Acute psychiatric illness may be accompanied by transient hyperthyroxinemia. The mechanism of this phenomenon was examined by determining the role of thyrotropin (TSH) in the genesis of this state. Serial measurements of TSH, thyroxine (T4), free T4 index (FT4I), triiodothyronine (T3), and free T3 index (FT3I) were performed in 45 acutely hospitalized patients with major psychiatric disorders. Twenty-two (49%) patients exhibited significant elevations (greater than or equal to 2 SD above mean value of controls) of one or more thyroid hormone (or index) levels. Among depressed patients with elevated FT4I, TSH was higher (p less than .05) on the day of the peak FT4I than on the day of the FT4I nadir. There were significant positive correlations between psychiatric symptom severity and levels of FT4I among both depressed (p less than .01) and schizophrenic (p less than .025) patients. These data show that elevations of T4, FT4I, T3, and FT3I are common among psychiatric inpatients, especially early in their hospitalization, and that levels of thyroid hormones are correlated with severity of psychiatric symptomatology. TSH is higher early in the acute phase of illness and is not suppressed in the face of elevated thyroid hormone levels, a finding that distinguishes this phenomenon from ordinary hyperthyroidism. Elevations of peripheral thyroid hormone levels, particularly among depressed patients, may result from a centrally-mediated hypersecretion of TSH.

Thyroid function was evaluated in 58 patients with breast cancer and compared with data obtained from an age-matched control group of healthy women. Thyroid antibodies at low levels were present in 29 patients (50%): 21 patients (36%) had thyroid stimulating antibodies at low activity. Ten patients (17%) had thyroglobulin antibodies compared with 3 in the control group (P less than 0.05). Nine of 10 patients with thyroglobulin antibodies had microsomal antibodies as well. Two patients had only microsomal antibodies. Additionally 10 autoimmune antibodies were determined. These were, however, either absent or present in low concentrations in serum. Independent of the stage of disease, no differences were demonstrated between patients and controls in serum levels of triiodothyronine, thyroxine, free T3 index, free T4 index, thyroid stimulating hormone, and thyroglobulin. In conclusion, we found an increased frequency of thyroid autoantibodies in euthyroid patients with breast cancer compared with healthy controls suggesting a possible relation between this disease and autoimmune thyroid disease.

Hepatocytes isolated from neonatal (NN) and adult (AD) rats were seeded on fibronectin coated substratum and cultured in arginine-free medium supplemented with various combinations of insulin, dexamethasone, triiodothyronine (T3), albumin, and transferrin, in presence or absence of fibronectin depleted serum (FDS). The main finding is that in response to certain hormone mixtures, both NN and AD hepatocytes can be stimulated to proliferate, as revealed by an increase in cell number, a [3H]thymidine incorporation into nuclei, and extractable DNA as well as the appearance of mitotic figures. Moreover, this proliferative activity is associated with changes in hepatocyte ploidy. However, the proliferative response of NN hepatocytes to hormone action is much different from that of AD hepatocytes, and the addition of FDS amplifies this activity in NN but inhibits it in AD hepatocyte cultures. Measurements of tyrosine aminotransferase and lactate dehydrogenase activities indicate a good preservation of NN and AD hepatocyte functional integrity under certain culture conditions. A good maintenance of albumin production in NN and AD hepatocyte cultures requires the presence of dexamethasone, whereas the alpha-fetoprotein production in NN hepatocyte cultures is reduced quite rapidly under most conditions. No alpha-fetoprotein is detectable in AD hepatocyte cultures.

Chondrocytes from chicken embryo tibia can be maintained in culture as adherent cells in Coon's modified Ham's F-12 medium supplemented with 10% FCS. In this condition, they dedifferentiate, losing type II collagen expression in favor of type I collagen synthesis. Their differentiation to hypertrophy can be obtained by transferring them to suspension culture. Differentiation is evidenced by the shift from type I to type II and type IX collagen synthesis and the following predominant expression of type X collagen, all markers of specific stages of the differentiation process. To identify the factors required for differentiation, we developed a serum-free culture system where only the addition of triiodothyronine (T3; 10(-11) M), insulin (60 ng/ml), and dexamethasone (10(-9) M) to the F-12 medium was sufficient to obtain hypertrophic chondrocytes. In this hormonal context, chondrocytes display the same changes in the pattern of protein synthesis as described above. For proper and complete cell maturation, T3 and insulin concentrations cannot be modified. Insulin cannot be substituted by insulin-like growth factor-I, but dexamethasone concentration can be decreased to 10(-12) M without chondrogenesis being impaired. In the latter case, the expression of type X collagen and its mRNA are inversely proportional to dexamethasone concentration. When ascorbic acid is added to the hormone-supplemented medium, differentiating chondrocytes organize their matrix leading to a cartilage-like structure with hypertrophic chondrocytes embedded in lacunae. However, this structure does not present detectable calcification, at variance with control cultures maintained in FCS. Accordingly, in the presence of the hormone mixture, the differentiating chondrocytes have low levels of alkaline phosphatase activity. This report indicates that T3 and insulin are primary factors involved in the onset and progression of chondrogenesis, while dexamethasone supports cell viability and modulates some differentiated functions.

Environmentally relevant concentrations of selected polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) flame retardant congeners and their hydroxylated (OH) and methoxylated (MeO) analogues that can perturb thyroid hormone-dependent processes were comparatively examined with respect to competitive binding with thyroxine (T(4)) and 3,5,3'-triiodothyronine (T(3)) thyroid hormones (THs) on recombinant human and gull albumin and transthyretin transport proteins. The liver tissue was from glaucous gulls (Larus hyperboreus) from Norway and herring gulls (Larus argentatus) from the Great Lakes of North America. We isolated, cloned, sequenced, purified, and expressed the cDNA (cDNA) of albumin from liver of herring and glaucous gull. Albumin amino acid sequences were identical for both gull species. Concentration-dependent, competitive binding curves were generated for T(4) and T(3) binding alone and for selected substrates using gull and human recombinant albumin (recALB). Human recALB had high preference for T(4) relative to T(3), whereas it was reversed for gull recALB. Binding assays with recALB and recTTR gull proteins showed that relative to 2,2',4,4'-tetrabromoDE (BDE-47) and 2,2',3,4',5,5',6-heptaCB (CB-187) and the MeO-substituted (4-MeO-CB187 and 6-MeO-BDE47) analogues, 4-OH-CB187, 6-OH-BDE47, and 4'-OH-BDE49 had the greatest binding affinity and potency, and that competitive binding was greater for T(3) relative to T(4). These results indicate that xenobiotic ligand binding to human ALB or TTR cannot be used as a surrogate for gull binding interactions. The combination of TH-like brominated diphenyl ether backbone (relative to the chlorinated biphenyl backbone), and the presence of OH-group produced a more effective competitive ligand on human and gull recALB and recTTR relative to both T(3) and T(4). This suggests the possibility that OH-substituted organohalogen contaminants may be an exposure concern to the thyroid system in free-ranging gulls as well as for humans.

BACKGROUND

Several our previous studies showed associations of increasing blood level of persistent organochlorinated pollutants (POPs) with individual thyroid and metabolic adverse health signs in subjects from heavily polluted area (POLL) compared to these from the area of background pollution (BCGR). In this study we present increasing number of subjects with multiple adverse signs positively associated with blood level of polychlorinated biphenyls (PCBs) which is used as a marker of other POPs cocktail.

METHODS

In a total of 2046 adults (834 males and 1212 females; age range 21-75) from POLL and BCGR the serum level of major POPs such as of 15 most abundant PCBs congeners, dichlorodiphenyl-dichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) was estimated by high resolution gas chromatography. In addition, the data on thyroid volume by ultrasound and body mass index were obtained and serum level of thyroperoxidase and thyrotropin receptor antibodies as well as that of free thyroxine, total triiodothyronine, thyrotropin, thyroglobulin, fasting glucose and insulin, cholesterol and triglycerides was measured. Thus, a total of 13 adverse signs were defined and the interrelations between PCBs level and increasing number of subjects with increasing number of adverse signs were evaluated.

RESULTS

Because of high correlation between major POPs (PCB, DDE and HCB), for this purpose the level of PCBs was considered as a marker also for the presence of DDE and HCB. Thus, if all data obtained from 2046 subjects were stratified according to quintiles of PCBs level, highly significant increase was found (p < 0.02 to 0.0000 by chi-sqauare) for the frequency of 8 among 13 signs, while the increase of one additional sign was slightly above significance limit and that in 4 other was not significant. Also the number of subjects with multiple adverse signs was significantly higher in POLL than in BCGR. For instance, in BCGR area (1038 subjects; median PCB level of 744 ng/g and 5%-95% range of 423 - 1329 ng/g serum lipids) there were 84 (8.1%) cases with 6 or 7 adverse health signs, while in POLL area (1008 subjects; median PCB level of 1892 ng/g; 5%-95% range of 685 - 9016 ng/g) the prevalence of respective cases was twice as high (195 cases = 19.3%; p < 0.001 by chi-square). For the subjects with the same PCB levels, but with 8 or 9 adverse signs the respective values were 22/1038 (2.1%) vs. 54/1008 (5.3%; p < 0.001).

CONCLUSIONS

Significantly higher accumulation of adverse signs in subjects with high POPs level was found in POLL thus supporting the conclusion that POPs appear to increase the prevalence of several subclinical and overt thyroid and metabolic disorders.

DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) are not manufactured commercially other than for scientific research purposes. The main sources of TCDD and PeCDF releases into the environment are from metal smelting, refining, and processing; combustion and incineration sources; chemical manufacturing and processing; biological and photochemical processes; and existing reservior sources that reflect past releases. PCB mixtures were commercially produced and used in the electric power industry as dielectric insulating fluids in transformers and capacitors and used in hydraulic fluids, plastics, and paints. TCDD, PeCDF, and PCB 126 were selected for study by the National Toxicology Program as part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLC's, structurally related PCBs, and mixtures of these compounds. Female Harlan Sprague-Dawley rats were administered a mixture of TCDD, PeCDF, and PCB 126 (henceforth referred to as the TEF mixture) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the present study of the mixture of TCDD, PeCDF, and PCB 126 are presented and discussed. 2-YEAR STUDY: Groups of 81 female rats were administered 10, 22, 46, or 100 ng toxic equivalents (TEQ)/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Actual doses used for each compound in the mixture were: for 10 ng TEQ/kg: 3.3 ng/kg TCDD, 6.6 ng/kg PeCDF, and 33.3 ng/kg PCB 126; for 22 ng TEQ/kg: 7.3 ng/kg TCDD, 14.5 ng/kg PeCDF, and 73.3 ng/kg PCB 126; for 46 ng TEQ/kg: 15.2 ng/kg TCDD, 30.4 ng/kg PeCDF, and 153 ng/kg PCB 126; and for 100 ng TEQ/kg: 33 ng/kg TCDD, 66 ng/kg PeCDF, and 333 ng/kg PCB 126. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control group. Mean body weights of the 22 and 46 ng TEQ/kg groups were less than those of the vehicle control groups after week 69 of the study. Mean body weights of the 100 ng TEQ/kg group were less than those of the vehicle control group after week 37 of the study. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone concentrations were evaluated at the 14-, 31-, and 53-week interim evaluations. At 14, 31, and 53 weeks, there were dose-dependent reductions in total serum and free thyroxine concentrations. There were dose-dependent increases in serum triiodothyronine concentrations at 14 and 31 weeks. No changes in serum thyroid stimulating hormone concentrations were observed at any time point. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the interim evaluations. At 14 weeks, no effects on the hepatocellular labeling index were observed in the dosed groups compared to the vehicle controls. At 31 and 53 weeks, the hepatocellular labeling index was significantly higher in the 46 and 100 ng TEQ/kg groups compared to the vehicle controls. Cytochrome P450 Enzyme Activities: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at the interim time points. Liver and lung EROD (CYP1A1) activities and hepatic A4H (CYP1A2) activities were significantly greater in all dosed groups than in the vehicle controls at all interim evaluations (14, 31, and 53 weeks). Determinations of TCDD, PeCDF, and PCB 126 Concentrations in Tissues: Tissue concentrations of TCDD, PeCDF, and PCB 126 were analyzed in the fat, liver, lung, and blood at each interim evaluation and at the end of the 2-year study (105 weeks). The highest concentrations of TCDD, PeCDF, and PCB 126 were observed in the liver followed by fat. Liver and fat concentrations of TCDD, PeCDF, and PCB 126 at each interim evaluation and at 105 weeks were higher in groups with increasing doses of the mixture and generally increased with duration of dosing. In the lung, PeCDF was present at detectable concentrations in the 46 and 100 ng TEQ/kg groups at 14 and 31 weeks. Measurable concentrations of TCDD and PCB 126 were observed at 14 and 31 weeks in the lung of rats in all dosed groups with the highest concentrations observed in the 100 ng TEQ/kg group. At 53 weeks, concentrations of TCDD, PeCDF, and PCB 126 in the lung generally increased with increasing dose. At 105 weeks, detectable concentrations of TCDD, PeCDF, and PCB 126 in the lung were observed in all dosed groups. In blood, TCDD and PCB 126 concentrations at 14 and 31 weeks generally increased with increasing dose. Blood concentrations of PeCDF were detectable in the 46 and 100 ng TEQ/kg groups at 14 weeks and at 22 ng TEQ/kg or greater at 31 weeks. At 53 and 105 weeks, concentrations of TCDD, PeCDF, and PCB 126 in blood generally increased with increasing dose and duration of dosing. Pathology and Statistical Analyses: Relative liver weights were significantly increased in all dosed groups at 14, 31, and 53 weeks and correlated with increased incidences of hepatocellular hypertrophy. Increasing duration of exposure led to an increase in the spectrum, incidence, and severity of nonneoplastic effects. The only significant effect at 14 weeks was increased incidences of hepatocellular hypertrophy. At 53 weeks, there was a significant effect on the incidences of hepatocellular hypertrophy, multinucleated hepatocytes, pigmentation, focal fatty change, bile duct hyperplasia, and toxic hepatopathy. At 2 years, there were significant increases in the incidences of hepatocellular adenoma and cholangiocarcinoma of the liver. There was an increase in hepatic toxicity characterized by increases in the incidences of numerous nonneoplastic lesions including hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, inflammation, diffuse fatty change, bile duct hyperplasia, oval cell hyperplasia, nodular hyperplasia, eosinophilic focus, cholangiofibrosis, bile duct cysts, necrosis, portal fibrosis, mixed cell focus, and toxic hepatopathy. In the lung, there were dose-dependent increases in the incidences of bronchiolar metaplasia of the alveolar epithelium at 53 weeks and at 2 years and squamous metaplasia at 2 years. At 2 years, there was a dose-dependent increase in the incidences of cystic keratinizing epithelioma. In the pancreas, there were increases in the incidences of numerous nonneoplastic lesions including arterial chronic active inflammation, acinar cytoplasmic vacuolization, acinar atrophy, chronic active inflammation, and duct dilatation. At 2 years, incidences of acinar adenoma or acinar carcinoma that exceeded the historical control ranges were seen in all dosed groups except the 100 ng TEQ/kg group. Treatment-related increases in the incidences of nonneoplastic lesions were seen in other organs including hyperplasia, cystic degeneration, atrophy, and cytoplasmic vacuolization of the adrenal cortex; gingival squamous hyperplasia of the oral mucosa; squamous metaplasia of the uterus; atrophy of the thymus (incidence and severity); chronic active inflammation of the ovary; nephropathy of the kidney (incidence and severity); cardiomyopathy; bone marrow hyperplasia; transitional epithelium of the urinary bladder; chronic active inflammation of the mesenteric artery; and follicular cell hypertrophy of the thyroid gland. (ABSTRACT TRUNCATED).

We studied 160 consecutive patients (147 female and 13 male) with primary Sjögren syndrome (SS) to determine the prevalence and clinical significance of thyroid disease in a large series of patients with primary SS from our unit and to compare the prevalence and significance with those in 75 individuals without SS from a primary care center. Serum levels of thyroid hormones (free thyroxine, triiodothyronine, and thyroid-stimulating hormone) and autoantibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) were measured in all SS patients and in 75 control patients. Fifty-eight (36%) of the 160 patients with primary SS had evidence of thyroid disease. Autoimmune thyroid disease (ATD) was diagnosed in 32 (20%) patients and nonautoimmune thyroid disease (NATD) in 26 (16%). No significant differences were found when these prevalences were compared with those in control patients. On the other hand, comparing those patients with altered hormonal profiles, patients with NATD showed mainly hyperthyroidism (10/17, 59% versus 2/20, 10% in patients with ATD, p = 0.001). Finally, when clinical and immunologic manifestations of SS were analyzed in patients with and without thyroid disease, respectively, we found that patients with thyroid disease had a higher prevalence of female gender (98% versus 88%, p = 0.03), antiparietal cell autoantibodies (33% versus 12%, p = 0.002), TgAb (30% versus 5%, p < 0.001), and TPOAb (40% versus 5%, p < 0.001). In conclusion, thyroid disease occurred in more than one-third of patients with primary SS; the main cause was ATD, which was present in 20% of the patients studied. We note that no significant differences were observed when the prevalence of thyroid disease (either ATD or NATD) was compared with that in a control group of similar age and gender. Our results indicate that middle-aged women (with or without SS) should be screened periodically for thyroid function.

Food intake, body weight, serum levels of triiodothyronine (T3) and free thyroxine (FT4), and metabolic rate were measured at intervals in Svalbard (SR) and Norwegian (NR) reindeer. From summer to winter food intake decreased 57 (SR) and 55% (NR), while body weight decreased 8.6 (SR) and 3.8% (NR). In SR T3 and FT4 changed seasonally, whereas this was only evident for T3 in NR. Resting (standing) metabolic rate (RMR) in winter was 1.55 (SR) and 2.05 W X kg-1 (NR), lower critical temperature (TLC) being -50 (SR) and -30 degrees C (NR). RMR in summer was 2.15 (SR) and 2.95 W X kg-1 (NR), TLC being -15 (SR) and 0 degrees C (NR). Seasonal changes in T3 and FT4 did not coincide with changes in food intake or RMR in either SR or NR. RMR did, however, correlate with food intake. This indicates that seasonal changes in RMR are due to the thermic effects of feeding and represent no physiological adaptation aimed at conservation of energy during winter.

OBJECTIVE

Overt and subclinical hypothyroidism are risk factors for atherosclerosis. It is unclear whether thyroid hormone levels within the normal range are also associated with atherosclerosis measured by coronary artery calcium (CAC).

RESULTS

We conducted a cross-sectional study of 41 403 apparently healthy young and middle-aged men and women with normal thyroid hormone levels. Free thyroxin, free triiodothyronine, and thyroid-stimulating hormone levels were measured by electrochemiluminescent immunoassay. CAC score was measured by multidetector computed tomography. The multivariable adjusted CAC ratios comparing the highest versus the lowest quartile of thyroid hormones were 0.74 (95% confidence interval, 0.60-0.91; P for trend <0.001) for free thyroxin, 0.81 (0.66-1.00; P for trend=0.05) for free triiodothyronine, and 0.78 (0.64-0.95; P for trend=0.01) for thyroid-stimulating hormone. Similarly, the odds ratios for detectable CAC (CAC >0) comparing the highest versus the lowest quartiles of thyroid hormones were 0.87 (0.79-0.96; P for linear trend <0.001) for free thyroxin, 0.90 (0.82-0.99; P for linear trend=0.02) for free triiodothyronine, and 0.91 (0.83-1.00; P for linear trend=0.03) for thyroid-stimulating hormone.

CONCLUSIONS

In a large cohort of apparently healthy young and middle-aged euthyroid men and women, low-normal free thyroxin and thyroid-stimulating hormone were associated with a higher prevalence of subclinical coronary artery disease and with a greater degree of coronary calcification.

Prolonged coma afterhead trauma is associated with depletion of 3', 5' cyclic adenosine monophosphate (cAMP) in the cerebrospinal fluid (CSF). Because cAMP has previously been implicated in neurorendocrine secretion, this study examines the pituitay-hypothalamic function in 15 adult male patients (to exclude the effects of puberty and menses) with traumatic coma lasting longer than 2 weeks. Ventricular CSF cAMP was measured at 2- to 4-day intervals for 10 to 25 days. Simultaneously, plasma hormone concentrations were also determined. In all 15 cases, CSF cAMP and plasma levels of thyroid-stimulating hormone (TSH), thyroxine (T4), free T4, triiodothyronine (T3), luteinzing hormone (LH), follicle-stimulating hormone (FSH), and testerone became subnormal. In 11 patients whose level of consciousness fluctuated, the reduction in plasma T4 and testerone were proportional to both severity of coma ( r greater than 0.81, p less than 0.05) and depletion of CSF cAMP (r greater than 0.81, p less than 0.05). In four patients who remained deeply comatose for 17 to 25 days, the hypothyroidism and hypogonadism persisted. In six patients who regained consciousness, both endocrine defects improved partially or completely. Injection of 1) thyrotrophic-releasing hormone and 2) gonadotrophic-releasing hormone elicited normal or supernormal increases in plasma concentrations of 1) TSH, and 2) LH and FSH, reduced, respectively, suggesting a suprahypophyseal deficiency. These observations demonstrate that suprahypophyseal hypothryoidism and hypogonadism may occur regularly in patients with traumatic coma lasting longer than 2 weeks.

Previous studies have demonstrated that full recovery from weight loss may take months or years. The present investigation examined short-term recovery (5 wks "post") of physical performance (muscular strength, muscular power, vertical jump), body composition, metabolic hormones (testosterone, luteinizing hormone, sex hormone binding globulin, insulin-like growth factor-1, triiodothyronine, thyroxine, thyroid binding globulin, and thyroid-stimulating hormone) and metabolic markers (transferrin, ferritin, prealbumin, glycerol, nonesterified fatty acids, high-density lipoproteins, and lactate) in 10 healthy young men after an 8-week Army course with an energy deficit (1000 kcal/d) and loss of body mass (-12%). Subjects ate ad libitum after the course ended ("post"). Body composition was determined by dual-energy X-ray absorptiometry; strength from a simulated power clean, power from body mass and jump height, and metabolic hormones were measured in morning-fasted blood by radioimmunoassay. With the exception of transferrin and glycerol, all study parameters were significantly (p<.05) altered by the training course. At 5 weeks post fat-free mass along with all physical performance measures returned to initial levels; however, fat mass had significantly (p<.05) increased over initial levels. Also, with the exception of lactate, all measured hormones and markers were close to initial levels and within normal ranges. Reported complications during recovery included sleep irregularities, diarrhea, loss of motivation and feelings of fatigue. While the long range effect of this energy deprivation experience is uncertain, these data do suggest that severe weight loss does not result in lasting alterations of the contractile and metabolic properties of skeletal muscle in young, lean, healthy men.

Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin (TSH) receptor (TSHR) gene. We describe an extended Welsh kindred with toxic thyroid hyperplasia affecting 8 family members in three generations and a history consistent with thyrotoxicosis in a further three generations now deceased. A novel heterozygous germline mutation (ATG ->> GTG; Met463Val) was identified in the second membrane spanning TSHR region in 6 relatives with thyrotoxicosis and goiter and absence of TSHR antibodies. Screening of 5 additional family members led to the identification of 2 siblings with the mutation, who were asymptomatic at the time, although subsequent thyroid function tests in these children showed suppressed serum TSH and increased serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. Functional studies of the novel TSHR germline mutation demonstrated a constitutive activation of the cAMP pathway, which in the thyroid controls both thyroid hormone production and stimulation of thyroid growth. The molecular diagnosis in this family has clinical implications: genetic counseling is required, and primary thyroid ablation should be advocated as the preferred treatment in the patients with the constitutively activating TSHR germline mutation.

OBJECTIVE

The study aims to evaluate the efficacy of combination therapy with propylthiouracil (PTU) and cholestyramine in the treatment of Graves' hyperthyroidism.

BACKGROUND

Thyroxine (T4) is metabolized mainly in the liver by conjugation to glucuronides and sulphates that enter the enterohepatic circulation. Thyrotoxic patients have an abnormal increase in thyroid hormone in their enterohepatic circulation. Previous studies on combination therapy with methimazole and cholestyramine for Graves' hyperthyroidism have shown it to be an effective adjunctive treatment. In this study, we examined the efficacy of combination therapy with PTU and cholestyramine in the treatment of Graves' hyperthyroidism.

METHODS

Thirty patients with newly diagnosed Graves' hyperthyroidism were randomly divided into two groups: group I (n = 15) received PTU 100 mg twice a day, propranolol 40 mg twice a day and cholestyramine 4 g twice a day for 4 weeks; group II (n = 15) received PTU 100 mg twice a day and propranolol 40 mg twice a day for 4 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), free thyroxine (FT4) and TRAb levels at baseline, and at the end of 2 and 4 weeks during the study period.

RESULTS

There was no significant difference in baseline thyroid function parameters. At the end of 2 and 4 weeks of the study period, serum TT3 and FT4 levels of group I were significantly lower than those of group II. No significant differences in the TRAb level were found between the two groups.

CONCLUSIONS

Cholestyramine contributed to a more rapid and complete decline in thyroid hormone levels in patients with Graves' hyperthyroidism. It was thus proved to be an effective and well-tolerated adjunctive therapy.

Bromocriptine redirects metabolism and prevents seasonal onset of the obese hyperinsulinemic state in Syrian hamsters. Metabolic and hormonal effects of bromocriptine were studied in seasonally obese female Syrian hamsters, Mesocricetus auratus. Daily injections of bromocriptine and vehicle (controls) were made at light onset (10:14-h light-dark cycle) for 10 wk. After 9 wk of treatment blood samples were taken every 4 h during a day for assays of hormones, glucose, triglyceride, and fatty acids, and after 10 wk of treatment, tests were carried out to measure insulin-stimulated glucose disposal during a hyperinsulinemic clamp, lipid mobilization (rate of glycerol appearance), protein turnover (lysine flux and deamination), and body composition (deuterium dilution). Bromocriptine reduced percent body fat by 53% and increased percent lean body mass by 8%. It also decreased triglyceride levels by 52% and plasma free fatty acid concentration during the dark-near light onset by 49% and glycerol appearance by 25%. Protein synthesis and catabolism were increased by 62 and 56%, respectively, and deamination of amino acid was decreased by 53% by bromocriptine. Bromocriptine reduced plasma concentration of insulin throughout the day, especially at light onset, by 78% without change in baseline glucose level and markedly decreased steady state plasma glucose (by 40%) during a continuous infusion of insulin and glucose. It also reduced the nocturnal plasma concentration of prolactin by 90%, cortisol by 70%, and thyroid hormones (thyroxine and triiodothyronine) by 50% and dramatically altered the circadian profiles of these hormones and insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to examine the effects of habitual consumption of Taiwanese vegetarian diets on hormonal secretion, and on lipid and glycaemic control. Of the ninety-eight healthy female adults recruited from Hualien, Taiwan (aged 31-45 years), forty-nine were Buddhist lactovegetarians and forty-nine were omnivores. Dietary intakes were measured, and blood levels of nutrients and hormones were analysed. Vegetarians consumed less energy, fat and protein, but more fibre than the omnivores. Compared with the omnivores, the vegetarians had, on average, lower BMI and smaller waist circumference. Except for slightly lower levels of thyroxine (T4) in vegetarians, vegetarians and omnivores both showed similar levels of triiodothyronine (T3), free T4, thyroid-stimulating hormone, T3:T4 ratio and cortisol. Compared with the omnivores, the vegetarians had significantly lower levels of fasting insulin (median: 35.3 v. 50.6 pmol/l) and plasma glucose (mean: 4.7 (se 0.05) v. 4.9 (se 0.05) mmol/l). Insulin resistance, as calculated by the homeostasis model assessment method, was significantly lower in the vegetarians than in the omnivores (median: 1.10 v. 1.56), while beta-cell function was not different between the two groups. BMI and diet were both independent predictors for insulin resistance, and contributed 18 and 15 % of the variation in insulin resistance, respectively. In conclusion, Taiwanese vegetarians had lower glucose and insulin levels and higher insulin sensitivity than did the omnivores. Diet and lower BMI were partially responsible for the high insulin sensitivity observed in young Taiwanese vegetarians.

BACKGROUND

Subclinical hypothyroidism, defined as high serum thyroid-stimulating hormone (TSH) levels and normal serum free-triiodothyronine (fT3) and serum free-thyroxine (fT4) levels, is a common medical problem among the elderly, but it is unclear whether it should be treated with thyroid hormone replacement therapy.

RESULTS

A cross-sectional study of 3,607 participants in a community health survey in Suita, in the northern part of Osaka, was performed. Participants were categorized into 5 groups: normal, hyperthyroidism, hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism. The association between each group and various phenotypes was examined, in relation to cardiovascular disease and metabolic syndromes. Serum TSH levels increased and fT3 and fT4 levels decreased with age. A total of 14.6% of subjects aged 70-80 years and 20.1% of subjects aged older than 80 years were classified as having subclinical hypothyroidism. Subclinical hypothyroidism was not associated with glycol-hemoglobin A1c, body mass index, pulse rate, hypertension, total cholesterol, high-density lipoprotein cholesterol or triglyceride levels or intima-media thickness. It was only associated with higher fasting blood glucose and glycol-hemoglobin A1c levels compared with euthyroidism.

CONCLUSIONS

The present observation does not support the need for treatment of subclinical hypothyroidism or subclinical hyperthyroidism.

OBJECTIVE

Since little information is available on the capacity of the non-obese to adapt to a moderate decrease in energy intake, the effect of a 10-week moderately energy-restricted diet (ER) on energy expenditure and body composition was studied.

METHODS

A controlled intervention study. After a weight-maintaining run-in period of 2 weeks, the ER group received a diet that contained 9.2 MJ/day on average, i.e. 80% of the energy of their habitual diet (estimated by means of a 7-day dietary record) for the next ten weeks while the control group received the weight-maintaining diet.

METHODS

Subjects continued daily life habits and came to the Institute every evening to have dinner and to receive food for the next 24 h.

METHODS

24 healthy non-obese, middle-aged men participated. Subjects were matched for age and body mass index and randomly assigned to a control group (n = 8) or an ER group (n = 16).

RESULTS

Average daily metabolic rate (ADMR, i.e. total energy expenditure), measured with doubly labeled water in eight subjects of the ER group, appeared to be 82.5% of reported energy intake resulting in an actual level of energy restriction in these eight subjects of 33% on average (range 18-42%), rather than 20%. Subjects in the ER group lost 7.4 +/- 1.7 kg; 83% of this weight loss was fat mass, 17% was fat-free mass. Subjects in the control group lost some weight too (2.1 +/- 1.5 kg). Resting metabolic rate (RMR) (MJ/day) decreased in the ER group (P < 0.001). In this group the thyroid hormone triiodothyronine (T3) decreased (P < 0.001), while reverse T3 (rT3) increased (P < 0.05). ADMR decreased significantly.

CONCLUSIONS

Under conditions of a controlled moderately energy-restricted diet in daily life a significant weight loss can be induced, similar to that observed after a balanced dietary deficit, providing 5 MJ/day. In addition, moderate energy restriction induces a decrease in fat-free mass and a fall in RMR.

OBJECTIVE

To determine the log-linear relationship between TSH and free thyroxine in healthy subjects, and the variation in baseline TSH/free thyroxine (FT(4)) combination in each individual.

METHODS

Twenty-one healthy volunteers (nine males and 12 females; mean age 60 years, range 51-74) were randomized to receive at 2300 h with 2-week intervals a single dose of placebo, 125 microg T(4) and 250 microg T(4) (arm 1, n=10), or placebo, 25 microg triiodothyronine (T(3)) and 50 microg T(3) (arm 2, n=11). Blood samples were taken in the morning (0800-1100 h) before and following the administration of the drug for the assessment of TSH, FT(4) and T(3).

RESULTS

Intra- and inter-individual variation and the individuality index of the four baseline serum samples were respectively 21.6%, 41.9% and 0.52 for TSH; 9.9%, 16.5% and 0.60 for FT(4); and 9.3%, 16.0% and 0.58 for T(3). Substantial differences existed in the location of individual working points within the reference range. T(4) administration increased FT(4) (but not T(3)) and decreased TSH, resulting in a log-linear relationship (log TSH=1.50-0.059xFT(4), P<0.05) for the whole group. T(3) administration increased T(3) and decreased TSH (but not FT(4)), resulting in a log-linear relationship (log TSH=0.790-0.245xT(3), P<0.001) for the whole group. Log-linear relationships were not always significant when assessed for each subject separately.

CONCLUSIONS

Individuality indices of TSH, FT(4) and T(3) are all <or=0.6, thereby limiting the usefulness of the population-based reference values. Accurate assessment of individual setpoints of the HPT axis was not possible with the applied single doses of T(4) or T(3), and will require either prolonged administration or higher single doses of thyroid hormone.

The relationship between alcoholic liver disease and circulating thyroid hormones was investigated in 124 hospitalized patients treated with placebo or propylthiouracil (PTU) for a maximum of 46 days in a double-blind study. Serum triiodothyronine (T3) levels on admission were significantly (P less than 10(-6) and inversely correlated with the severity of alcoholic liver disease. After hospitalization, changes in T3-levels in patients with low admission T3 significantly correlated (P less than 0.001) with the degree of spontaneous improvement of liver function (placebo group). Treatment with 300 mg of PTU daily (Orrego et al. Gastroenterology 76:105--115, 1979) markedly increased the rate of improvement in severely ill patients with low T3 on admission. In this group, serum T3-levels were also increased after PTU, but this increase did not correlate with the change in the patient's condition. It is suggested that the known inhibitory effect of PTU on peripheral deiodination of T4 to T3 is marked by a more marked improvement in liver function in this group. PTU treatment in this group reduced the free T4-index and increased TSH levels markedly (16%; P less than 0.02) toward levels found in hypothyroidism. PTU did not improve the condition of mildly ill patients with normal admission T3-levels, nor did it alter free T4-index or serum TSH levels in these patients. Serum T3-levels provide a sensitive indicator of the severity of alcoholic liver disease and of its response to conventional treatment. Serum T3-levels also distinguish between a group of patients, in whom low-dose PTU administration results in a beneficial effect, and another group, in whom no therapeutic effect of PTU is observed.

Thyroid hormone status was assessed in 132 children with congenital heart defects undergoing cardiac surgery (median age 3.1 y; range 2 d to 16.2 y). Plasma TSH, thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3), reverse triiodothyronine (rT3), thyroglobulin (Tg), and urinary iodine excretion were measured before and every other day after cardiac surgery (d 1-21). After surgery we observed strikingly low plasma concentrations of TSH (0.4 mU/L; 0.2-1.3), T3 (0.6 nmol/L; 0.3-1.2), T4 (48.9 nmol/L; 12.9-82.4), IT4 (12.9 pmol/L; 5.1-19.3), and Tg (9.4 micrograms/L; 1.5-20.6), whereas rT3 plasma concentrations increased (0.13 pmol/L; 0.05-0.3; n = 40). The maximal post-operative changes of TSH and rT3 preceded changes of T3, T4, fT4, and Tg. Postoperative urinary iodine excretion increased significantly (n = 109). Thyroid hormone plasma concentrations were lowest after cardiopulmonary bypass operations and in patients treated with dopamine. In patients with postoperative T3 plasma concentrations less than 0.6 nmol/L (n =52) the period of mechanical ventilation and intensive care treatment was significantly prolonged. Furthermore, the cumulative doses of inotropic and vasoactive catecholamines and furosemide were significantly higher in this patient group. Our results demonstrate transient secondary hypothyroidism in children after cardiac surgery that may contribute to postoperative cardiac and respiratory dysfunction and may delay recovery. Possible benefits of thyroid hormone replacement therapy need to be thoroughly examined.

BACKGROUND

The purpose of this study was to prospectively observe the relative contribution of each viable mechanism such as hyperphagia, physical activity, body composition, steroid hormonal and thyroid function, fatigue scores on changes in body weight in breast cancer patients, receiving adjuvant chemotherapy.

METHODS

This was a prospective observational research design where 198 consecutive breast cancer patients receiving adjuvant chemotherapy were monitored from start to end and 6 months post-therapy on changes in anthropometics, fatigue, nutritional intake, physical activity, thyroid and steroid hormones.

RESULTS

We observed a weight gain over >5 lb in 22.2% of this patient population with a significant and progressive gain of 6.7 lb (P < 0.0001) at 6 months. Ninety four percent of all patients reported fatigue and 56% of patients reported lowered physical activity. A significant reduction in serum free and total estradiol (P < 0.0001) was observed indicative of reduction in ovarian function with 86% amenorrehic at the end of treatment. A significant reduction in mean serum triiodothyronine uptake levels (P < 0.05), in addition to a significant increase in TBG (P < 0.0001) from baseline to end of chemotherapy, was observed. In addition 20-25% of this patient group was already diagnosed with clinical hypothyroidism at diagnosis and treated. Changes in fatigue frequency and serum sex-hormone-binding globulin (SHBG) were variables significantly predictive of weight gain (P < 0.0001).

CONCLUSIONS

Cytotoxic agents may influence thyroid function in breast cancer patients contributing to and progressively worsening symptoms such as weight gain, amenorrhea, fatigue and lowered physical activity in this population. The present study indicates the value of screening breast cancer patients for thyroid function at diagnosis or pre-treatment.

BACKGROUND

Heavy metals, such as lead (Pb), mercury (Hg), and cadmium (Cd), are known toxicants, but their associations with the thyroid axis have not been well quantified at U.S. background levels.

OBJECTIVE

We investigated the relationships between thyroid hormones (total and free thyroxine [TT4 and FT4], total and free triiodothyronine [TT3 and FT3], thyroid-stimulating hormone [TSH], and thyroglobulin [Tg]) and levels of Pb, Hg, and Cd in blood and Cd in urine.

METHODS

We separately analyzed a sample of 1,109 adolescents (12-19 years of age) and a sample of 4,409 adults from the U.S. National Health and Nutrition Examination Survey (NHANES) 2007-2008. We estimated associations after adjusting for age, sex, race, urinary iodine, body mass index, and serum cotinine.

RESULTS

The geometric mean (GM) levels of blood Pb (BPb), total Hg, and Cd were 0.81 µg/dL, 0.47 µg/L, and 0.21 µg/L in adolescents and 1.43 µg/dL, 0.96 µg/L, and 0.38 µg/L in adults, respectively. The GMs of urinary Cd were 0.07 and 0.25 µg/g creatinine in adolescents and adults, respectively. No consistent pattern of metal and thyroid hormone associations was observed in adolescents. In adults, blood Hg was inversely related to TT4, TT3, and FT3 and urinary Cd was positively associated with TT4, TT3, FT3, and Tg, but there were no associations with Pb. Associations were relatively weak at an individual level, with about 1-4% change in thyroid hormones per interquartile range increase in Hg or Cd.

CONCLUSIONS

Our analysis suggests an inverse association between Hg exposure and thyroid hormones, and a positive association between Cd exposure and thyroid hormones in adults.

In polluted district of Michalovce in East Slovakia (POLL) and two districts with background pollution (BCGR) 2046 adults (834 males and 1212 females aged 20-75 years) were examined. Serum levels of thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (TT3) and antithyroperoxidase antibodies (TPOab) were estimated by electrochemiluminiscent assay and also these of 15 polychlorinated biphenyl congeners (PCBs), p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane were measured by high resolution gas chromatography/mass spectrometry. In addition, also dioxins, furans, coplanar- and mono-ortho-PCBs as well as selected hydroxylated and methylsulphonated PCBs and DDE metabolites were measured by appropriate methods based on gas chromatography/mass spectrometry principle. In POLL significantly higher levels of all organochlorines were found than these in BCGR. When pooled values from both areas were stratified in terms of PCBs level and treated as continuous variables, positive association of PCBs with FT4 and TT3 was found, the latter two being also mutually associated. However, within the category of PCBs level <530 ng/glipid (n=232) the association between PCBs and both the FT4 (p<0.09) and TT3 (p<0.03) was negative and any association of these was not found within the category of PCBs level of 531-1000 ng/g (n=691). In contrast, in the category of 531-2000 ng/g (n=1307) positive association appeared between PCBs and FT4 (p<0.001) as well as TT3 (p<0.05). Highly significant association of PCBs with FT4 (p<0.001) was further found in the categories with PCBs level of 1001-101414 ng/g (n=1307) and 2001-101414 (n=1123), while significant association with TT3 was observed only in the category of 531-2000 ng/g. Such findings suggest possible threshold level in positive effect of PCBs on FT4 and TT3 level which seems to be individual and located somewhere around the PCBs level of 1000 ng/g. However, highly significant negative association of both FT4 and TT3 with TSH was found in each of above indicated PCBs categories. Considerable difference in FT4 and TT3 level between large groups of subjects with the same range of PCBs level was also found suggesting different individual susceptibility to the effects of organochlorines. Among a total of 26 cases from POLL with very low TSH level (<0.5 mU l(-1)) 13 cases showed very high level of PCBs, FT4 and TT3, thus supporting a hypothesis on a novel sporadic form of high PCBs related peripheral subclinical hyperthyroidism possibly resulting from the long-term disruption of equilibrium between bound and free thyroxine in plasma by high PCBs level followed by a striking inhibition of TSH release from the pituitary.