The role of triiodothyronine (T3) in the differentiation process of Ob1771 mouse preadipocyte cells has been studied under serum-free and hormone supplemented culture conditions which were previously shown to lead to terminal differentiation. In the absence of T3, a dramatic decrease in the adipogenic activity of the culture medium (EC50 = 0.1 nM) could be observed, as indicated 12 days after confluence by the low levels of late markers of differentiation such as adipsin, lipid-binding protein aP2 and glycerol-3-phosphate dehydrogenase as well as the sharp reduction of the number of triacyglycerol-containing cells. This decrease in adipogenic activity was accompanied by a parallel increase of the mitogenic potency of the culture medium. Therefore, T3 appears to be a hormone capable of modulating both proliferation and differentiation of preadipocytes. T3 ceased to be necessary provided the culture medium was supplemented with high concentrations of inducers of differentiation, such as 8-bromo-cAMP or carbaprostacyclin.

BACKGROUND

Subclinical hypothyroidism (SH) is defined by increased thyrotropin (TSH) and normal free thyroxine (fT4) and free triiodothyronine (fT3) levels. Resistin is secreted from adipose tissue and is reported to be associated with insulin resistance and/or inflammation. High sensitive CRP (hs-CRP) is a reliable marker of inflammation. Data related to levels of resistin and hs-CRP in SH and the effect of L-thyroxine treatment on those is limited. We aimed to determine the levels of resistin and hs-CRP in women with SH, and potential effects of L-thyroxine therapy on those levels.

METHODS

Thirty-six patients with SH and 27 age- and BMI-matched healthy control women were included. Waist circumference (Wc), waist-to-hip ratio (WHR), resting energy expenditure (REE), fat mass (FM) and lean mass (LM), TSH, free T4 (fT4), free T3 (fT3), total cholesterol (TC), triglycerides (TG), and HDL- and LDL-cholesterol were determined in all participants. Patients received L-thyroxine treatment for 6 months, after which all measurements were repeated. Resistin and hs-CRP levels were studied from frozen samples after the completion of the study.

RESULTS

The 2 groups had similar values for Wc, WHR, FM, LM, TC, TG, HDL-C, LDL-C, resistin, and hs-CRP at the beginning. fT4 were higher, whereas TSH was lower in the control group. Resistin and hs-CRP levels did not change after treatment. hs-CRP correlated with BMI and FM before and after treatment.

CONCLUSIONS

Our results suggest that achievement of euthyroid status by replacement therapy did not change resistin or hs-CRP levels in women with SH. hs-CRP correlated with parameters of obesity, which emphasizes the role of body weight in inflammation.

OBJECTIVE

It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T(3)), free thyroxine (FT(4)), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships.

METHODS

We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma.

METHODS

We measured BMD of the femoral neck and lumbar spine. FT(4), T(3), TSH, bone-specific alkaline phosphatase, procollagen type 1 aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727Glu polymorphism were determined by Taqman assay.

RESULTS

We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT(4) and T(3) levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727Glu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index.

CONCLUSIONS

We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed.

Rat hepatocytes were maintained for the first 24 h in culture in the presence of 10% (v/v) newborn calf serum and then for a further 16 h in serum-free medium containing 2 g bovine serum albumin per litre. The presence of 1-100 nM triiodothyronine (T3) in the second incubation significantly increased binding of human 125I-LDL to the LDL receptor. Unlike insulin, T3 was unable to reverse the decrease in binding brought about by dexamethasone. The increased binding to the LDL receptor produced by insulin and T3 was additive. We conclude that T3, insulin and glucocorticoids may play important roles in regulating plasma LDL concentrations by direct effect on LDL uptake by the liver.

The hypothesis that the growth of mammalian cells is regulated by hormones is now supported by considerable evidence. Two rat pituitary cell lines, GH3 and GC, a mouse melanoma, M2R (B16), and a human cervical carcinoma cell, HeLa S-3, have been grown indefinitely in serum-free (SF) hormone-supplemented medium. No visible changes of growth characteristics were observed in the cells grown continuously in the SF condition. However, changes in the activity of a plasma membrane enzyme, alkaline phosphatase, and in the relative intensity of surface proteins that are labeled by the [125I] lactoperoxidase technique were found in HeLa cells grown in the SF condition. To study the role of hormones required in the regulation of cell growth, HeLa cells were grown in the absence of one of the required hormones. The following results were obtained. Epidermal growth factor is probably involved in the regulation of the synthesis of macromolecules such as RNA and of the protein content per cell. Transferrin, the accessory factor in the SF condition, supplies iron for cells. The two basic peptides in this SF system, fibroblast growth factor and insulin, are probably involved in the balance of nutrients and energy inside the cell. The replacement of F12 medium with a better-balanced medium, MCDB 105, can mimic the requirements for these two peptides. The steroid hydrocortisone (HC) is probably involved in alteration of the cell surface. This is indicated by the effects of HC on cell morphology, rate of detachment from the dish, and the pattern of [125I] lactoperoxidase labeling of surface proteins. In addition, it is necessary to change the medium more frequently to maintain the culture in the medium without HC. This observation suggests that HC may be involved in the control of homeostatic properties of the cell surface. The production of rat prolactin by GH3 cells was also studied. GH3 cells in the SF condition produce 1.6 microgram prolactin per 10(5) cells in 24 h, while 2.4 microgram is produced in the presence of serum. Prolactin production in the SF condition is enhanced by the presence of thyrotropin-releasing hormone and inhibited by triiodothyronine (T3). T3 is the major growth factor for these cells. Without it cell growth is severely limited, while prolactin production is elevated. This result suggests that the GH3 cell line in the SF condition may be an ideal system for the study of hormonal regulation of cell growth and specific gene expression.

Organochlorine pesticides can interfere with the thyroid hormones that play an important role in early neurodevelopment. Although organochlorine pesticides have been banned in China since 1983, their residues are still detectable in the environment. However, few studies have investigated the adverse health effects of prenatal exposure to organochlorine pesticide residues on newborns in China. The present study, conducted in Yancheng City, Jiangsu Province, China, aimed to examine the association between the levels of organochlorine pesticides in maternal and cord sera and to assess the impact of prenatal exposure to organochlorine pesticides on thyroid hormone levels in cord serum. Eleven organochlorine pesticides in maternal and cord sera were measured in 247 mother-infant pairs recruited from Yancheng City between February 2010 and June 2010. The concentration of the thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) were determined in cord serum. Among the 11 tested organochlorine pesticides, the detectable levels of hexachlorobenzene (HCB), β-hexachlorocycolohexane (β-HCH) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in both maternal and cord sera were above 50%. The levels of β-HCH and p,p'-DDE in maternal sera were positively associated with the levels in cord sera (r=0.421, P<0.01; r=0.288, P<0.01). After adjusting for confounders, the TSH level in cord serum samples was negatively associated with the HCB level (OR=0.535, 95% CI=(0.304-0.941)). Our data demonstrated that DDT, β-HCH and HCB residues bioconcentrate in maternal and cord sera. Moreover, the correlation analysis suggested that organochlorine pesticides in maternal blood can transfer through the placenta and affect newborn thyroid hormone levels.

Five healthy male volunteers (aged 25 to 28 years) were studied both after 4 weeks of treatment with 200 micrograms iodine/d orally (PO) and following experimental iodine depletion by treatment with 3 x 300 mg perchlorate/d PO over a 4-week period, in an attempt to better define the early adaptive responses to an alteration in iodine supply in thyroid function. Intrathyroidal iodine, serum triiodothyronine (T3), free T3 (FT3), thyroxine (T4), free T4 (FT4), reverse T3 (rT3), thyroxine-binding globulin (TBG), thyroglobulin (Tg), and thyrotropin (TSH) levels (10-minute sampling over 24 hours) were measured at the end of iodine administration and at the end of perchlorate treatment. Thyroid volume was determined by sonography, and iodine content was determined by fluorescence scintigraphy. TSH pulses were analyzed by computer-assisted programs. Comparing both experimental situations, perchlorate treatment significantly reduced intrathyroidal iodine concentration (4.0 +/- 1.3 to 3.0 +/- 1.2 nmol/mL, P less than .05), but thyroid volume and total serum T4, T3, FT3, and TBG levels were not altered. Mean 24-hour serum TSH levels (1.8 +/- 0.3 to 1.0 +/- 0.3 mU/L, P less than .001), amount of TSH secreted/pulse (0.5 +/- 0.1 to 0.3 +/- 0.1 mU/L, P less than .001), and FT4 levels (15.7 +/- 1.7 to 14.3 +/- 1.4 pmol/L, P less than .005) were significantly diminished, whereas Tg levels (18.6 +/- 10.0 to 35.1 +/- 14.0 ng/mL, P less than .01) were significantly increased. Thyroid-specific antibodies were normal and were not altered by treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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 human 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. 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) is not manufactured commercially other than for scientific research purposes. The main sources of PeCDF releases into the environment are from combustion and incineration sources. PeCDF was selected for study by the National Toxicology Program as a 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 DLCs, structurally related PCBs, and mixtures of these compounds. 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 PeCDF study are presented and discussed. Female Harlan Sprague-Dawley rats were administered PeCDF (at least 97% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. 2-YEAR STUDY: Groups of 81 female rats were administered 6, 20, 44, 92, or 200 ng PeCDF/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. Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. A stop-exposure group was administered 200 ng/kg PeCDF in corn oil:acetone (99:1) by gavage for 30 weeks and then the vehicle for the remainder of the study. The PeCDF in this study was at least 97% pure. Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of the 200 ng/kg core and stop-exposure groups were less than those of the vehicle controls during year 2 of the study. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53-week interim evaluations. There were significant decreases in total serum thyroxine (T(4)) levels at the 14-week interim evaluation. There were no significant differences observed in serum free T(4), total triiodothyronine (T(3)), or thyroid stimulating hormone (TSH) at 14 weeks. At both 31 and 53 weeks, there were treatment-related decreases in free and total T(4) concentrations and increases in serum T(3) levels. Serum TSH levels in dosed groups at 31 and 53 weeks were not significantly different than in the vehicle controls. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine (BrdU) was conducted at the 14-, 31-, and 53-week interim evaluations. At 14 and 53 weeks, hepatocyte BrdU-labeling indices were significantly higher in the 200 ng/kg groups compared to time-matched vehicle controls. No significant differences were observed between the dosed groups and vehicle controls at 31 weeks. 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 14-, 31-, and 53-week interim evaluations. Hepatic EROD and A4H activities were significantly higher in all groups administered PeCDF relative to the vehicle controls at all three interim evaluations. Pulmonary EROD was also significantly higher in all dosed groups compared to vehicle controls at 14, 31, and 53 weeks. Determinations of PeCDF Concentrations in Tissues: The tissue disposition of PeCDF was analyzed in the liver, lung, fat, and blood of all animals at the 14-, 31-, and 53-week interim evaluations, and in 10 animals per group at the end of the 2-year study (105 weeks). In the liver of vehicle controls, PeCDF concentrations were detectable at 105 weeks. Measurable concentrations of PeCDF were not detected in fat or lung from vehicle control rats at any of the interim evaluations or at 105 weeks. Hepatic and fat concentrations were higher in groups with increasing doses of PeCDF, demonstrating a dose-related increase in tissue burden of PeCDF at each time point. No measurable concentrations of PeCDF were detected in the lungs of vehicle controls or any of the dosed groups at 14 weeks or in the lungs of the vehicle control group at 31, 53, and 105 weeks, or the 6 ng/kg group at 31 and 53 weeks. In groups with measurable levels, PeCDF concentrations were higher with respect to increasing doses. Mean levels of PeCDF in the liver, fat, lung, and blood in the 200 ng/kg group at the end of the 2-year study were 500 ng/g, 7.75 ng/g, 0.28 ng/g and 0.04 ng/mL, respectively. Negligible PeCDF concentrations were observed in blood of the 200 ng/kg group at 53 weeks and the 92 and 200 ng/kg groups at 105 weeks. In liver and fat from the stop-exposure group, the PeCDF concentrations were between the levels observed in the 6 and 20 ng/kg groups. In the stop-exposure group, PeCDF concentration in lung was comparable to levels observed in the 6 ng/kg group. No measurable concentrations were observed in blood from the stop-exposure group. Pathology and Statistical Analyses: There were dose-dependent increases in both absolute and relative liver weights at 4, 31, and 53 weeks, and these tended to correlate with increased incidences of hepatocellular hypertrophy. In the liver at 14 weeks, the only significant effect was an increase in the incidences of hepatocellular hypertrophy. At 53 weeks, there were significant increases in the incidences of hepatocellular hypertrophy and pigmentation. At 2 years, there were significant dose-dependent trends for increased incidences of hepatocellular adenoma and cholangiocarcinoma of the liver. A significant dose-dependent increase in hepatic toxicity was observed and was characterized by increased incidences of numerous nonneoplastic lesions including hepatocellular hypertrophy, multinucleated hepatocytes, oval cell hyperplasia, diffuse fatty change, pigmentation, nodular hyperplasia, eosinophilic foci, hepatocellular necrosis, bile duct hyperplasia, bile duct fibrosis, cholangiofibrosis, and toxic hepatopathy. At 2 years, three gingival squamous cell carcinomas of the oral mucosa were seen in the 200 ng/kg core and stop-exposure groups, two occurred in the 6 ng/kg group, and one occurred in each of the vehicle control, 20 ng/kg, and 92 ng/kg groups. Gingival squamous hyperplasia occurred in all groups including the vehicle controls, with increasing incidences in groups administered 44 ng/kg or greater. The incidence of carcinoma of the uterus was marginally increased in the 92 ng/kg group at 2 years. Increased incidences of chronic active inflammation of the uterus were observed in all dosed groups, and the incidence in the 200 ng/kg stop-exposure group was greater than those in the vehicle control and 200 ng/kg core study groups. Increased incidences of squamous metaplasia of the uterus occurred in all dosed groups. In the 200 ng/kg stop-exposure group, the incidence of squamous metaplasia was significantly greater than that in the vehicle controls, but was lower than that in the 200 ng/kg core study group. At 14-weeks, lung weights were significantly increased in the 200 ng/kg group compared to the vehicle controls. A single occurrence of a multiple cystic keratinizing epithelioma of the lung was observed in the 200 ng/kg core study group. There were increases in the incidences of bronchiolar metaplasia of the alveolar epithelium and sporadic incidences of squamous metaplasia. One pancreatic acinar adenoma and one pancreatic acinar carcinoma were each observed in the 92 ng/kg group and in the 200 ng/kg stop-exposure group at 2 years. Significantly increased incidences of acinar cytoplasmic vacuolization and arterial chronic active inflammation and increased severity of chronic active inflammation were observed in the 200 ng/kg core study group. Numerous nonneoplastic effects were seen in other organs including thyroid follicular cell hypertrophy, thymic atrophy, adrenal cortex cystic degeneration, nephropathy, cardiomyopathy, and squamous hyperplasia of the forestomach.

Admission serum triiodothyronine (T3) values in 124 patients hospitalized for alcoholic liver disease were correlated with clinical and laboratory indices of liver function and commonly used determinants of thyroid function. Patients with low admission serum T3 levels had significant alterations in serum albumin, bilirubin, prothrombin time, and alkaline phosphatase associated with clinical signs of portal hypertension and collateral circulation, with little difference in serum glutamic-oxaloacetic transaminase, serum gamma glutamyl transpeptidase, or serum ornithine carbamyl transferase. This group also had a significant decrease in free T3 index despite an increase in T3 uptake; the slight reduction in total thyroxine (T4) was associated with an increase in free T4 index and no change in serum thyrotropin (TSH). For patients with alcoholic liver disease, low admission serum T3 and free T3 index values when accompanied by normal serum T4, free T4 index, and TSH levels appear to be indicative of severe liver dysfunction and increased mortality risk.

OBJECTIVE

The aim of the present study was to investigate the anthropometric and endocrine characteristics of subjects with amenorrhea related to eating disorders after weight recovery, in order to identify factors connected with the resumption of menses.

METHODS

Clinical data, body composition parameters and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, cortisol, leptin and insulin were assessed in two groups of young women classified according to menstrual status after weight rehabilitation: 43 subjects who displayed persistent amenorrhea and 34 who resumed menses. Univariate and multivariate logistic regression analyses were used to examine the relationships between the different parameters and menstrual recovery.

RESULTS

The patients who resumed menses had low initial weight and BMI, and a greater difference between current and initial BMI (DeltaBMI), than those with amenorrhea. No differences were observed in lean mass, body fat or bone density between the two groups. Moreover, the reduction in FSH and the increase in LH, insulin and leptin emerged as significant predictors of menstrual recovery. Increased DeltaBMI and insulin continued to be positive predictors in the multivariate analysis.

CONCLUSIONS

Following weight rehabilitation, the individual's metabolic set point before weight loss and the current insulin levels appear significant in predicting the reactivation of reproductive function.

In a previous report, we showed that physiological concentrations of calcitriol (1 alpha,25-(OH)2 vitamin D3 or VD), markedly stimulated the terminal adipose differentiation of Ob 17 preadipocytes cultured under standard conditions with fetal calf serum (FCS), and increased the differentiating effect of triiodothyronine (T3) reported as a necessary adipogenic factor in these cells. Here, we demonstrate, for the first time, that VD is an intrinsic strong adipogenic factor for the Ob 17 preadipocytes cultured in thyroid hormone-deprived medium (adipogenic concentrations: 0.025-0.25 nM in the presence of stripped FCS, 1-10 pM under serum-free conditions). VD action was potentiated by the coaddition of either T3, or arachidonic acid, two agents which also bear proper adipogenic properties. The efficient concentration ranges of other vitamin D3 metabolites suggest a mediation through the VD nuclear receptor (VDR). An expression of the VDR gene is here demonstrated in the Ob 17 cells, and evidence is given that VDR mRNA level increased during the differentiation process and that this increase is moderately amplified under long term treatment with adipogenic concentrations of VD. Our results strongly suggest that adipose differentiation is under the control of different closely related nuclear receptors acting at an early preadipocyte step and probably in an interchangeable manner depending on the availability of their respective ligands. The existence of an interplay between these receptors in exerting their adipogenic action is suggested.

From 5 young males and 5 young females blood was drawn under highly standardized conditions at 6 to 10 occasions during 4 months. The serum constituents thyroglobulin, thyroxine, triiodothyronine, T3-uptake test, TBG and TSH were determined, and four indices were calculated. The biological intra-individual coefficients of variation were below 0.14 for thyroglobulin, and the inter-individual coefficients for variation ranged from zero for T3-uptake test to 0.35 for thyroglobulin. All results were within the generally accepted reference ranges for normals. Within these ranges the calculations of indices for free thyroxine and triidothyronine according to T3-uptake test and TBG, did not significantly reduce the coefficients of variation for these serum constituents. Thyroglobulin concentrations did not correlate to any of the measured or calculated constituents. The knowledge of these intra- and inter-individual variations of serum thyroglobulin in healthy persons is of importance for the interpretation of variations found in patients.

Associations were determined between retinol and the thyroid hormones thyroxine (T4) and triiodothyronine (T3), respectively, and the organochlorine contaminants (OCs) polychlorinated biphenyls (PCBs), 1, 1-dichloro-2,2-bis-(4-chlorophenyl)ethylene (DDE), hexachlorobenzene (HCB), and hexachlorocyclohexanes (HCHs) in blood plasma from polar bears (Ursus maritimus) caught at Svalbard. The blood samples were collected from free-ranging polar bears of different age and sex in 1991-1994. The retinol concentration and the ratio of total T4 (TT4) to free T4(FT4) (TT4/FT4 ratio) decreased linearly with increasing concentrations of PCBs and HCB. Retinol was also negatively associated with HCHs, while the TT4/FT4 ratio was positively associated with DDE. The concentrations of retinol and thyroid hormones were significantly higher in females than in males. However, the TT4/FT4 and TT3/FT3 ratios were significantly higher in males than in females. The concentrations of thyroid hormones were negatively correlated with age in male bears, while in females, thyroid hormones did not change with age. The OCs were found to explain 12, 30, and 7% of the variation of retinol concentrations and the TT4/FT4 and TT3/FT3 ratios, respectively, after correcting for age and sex. The potential consequence of these associations for the individual and the population is unknown.

BACKGROUND

Several epidemiological studies have reported that some organochlorine compounds (OCs), such as polychlorobiphenyls (PCBs) and 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (4,4'-DDE), may alter thyroid function.

OBJECTIVE

The aim of the present study was to investigate the association of maternal serum OC concentrations of 4,4'-DDE and the sum of seven PCB congeners (PCB 28, 52, 101, 118, 138, 153, and 180) with thyroid hormone (TH) status.

METHODS

We measured OC concentrations in 157 maternal serum samples at 12 weeks of pregnancy in a cohort from Valencia (Spain). Thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), and free thyroxine (FT4) were measured as biomarkers of thyroid function in the same samples. Linear and logistic regression analyses were performed between OCs and TH levels, and variables were log transformed.

RESULTS

Mothers with higher levels of 4,4'-DDE had higher odds of having TSH levels >2.5 mIU/L (OR=2.53; 95% CI=1.36; 4.73; p=0.004), and we found a significant negative association between serum 4,4'-DDE concentrations and FT4 levels (beta=-0.03; 95% CI=-0.05; 0.00; p=0.050) after adjustment for covariates and total lipids. No association was found between sum of PCBs and TH levels.

CONCLUSIONS

Serum concentrations of 4,4'-DDE were associated with increased TSH and reduced FT4 but not TT3 levels. Our results suggest that some environmental chemicals may interfere with the thyroid system of pregnant women. The major role that maternal THs may play in fetal neurodevelopment makes these findings especially relevant.

Thyroid hormone abnormalities are common in critically ill patients. For over three decades, a mild form of these abnormalities has been described in patients with several diseases under outpatient care. These alterations in thyroid hormone economy are a part of the nonthyroidal illness and keep an important relationship with prognosis in most cases. The main feature of this syndrome is a fall in free triiodothyronine (T3) levels with normal thyrotropin (TSH). Free thyroxin (T4) and reverse T3 levels vary according to the underlying disease. The importance of recognizing this condition in such patients is evident to physicians practicing in a variety of specialties, especially general medicine, to avoid misdiagnosing the much more common primary thyroid dysfunctions and indicating treatments that are often not beneficial. This review focuses on the most common chronic diseases already known to present with alterations in serum thyroid hormone levels. A short review of the common pathophysiology of the nonthyroidal illness is followed by the clinical and laboratorial presentation in each condition. Finally, a clinical case vignette and a brief summary on the evidence about treatment of the nonthyroidal illness and on the future research topics to be addressed are presented.

The purpose was to compare the resting metabolic rate (RMR) and thermic effect of a meal (TEM) in exercise trained and untrained individuals. TEM was measured for 180 min and blood samples were drawn for determination of plasma insulin, glucose, triiodothyronine (T3) and thyroxine (T4). Results indicated that highly trained subjects demonstrated a higher RMR when expressed in kilocalories per minute and per kilogram fat-free weight (FFW) than do untrained subjects. TEM was lower in trained (55.8 +/- 3.1 kcal) than in untrained (79.2 +/- 3.7 kcal) subjects. No differences were noted between the two groups for plasma levels of insulin, glucose, T3, and T4. A higher RMR and lower TEM persisted in the trained group compared with the untrained group when groups were matched for FFW and body fat. Results support a higher RMR in endurance athletes and a lower TEM even after control is exerted over differences in body composition.

Timely diagnosis and treatment of thyroid dysfunction is compelling given the prevalence and severity of the disease. It requires reliance on adequate laboratory testing of serum TSH as a hallmark in combination with free thyroxine/triiodothyronine. Free hormone methods have to accommodate variations in the concentration and binding capacity of binding proteins. This is a challenge because none of the methodologies developed so far measures the actual unbound hormone in serum. The indirect methods provide an approximation while the direct ones estimate the free hormone concentration either in the presence of the protein-bound counterpart, or after physical separation of the free from bound fraction. The ongoing controversy on the validity and lack of comparability of methodologies points to their imperfectness to reflect real in-vivo free hormone concentrations. Therefore, laboratories and clinicians should know the window of validity and limitations of their methods. The recently developed reference measurement system is a key advance towards improved standardization and clinical validity of free thyroid hormone measurements.

BACKGROUND

Vitiligo is the most common pigmentation-related disorder worldwide. An autoimmune etiology is widely considered, and genetic factors may play an important role in its pathogenesis. The purpose of this study was to assess the incidence of thyroid dysfunctions and autoimmune thyroiditis in children with vitiligo and to identify related factors.

METHODS

Fifty children with vitiligo and 50 control children were enrolled. Data on age, onset, duration, disease activity, presence of thyroid disorder, other autoimmune diseases, halo nevi, poliosis, and mucosal vitiligo were determined. Serum free triiodothyronine, free thyroxine, total T3, total T4, thyroid-stimulating hormone, and antibodies to thyroperoxidase and thyroglobulin were measured. Thyroid gland efficiency was evaluated.

RESULTS

The mean age at onset of vitiligo was 7.26 ± 4.43 years. The duration of vitiligo was 2.26 ± 2.95 years. Vulgaris-type vitiligo was the most common form in our patients (56%), and 42% reported at least one family member with thyroid disorder, autoimmune disease, or both. Overt hypothyroidism or hyperthyroidism were not detected. We found a significant association between autoimmune thyroiditis and both sex and disease duration (P = 0.046 and P = 0.07, respectively), but no association between autoimmune thyroiditis and age, age at onset of vitiligo, halo nevi, poliosis, mucosal involvement, disease activity, or family history of vitiligo, autoimmunity, or thyroid disorders.

CONCLUSIONS

Children with vitiligo show an increased incidence of autoimmune thyroiditis. Children with vitiligo, especially girls and subjects with generalized/vulgaris-type vitiligo, should be screened annually for thyroid function and antithyroid antibodies to assist in the early diagnosis and therapy of autoimmune thyroiditis.

The effects of metabolic acidosis on thyroid function are unknown. We investigated the effects of chronic extrarenal acidosis on the hypothalamic-pituitary-thyroid axis. Chronic metabolic acidosis was induced by administering NH4Cl (4.2 mmol.kg body wt-1.day-1) to six normal male volunteers during metabolic balance conditions. Plasma bicarbonate concentration decreased from 25.0 +/- 0.4 to 15.5 +/- 0.9 mmol/l (P < 0.001). Metabolic acidosis significantly decreased serum-free 3,5,3'-triiodothyronine (T3) concentrations from 373 +/- 18 (control) to 251 +/- 13 pg/dl (P < 0.001) and decreased serum-free L-thyroxine (T4) from 1.55 +/- 0.42 to 1.25 +/- 0.37 ng/dl (P < 0.002), whereas serum total reverse T3 did not change significantly. Consequently, the reverse T3-to-free T4 ratio increased. Serum thyroid-stimulating hormone (TSH) levels increased significantly from 0.70 +/- 0.07 during control to 1.30 +/- 0.12 mU/l during acidosis (P < 0.003). The TSH response to thyrotropin (TRH, 2 mg intranasally) was exaggerated in acidosis: the partial area under the concentration curve for the TSH response (210 min post-TRH) was 902 +/- 167 during control compared with 1.394 +/- 209 mU.min.l-1 during acidosis (P = 0.0139). Chronic metabolic acidosis, as produced by the model employed here, induces a decrease in thyroid hormone secretion and might exert additional effects on thyroid hormone metabolism in humans. The acidosis-induced decrease in thyroid function might modulate some of the reported effects of metabolic acidosis, such as on nitrogen balance, protein synthesis, lean body mass, insulin-like growth factor I levels, renal acidification, and cardiac contractile function.

We prospectively evaluated the effect of thyrotropin (TSH)-suppressive therapy with levothyroxine (LT4) on the size of a benign, solitary, solid nodule and multinodular goiter in a relatively low iodine intake area. In this study, 101 euthyroid subjects with a benign, solitary, predominantly solid nodule (n = 54) confirmed by biopsy or multinodular goiter (n = 47) received 200 microg of levothyroxine daily as a single morning tablet for 12 months. Thirty-five receiving no therapy were considered as controls (solitary nodules, n = 20, multinodular, n = 15). Patients were admitted to the study after evaluation of thyroid biochemical parameters (thyroxine [T4], free thyroxine [FT4], triiodothyronine [T3], thyrotropin [TSH], and thyroglobulin [Tg]), thyroid scanning, ultrasound examination, and fine-needle aspiration biopsy. Every 3 months, thyroid function tests and every 6 months ultrasound examinations were repeated. Twelve months later 20 of 54 (37.1%) patients with single, solid nodules had 50% or more regression of the nodular volume (responders). Eleven of 54 (20.3%) patients had more than 20%, but less than 49.9% reduction of nodular volume (partial responders). Nonresponders were 23 of 54 (42.5%). One-third of subjects with multinodular goiter had 50% or more regression of the glandular volume, whereas 46.8% were considered as nonresponsive. The mean serum Tg levels decreased significantly only in responders with solitary nodular disease or multinodular goiter. In the control group only 1 patient (5% of total) with a solitary nodule had a 50% reduction in the nodular volume. Five others had a partial response (<49%, >20% reduction). None of the patients with multinodular goiter had a significant reduction (>50%) of the combined nodular volumes. We concluded that LT4 may be effective, among other factors, in arresting the growth or in reducing the volume of relatively small, benign, solitary, solid thyroid nodules or the combined nodular volume of multinodular goiter.

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.

Thyroid function tests were studied in patients undergoing long-term treatment with various anticonvulsant drugs. Previous reports that diphenylhydantoin induces a decrease in the serum concentrations of total and free thyroxine (T4) and triiodothyronine (T3) without a change in the TSH concentration were confirmed. Diphenylhydantoin had no effect on reverse T3. Carbamazepine was also found to decrease serum T4, the free T4 index and T3 but, with the exception of T3, the decrease was smaller than that induced by diphenylhydantoin. Dipropylacetic acid did not influence the serum thyroid hormone concentrations, and neither did primidone. This demonstrates that the interaction between anticonvulsant drugs of different chemical structure and thyroid hormone metabolism is diverse. None of the drugs tested altered serum TSH or the T3 uptake test for the estimation of unsaturated thyroid hormone binding-capacity in serum. These two tests are considered diagnostically more dependable than the measurement of thyroid hormones in serum when diphenylhydantoin and carbamazepine are administered.

BACKGROUND

Iron overload is a major problem in patients with b-thalassemia major, and it has many structural and metabolic consequences. In this study, we aimed to consider the prevalence of endocrine abnormalities in patients with β-thalassemia major and thalassemia intermedia.

METHODS

We ordered following tests for consideration endocrine abnormalities: fasting plasma glucose, oral glucose tolerance, iron, total iron binding capacity, ferritin, thyroid-stimulating hormone (TSH), free thyroxin (fT4), free triiodothyronine (fT3), parathyroid hormone levels.

RESULTS

According to our study including 70 patients with thalassemia major, 7 (10%) had diabetes, 5 (7.1%) had impaired glucose tolerance, 9 (12.8%) had hypothyroidism, 2 (2.8%) had hypoparathyroidism, 2 (2.8%) had hyperparathyroidism. Of 22 patients with thalassemia intermedia, 1 (4.5%) had diabetes.

CONCLUSIONS

These findings reinforce the importance of regular follow-up of patients with b-thalassemia major and thalassemia intermedia for early detection and management of associated complications. In this way, the prevalence of endocrine abnormalities can be decreased in future.

Despite a lack of documented efficacy in controlled trials, triiodothyronine (T3) is frequently administered as an adjunctive therapy for tricyclic resistant depressions. In this study, we tested the efficacy of T3 as an adjunctive treatment using a double-blind, placebo-controlled crossover design. Sixteen depressed patients who were unresponsive to 4 weeks of imipramine therapy (mean dose = 206 +/- 54 mg daily, mean combined blood level = 220 +/- 132 ng/dl) received T3 25 micrograms and placebo for 2 weeks each. There was no evidence of a T3 effect using both Hamilton depression scores and global improvement. No subgroup of responders using baseline TRH stimulation tests could be identified. T3 treatment lowered plasma free T4 (P = 0.001) and TSH (P greater than 0.02) while raising plasma T3 levels (P less than 0.01), indicating the physiological effect of the drug.