic agonist methoxamine. The noradrenaline enhancement of creatine accumulation at 48 h was inhibited by the mixed alpha- and beta-antagonist labetalol and by the beta-antagonist propranolol, but was unaffected by the alpha 2 antagonist phentolamine; greater inhibition was caused by the beta 2 antagonist butoxamine than the beta 1 antagonist atenolol. Creatine accumulation at 48 h was increased to 230 +/- 6% of control by insulin and by 140 +/- 13% by IGF-I (both at 3 nM). Creatine accumulation at 48 h was also increased to 280 +/- 40% of control by 3,3',5-triiodothyronine (at 70 microM) and to 220 +/- 35% of control by amylin (60 nM). As 3,3', 5-triiodothyronine, amylin and isoproterenol all stimulate the Na+, K(+)-ATPase, we suggest that they stimulate Na(+)-creatine cotransport indirectly by increasing the transmembrane [Na+] concentration gradient and membrane potential.

OBJECTIVE

Thyroid hemiagenesis (THA) is an anomaly resulting from the developmental failure of one thyroid lobe. Etiopathogenesis, clinical significance, and management of patients in whom THA is diagnosed are still a matter of debate. The aim of the study is to provide the first systematic analysis of a large cohort of subjects with THA.

METHODS

Forty patients with THA are described in comparison to a control group of 80 subjects with fully developed thyroid gland.

METHODS

Serum concentrations of thyrotropin (TSH), free thyroxine (FT(4)), free triiodothyronine (FT(3)), and thyroid autoantibodies were measured. In 37 patients, thyroid ultrasonography and Tc-99m thyroid scintiscan were performed, followed by fine-needle aspiration biopsy if indicated. The remaining archival three cases were diagnosed with the use of I-131 scintiscan under basal conditions and after TSH stimulation.

RESULTS

Patients with THA, while usually clinically euthyroid, presented with significantly higher levels of TSH and FT(3) as well as with higher FT(3)/FT(4) concentration in comparison to the control group. Furthermore, a higher incidence of associated functional, morphological, and autoimmune thyroid disorders in patients with THA was observed when compared to subjects with bilobate thyroid (P<0.05).

CONCLUSIONS

Our results revealed that individuals with THA are more likely to develop thyroid pathology. The observed high incidence of associated pathologies is presumably due to long-lasting TSH overstimulation. Therefore, THA diagnosis should be followed by systematic observation and adequate levothyroxine treatment in patients with elevated TSH level.

OBJECTIVE

As hormones are strongly associated with mortality in critically ill patients, we investigated whether mortality prediction based on the Acute Physiology and Chronic Health Evaluation (APACHE) is improved by combining this score with hormone measurements.

METHODS

Intensive care units in three hospitals.

METHODS

113 patients admitted to.

METHODS

Within the first hour after ICU admission we measured total triiodothyronine, total thyroxine, free thyroxine, thyrotropin, cortisol, growth hormone, dehydroepiandrosterone, and prolactin levels and administered the APACHE. Patients were followed until they died or were discharged from the ICU.

RESULTS

The best logistic regression model for ICU mortality included the APACHE score and thyroid-stimulating hormone and triiodothyronine levels. This model had an area under the receiver operating characteristic curve of 0.88, significantly higher than the APACHE score alone with 0.75. The model with hormone levels and APACHE score was also significantly better calibrated than the model with only the APACHE score.

CONCLUSIONS

The addition of thyroid hormones to the APACHE score improves the prediction of mortality for ICU patients.

Our previous data showed that vitamin A deficiency (VAD) induces, in whole brain, a reduced amount of mRNA for brain retinoic acid (RA) and triiodothyronine (T3) nuclear receptors (i.e., RAR, RXR, and TR, respectively), which is accompanied by reduced amounts of mRNA and protein of neurogranin (RC3, a neuronal protein involved in synaptic plasticity) as well as selective behavioral impairment. Given the important role of retinoids for optimal brain functioning, the effects of vitamin A depletion and subsequent administration of RA or T3 on the mRNA levels of RA and T3 nuclear receptors and on two target genes' (RC3 and neuromodulin or GAP43) mRNA and protein levels were examined in the hippocampus, striatum, and cerebral cortex. A quantitative real-time polymerase chain reaction (PCR), in situ hybridization, and Western blot analysis demonstrated that the striatal region is the brain site where both RA and T3 signaling pathways are most affected by VAD. Indeed, rats fed a vitamin A-free diet for 10 weeks exhibited decreased expression of RAR, RXR, TR, RC3, and GAP43 in the striatum. The administration of T3 to these vitamin A-deprived rats reversed the reduction in mRNA levels of RA and T3 nuclear receptors and in mRNA and protein levels of target genes in this region. These data suggest that modifications that appear preferentially in the striatum, a region highly sensitive to vitamin A bioavailability, may contribute to neurobiological alterations and the spatial learning impairment that occurs in vitamin A-deprived animals.

BACKGROUND

The purpose of this study was to examine the relationship of phthalates exposure with thyroid function in pregnant women and their newborns.

METHODS

One hundred and forty-eight Taiwanese maternal and infant pairs were recruited from E-Da hospital in southern Taiwan between 2009 and 2010 for analysis. One-spot urine samples and blood samples in the third trimester of pregnant women and their cord blood samples at delivery were collected. Nine phthalate metabolites in urine were determined by triple quadrupole liquid chromatography tandem mass spectrometry, whereas serum from pregnant women and their cord blood were used to measure thyroid profiles (thyroid-stimulating hormone [TSH], thyroxine, free thyroxine, and triiodothyronine) by radioimmunoassay.

RESULTS

Median levels of urinary mono-n-butyl phthalate, mono-ethyl phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate (μg/g creatinine) were the three highest phthalate metabolites, which were 37.81, 34.51, and 21.73, respectively. Using Bonferroni correction at a significance of < 0.006, we found that urinary mono-benzyl phthalate (MBzP) levels were significantly and negatively associated with serum TSH in cord blood (β = -2.644, p = 0.003).

CONCLUSIONS

Maternal urinary MBzP, of which the parental compound is butylbenzyl phthalate, may affect TSH activity in newborns. The alteration of thyroid homeostasis by certain phthalates in the early life, a critical period for neurodevelopment, is an urgent concern.

Muscle glutamine concentration ([GLN]) and protein synthesis rate (Ks) have been examined in vivo in well-fed, protein-deficient, starved, and endotoxemic rats. With protein deficiency (8 or 5% casein diet), [GLN] fell from 7.70 to 5.58 and 3.56 mmol/kg in the 8 and 5% diet groups, with Ks falling from 15.42 to 9.1 and 6.84%/day. Three-day starvation reduced [GLN] and Ks to 2.38 mmol/kg and 5.6%/day, respectively. In all these groups food intakes and insulin were generally well maintained (except in the starved group), whereas free 3,5,3'-triiodothyronine (T3) was depressed in the starved and 5% protein group. The E. coli lipopolysaccharide endotoxin (3 mg/kg) reduced [GLN] to 5.85 and 4.72 mmol/kg and Ks to 10.5 and 9.10%/day in two well-fed groups. Insulin levels were increased, and free T3 levels fell. Combined protein deficiency and endotoxemia further reduced [GLN] and Ks to 1.88 mmol/kg and 4.01%/day, respectively, in the 5% protein rats. Changes in both ribosomal activity (KRNA) and concentration (RNA/protein) contributed to the fall in Ks in malnutrition and endotoxemia, although reductions in the RNA concentration were most marked with protein deficiency and reductions in the KRNA dominated the response to the endotoxin. The changes in [GLN] and Ks were highly correlated as were [GLN] and both KRNA and the RNA concentration, and these relationships were unique to glutamine. These relationships could reflect sensitivity of glutamine transport and protein synthesis to the same regulatory influences, and the particular roles of insulin and T3 are discussed, as well as any direct influence of glutamine on protein synthesis.

BACKGROUND

Overt thyroid dysfunction, hypothyroidism in particular, may lead to coronary artery disease (CAD). Whether more subtle anomalies of thyroid hormone metabolism influence the progression of CAD remains a matter of speculation.

OBJECTIVE

The occurrence of CAD and long-term prognosis in patients without a history of either primary thyroid disease, myocardial infarction, or chronic heart failure is related to serum levels of biologically active free triiodothyronine (fT3).

METHODS

The cohort consisted of 1047 clinically and biochemically euthyroid patients (median age 65.6 y and 69% male) who underwent coronary angiography in our institute for suspected CAD.

RESULTS

Lower fT3 levels were predictive of both single-vessel (p = 0.012) and multivessel (p = 0.009) CAD. Through a multivariate logistic regression analysis, fT3 was still linked to the presence of CAD (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.34-0.68, p < 0.001). After a mean follow-up of 31 months, the survival rate was 95% and total mortality (log-rank 6.75, p = 0.009), as well as cardiac mortality (log-rank 8.26, p = 0.004), was greater among patients with low T3 (fT3 < 2.10 pg/mL) syndrome. At subsequent multivariate Cox regression analysis, the association between low T3 syndrome and survival was maintained (total mortality HR: 1.80, 95% CI: 1.05-3.10, p = 0.034; cardiac mortality HR: 2.58, 95% CI: 1.13-5.93, p = 0.025).

CONCLUSIONS

In this selected population, fT3 levels were inversely correlated to the presence of CAD and low T3 syndrome conferred an adverse prognosis, even after adjusting for traditional coronary risk factors.

BACKGROUND

Different studies, mostly cross-sectional, have found an association between low levels of thyroid hormones, even within the normal range, and a greater body mass index. The aim of this study was to determine the association between thyroid function and the risk for obesity.

METHODS

In this population-based prospective study, measurements were made of anthropometric parameters, thyroid hormone function and urinary iodine in a cohort of the Pizarra Study (n = 937), and repeated 6 years later (n = 784). At the second point, measurements were also made of leptin and adiponectin.

RESULTS

Among the persons who were not obese at the start of the study, the odds ratio (OR) of becoming obese for those in the fourth quartile (Q(4)) for free triiodothyronine (FT3) (versus those in Q(1)) was 2·94 (1·46-5·90) (P = 0·005). The OR of becoming obese in persons in Q(4) of FT4 (versus those in Q(1)) was 3·06 (1·23-7·43) (P = 0·01). Those persons in Q(4) of weight gain had a higher FT3 at the 6-year follow-up than those whose weight gain was in Q(1) (P < 0·001). Leptin correlated with thyrotropin (β = 0·58, P = 0·001) and the FT4 (β = -1·12, P = 0·005). Adiponectin correlated with FT3 (r = -0·24, P < 0·001). The urinary iodine correlated negatively with both the BMI (β = -0·08, P = 0·01) and the increase in weight (β = -0·08, P = 0·04).

CONCLUSIONS

The changes in the thyroid hormones could be the consequence, rather than the cause, of the increase in weight. The same pathophysiological mechanisms that induce obesity might also be modifying the thyroid hormone pattern.

Daily vaginal douching with polyvinylpyrrolidone-iodine in 12 euthyroid volunteers for 14 days resulted in a significant increase in serum total iodine concentration and urine iodine excretion. The increase in serum total iodine was associated with a marked decrease in 24-hour iodine 123 uptake by the thyroid and a small but significant increase in serum thyrotropin (TSH) concentration. However, values for serum TSH never rose above the normal range. No significant changes in serum thyroxine (T4), free T4 index (FTI), or triiodothyronine concentrations were observed, although serum T4 and FTI did decrease slightly during treatment. The findings suggest that iodine is absorbed across the vaginal mucosa and that the subsequent increase in serum total iodine does induce subtle increases in serum TSH concentration. There was no evidence, however, of overt hypothyroidism in these euthyroid women.

Patients with severe nonthyroidal illnesses (NTIs) frequently have decreased serum concentrations of triiodothyronine (T3) and less often of thyroxine (T4) without clear evidence of hypothyroidism. To determine whether T3 and T4 levels are also reduced in the tissues, we analyzed autopsy samples from 12 patients dying of NTI and 10 previously healthy individuals dying suddenly from trauma. Mean serum T3, T4, and free T4 index values were lower by 79%, 71%, and 49%, respectively, in the NTI group than in controls, but serum thyrotropin (TSH) values did not differ significantly. Mean T3 concentrations in cerebral cortex, hypothalamus, pituitary, liver, kidney, and lung were lower in the NTI group than in controls by 43% to 76%, but mean values in heart and skeletal muscle did not differ significantly between the groups. The mean liver T4 concentration was 66% lower in the NTI group, but mean T4 concentrations in the cerebral cortex were similar in the two groups. These results indicate that many tissues may be deficient in thyroid hormones in patients with fatal NTI, although the severity of the reduction in thyroid hormone concentrations may vary from one organ to another.

BACKGROUND

The severity of critical illness is associated with various patterns of thyroid hormone abnormalities. We sought to evaluate whether the outcome of patients with, specifically, sepsis or septic shock is associated with the thyroid function tests evaluated at diagnosis or admission in the intensive care unit (ICU).

METHODS

We performed a systematic review of relevant studies by searching PubMed.

RESULTS

We included nine studies that all had a prospective cohort design. Seven involved children or neonates, and two involved adults. Mortality was the outcome evaluated in eight studies, while the length of ICU stay was evaluated in the remaining study. In univariate analysis, six of the nine included studies showed that either, free or total, triiodothyronine or thyroxine was lower in the group of patients with sepsis or septic shock who had unfavorable outcome than in those who had favorable outcome. Two other studies showed higher TSH values in the group of patients with unfavorable outcome. No significant relevant findings were observed in the remaining study. Regarding the correlation of sepsis prognostic scoring systems with thyroid function tests, the three studies that provided specific relevant data showed variable findings.

CONCLUSIONS

Most of the relevant studies identified favor the concept that decreased thyroid function at baseline might be associated with a worse outcome of patients with sepsis or septic shock. Although these findings are not consistent, the role of thyroid function in affecting or merely predicting the outcome of sepsis or septic shock merits further investigation.

OBJECTIVE

Reported studies have showed alternations of thyroid hormones in critical illness mostly in adults and some in children. In this study, we aimed to measure thyroid hormone levels in children with sepsis and septic shock and investigate the relationship of these hormones with clinical state and survival.

METHODS

Thyroid hormone levels of children with sepsis and septic shock, and age- and sex-matched controls were measured.

RESULTS

There were 51 children in sepsis (group S), 21 children in septic shock (group SS) and 30 in the control (group C) group. Total triiodothyronine (TT3) levels were (nmol/l): 0.91 +/- 0.22, 0.64 +/- 0.23, 2.11 +/- 0.59; free triiodothyronine (FT3) (pmol/l): 0.027 +/- 0.006, 0.018 +/- 0.007, 0.049 +/- 0.010; total thyroxine (TT4) (nmol/l): 100.62 +/- 21.93, 65.79 +/- 19.35, 109.65 +/- 19.35; free thyroxine (FT4) (pmol/l): 18.06 +/- 3.87, 10.32 +/- 1.29, 19.35 +/- 3.87; and thyroid stimulating hormone (TSH) (mIU/ml): 5.0 +/- 2.0, 4.8 +/- 2.4, 5.2 +/- 3.0, in children with sepsis, septic shock, and controls, respectively. The TT3, FT3, TT4, and FT4 levels of group SS were significantly lower than those of groups S and C. The TT3 and FT3 levels of group S were lower than in group C, but there was no significant difference between TT4, and FT4 levels of groups S and C. TSH levels were slightly decreased in both sepsis and septic shock, but the difference was not significant. Eleven (21.6%) children with sepsis and 15 (71.4%) children with septic shock died (p < 0.001). The levels of TT3, FT3, TT4 and FT4 were markedly lower in non-survivors of groups S and SS compared to survivors (p < 0.001).

CONCLUSIONS

These changes in the hypothalamo-pituitary-thyroidal axis may suggest a possible prognostic value of thyroid hormone levels in children with sepsis and septic shock. To the best of our knowledge, this report is the first study to compare thyroid hormone levels in a large number of patients with sepsis and septic shock with those in healthy controls in childhood.

The finding of low values for serum thyroxine and estimated free thyroxine in seven of 12 workers referred because of elevated blood lead levels (greater than 40 mg/L) prompted further investigation. In a cross-sectional study of workers at a small foundry, both measurements were found to regress negatively with blood lead level. In 12 of 47 subjects, both indexes were in the hypothyroid range. Serum thyrotropin and triiodothyronine levels in patients and study subjects with low indexes were all normal. Physical examinations failed to demonstrate the classic features of hypothyroidism. These data are compatible with a central depression of the thyroid axis or an alteration in thyroxine metabolism or binding to proteins. Irrespective of mechanism, the association between low thyroid indexes and elevated lead levels merits attention because of the large number of workers exposed to lead and the similarities between the clinical features of adult lead poisoning and hypothyroidism.

We have stimulated in a cultured hepatocyte system the synergistic interaction between triiodothyronine (T3) and dietary carbohydrate in the induction of malic enzyme (ME). Kinetic studies revealed that isolated hepatocytes equilibrate with media T3 within 5 min; nuclei equilibrate with media T3 by 45 min; and the half-time of T3 metabolism was 10 h in 10% serum. We demonstrated nuclear T3 receptors in isolated hepatocytes and the induction of ME by T3 in physiological concentrations. However, in the complete absence of T3 glucose could still induce ME. At all concentrations of glucose (100-1,000 mg/dl), T3 (0.3 nM free T3) resulted in a relatively constant (1.4- to 1.7-fold) increase in ME response. The augmentation in ME activity was paralleled by an enhanced rate of enzyme synthesis as determined by [3H]leucine incorporation into immunoprecipitable ME. Cells cultured in serum free media also demonstrated a glucose-dependent increase in ME. Insulin greatly stimulated the glucose induction of ME, whereas dexamethasone had very little influence on ME induction. These studies demonstrate the usefulness of an adult hepatocyte tissue culture model for the study of the effects of T3 on gene expression in cells that are not derived from tumor. They clearly demonstrate that well established effects of T3 can be simulated in such a system at levels of free hormone that approximate those in extracellular body fluids. Our results indicate that an increased concentration of glucose per se can induce the formation of ME in the absence of alterations in extrahepatic hormones or factors. Moreover, our findings confirm inferences from in vivo studies that T3 acts as a multiplier of a glucose-induced signal.

OBJECTIVE

To investigate the prevalence of thyroid illness - especially hyperthyroidism - and exposure to thyroid hormones in patients with hip fracture.

METHODS

A case-control study.

METHODS

Two surgical/orthopaedic hospital units and 22 facilities for the aged in a moderately iodine-deficient region of Germany.

METHODS

A total of 116 postmenopausal females with hip fracture and 402 postmenopausal female controls.

METHODS

Hip fracture; thyroid disease confirmed by measurement of serum thyrotropin, total and free thyroxine and triiodothyronine; history of thyroid disease and thyroid medication obtained by a questionnaire.

RESULTS

Of the hip fracture patients 4.3% had overt untreated hyperthyroidism, and 6.9% gave a history of past hyperthyroidism (total, 11.2%). The corresponding figures for the controls were 2.0 and 2.7%, respectively (total, 4.7%). 7.8% of the cases had been exposed to levo-thyroxine for 3-29 years, compared to 11.2% of the controls. The odds ratio for hyperthyroidism (present and past) was 2.5 (1.2-5.3, 95% confidence interval), and the odds ratio for levo-thyroxine exposure was 0.67 (0.32-1.41) in the hip fracture patients.

CONCLUSIONS

Hyperthyroidism is found 2.5-fold more often in hip fracture patients than in controls. Hence, hyperthyroidism appears to be a significant risk factor for hip fracture and should be investigated by clinical and, when necessary, laboratory means in hip fracture patients. In contrast, no increased risk for hip fracture could be detected after exposure to levothyroxine.

Abnormalities in circulating thyroid hormone levels are very common in systemic nonthyroidal illnesses, such as acute myocardial infarction. In this study, thyroid parameters were determined in a series of 16 consecutive infarction patients treated by thrombolysis. Blood samples were taken before therapy as well as 2, 4, 6, 8, 12 and 72 h following admission. Total and free serum thyroxin and triiodothyronine decreased and reverse T3 increased significantly showing no major variations up to 72 h, whereas thyroid-stimulating hormone values remained almost unchanged during the observation period. Subjects with CK-MB levels of more than 150 ng/ml (n = 10) revealed similar changes in thyroid parameters in comparison to those with lower values (n = 6; NS). Thus, although hormone modifications very often occur following acute infarction, thyroid status may not serve as a marker for the extent of left ventricular dysfunction in the early phase of myocardial infarction.

Thyroid hormones influence both normal breast cell differentiation and breast cancer cell proliferation and stimulate the angiogenesis of certain cancer forms. Several cross-sectional studies have measured thyroid hormones/autoantibodies in breast cancer ceases vs. controls, but it is difficult to determine the cause-effect direction in these studies. Only three prospective studies have reported on the subject so far. The aim of our study was to investigate prediagnostically measured levels of thyroid hormones, thyrotropin (TSH) and thyroid autoantibodies in relation to subsequent risk of breast cancer. The Malmoe Diet and Cancer study examined 17,035 women between 1991 and 1996. Blood samples were collected at baseline and free triiodothyronine (T3), free thyroxin (T4), TSH and thyroid peroxidase autoantibodies (TPO-Ab) levels were measured in 676 cases and 680 controls. Relative risks with 95% confidence intervals were assessed using a logistic regression analysis adjusted for potential confounders. Free T4 levels were positively associated with a high risk of breast cancer, and the OR for women with free T4 levels above vs. below the median was 1.40 (1.10-1.77). This association was most pronounced in overweight women (1.51:1.07-2.12). Women with high levels of TPO-Ab had a lower risk of breast cancer, but only the analysis of TPO-Ab as a continuous variable reached statistical significance. Free T4 was in our study positively associated with a high risk of breast cancer. This association was most pronounced in overweight/obese women. Women with a high level of TPO-Ab had a relatively low risk of breast cancer.

Various kinds of hormones including insulin, triiodothyronine (T(3)) and fat-soluble vitamins have been proposed as mediators of adipocyte differentiation in mammals. To investigate the factors which are responsible for fish adipocyte differentiation, we developed a serum-free culture system of stromal-vascular cells of red sea bream adipose tissue and examined the effects of bovine insulin, T(3), and fat-soluble vitamins (all-trans retinoic acid, retinyl acetate and 1,25-dihydroxyvitamin D(3)) on the differentiation-linked expression of the lipoprotein lipase (LPL) gene. As assessed by the increase in LPL gene expression after 3 day cultivation, like in mammalian adipocytes, insulin enhanced the adipocyte differentiation in a concentration-dependent manner. During 2 week cultivation, bovine insulin promoted lipid accumulation in differentiating adipocytes concentration-dependently until the terminal differentiation. These results indicate that the differentiation of fish adipocytes is inducible by insulin alone. T(3) alone had no effect but enhanced the differentiation-linked LPL gene expression in the presence of insulin. Fat-soluble vitamins, unlike in mammalian adipocytes, did not show any significant effects. The method developed in this study should be of interest for the characterization of factors involved in fish adipocyte differentiation.

Thyroid hormone regulates metabolism through transcriptional and posttranscriptional mechanisms. The integration of these mechanisms in heart is poorly understood. Therefore, we investigated control of substrate flux into the citric acid cycle (CAC) by thyroid hormone using retrogradely perfused isolated hearts (n = 20) from control (C) and age-matched thyroidectomized rats (T). We determined substrate flux and fractional contributions (Fc) to the CAC by 13C-NMR spectroscopy and isotopomer analyses in hearts perfused with [1,3-(13)C]acetoacetic acid (0.17 mM), L-[3-(13)C]lactic acid (LAC, 1.2 mM), [U-13C]long-chain mixed free fatty acids (FFA, 0.35 mM), and unlabeled glucose. Some T hearts were supplied triiodothyronine (T3, 10 nM; TT) for 60 min. Prolonged hypothyroid state reduced myocardial oxygen consumption, although T3 produced no significant change. Hypothyroidism reduced overall CAC(flux) but selectively altered only FFA(flux) among the individual substrates, though LAC(flux) trended upward. T3 rapidly decreased lactate Fc and flux. 13C labeling of glutamine through glutamate was increased in T with further enhancement in TT. The glutamate-to-glutamine ratio was significantly lower in T and TT. Immunoblots detected a decrease in hypothyroid hearts for muscle carnitine palmitoyltransferase I (CPT I) and a marked increase in pyruvate dehydrogenase kinase (PDK)-2 with no changes in liver CPT I, PDK-4, or hexokinase 2. TT, but not T, displayed elevated glutamine synthetase (GS) expression. These studies showed that T3 regulates cardiac metabolism through integration of several mechanisms, including changes in oxidative enzyme content and rapid modulation of individual substrates fluxes. T3 also moderates forward glutamine flux, possibly by increasing the overall activity of GS.

Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. A possible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [3H]-ryanodine binding (B(max)) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor alpha2 subunit, and SR Ca2+ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and Bmax of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part, from decreased T3.

OBJECTIVE

This trial examined the effects of triiodothyronine (T3) and hydrocortisone on lung disease. We present here the placebo data as this provides a natural history of thyroid hormone changes in this group of very preterm infants. We also examined the relationship between thyroid hormone levels and the outcome death and ventilator dependence at 2 weeks.

METHODS

Plasma-free T3 (FT3), free thyroxine (FT4), total T3, total T4, and thyroid-stimulating hormone were measured prospectively in preterm infants who were <30 weeks' gestation during the first 14 days of life. The data were obtained from the placebo arm of a multicenter, randomized, double-blind, clinical trial of T3 and hydrocortisone, called the THORN Trial.

RESULTS

A total of 128 infants were recruited into the placebo group. The mean FT3 level at <5 hours of age was 4.9 pmol/L and remained below this level. FT4 levels decreased from 15 pmol/L to 9.7 pmol/L at 7 days and then increased to 11.0 pmol/L by day 14. Total T3 and total T4 levels fell after 5 hours of age and reached a minimum on day 3. Thyroid-stimulating hormone levels fell markedly from 9.2 mU/L to 1.8 mU/L at 72 hours and then increased to approximately 4 mU/L. We found that all thyroid hormones but particularly FT3 and FT4 hormones were highly significantly related to outcome. The lower the hormone levels, the worse the outcome (death or ventilator dependence at 2 weeks of age).

CONCLUSIONS

1) Thyroid hormone levels in preterm infants <30 weeks were much lower than in term infants, 2) the postnatal surge of thyroid hormones normally seen at 24 to 48 hours of age in term infants did not occur in our group of preterm infant, and 3) low FT3 and FT4 levels are associated with higher mortality and severity of lung disease.