BACKGROUND

In utero exposure to environmental chemicals can result in reproductive toxicity via endocrine disruption mechanisms. Whether some of those contaminants also have an impact on fetal thyroid function or pathways, and, thus, potentially on neuropsychological development, is still debated.

METHODS

We used samples from a cord blood (CB) and milk bank, established for a research on cryptorchidism and xenobiotic exposure to compounds known for their anti-androgenic and/or estrogenic activity, to study CB thyroid tests and their correlation with CB and milk xenobiotics concentrations in boys born in Nice area.

RESULTS

No difference was found in thyroid tests between 60 cryptorchid boys and 76 matched controls (median thyroid stimulating hormone 5.97 vs. 6.55 mUI/L, free thyroxine [fT4] 13.1 vs. 12.9 pmol/L, free triiodothyronine [fT3] 1.9 vs. 2.1 pmol/L), with no influence of season of birth, gestational age, maternal smoking, or mode of delivery (except for higher fT4 in control boys born vaginally). FT4 was correlated with fetal growth only in cryptorchid boys. Since we had previously shown differences between cryptorchid and controls exposure, we studied correlations of thyroid tests with xenobiotics in control boys only. All tested CB or maternal milk was contaminated by one or more selected xenobiotics, mainly polychlorinated biphenyls (PCBs), dichloro diphenyl dichloroethylène (DDE), dibutylphthalate, hexachlorobenzene, and bisphenol A. We found a significant negative correlation between fT4 and concentrations of PCB118, PC180, and DDE in milk (respectively r = -0.342, p < 0.03, r = -0.296, p = 0.031, r = -0.315, p = 0.016), persisting after adjustment for mode of delivery. There was a significant positive correlation of fT3 with milk concentrations of PCB138, PCB153, ΣPCB, and dibutylphthalate (respectively r = 0.31, p = 0.016, r = 0.28, p = 0.029; r = 0.34, p = 0.0079 and r = 0.272, p = 0.0295), with a trend for PCB180 (r = 0.259, p = 0.061). There was no correlation of thyroid stimulating hormone with any of the measured xenobiotics, except for a weak negative trend with CB bisphenol A (r = -0.25, p = 0.077).

CONCLUSIONS

CB thyroid tests are within normal range in cryptorchid boys, similar to controls. Our data in controls suggest a possible weak correlation between in utero exposure to some xenobiotics (PCBs, DDE) and fT3 and fT4 CB concentrations, with usually negative correlations with fT4 and positive with fT3 concentrations, which we speculate could suggest an impact on deiodinases.

Associations of thyroid hormones with visceral obesity and insulin resistance in obese subjects with euthyroidism have been reported. However, there are no such reports in subjects with type 2 diabetes. The purpose of our study is to observe a relationship between thyroid hormones and components of metabolic syndrome (MetS) in type 2 diabetic subjects with euthyroidism defined by normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels. Subjects were 301 Japanese patients with type 2 diabetes. Serum TSH, FT4, free triiodothyronine (FT3), and variables related to MetS were measured. MetS was defined by the Japanese criteria and the criteria of the National Cholesterol Education Program modified for Asians. We found that serum FT3 levels were significantly and positively associated with BMI, visceral fat area, systolic and diastolic blood pressure, estimated glomerular filtration rate, serum triglyceride, and urine C peptide as a marker of insulin production, whereas negatively with age and HbA1c. In contrast, fewer numbers of variables were associated with serum TSH and FT4 levels. By a multiple regression analysis, FT3 level was independently associated with components of MetS such as visceral fat area, systolic blood pressure, and fasting blood glucose levels. On the other hand, the presence of these MetS components was independently associated with FT3 levels and urine C peptide. In conclusion, these results suggest a significant relationship between serum FT3 levels and components of MetS in type 2 diabetic subjects with euthyroidism, and imply a role of FT3 in MetS in type 2 diabetes.

Thirteen vitamins, twenty amino acids, hormones, inorganic salts, and other chemical agents, which constitute typical serum-free media, were evaluated for the development of fortified medium to enhance cell growth and productivity of recombinant antibody in the cultures of the recombinant Chinese hamster ovary (rCHO) cells. Two different rCHO cell lines, rCHO-A producing recombinant antibodies against the human platelet and rCHO-B secreting recombinant antibodies against the S surface antigen of Hepatitis B, respectively, were cultivated in batch suspension mode. Concentration of interested component in the tested medium was doubled to examine the fortification effect. Growth of rCHO-A cell and its antibody production were slightly improved with addition of either choline chloride, folic acid, thiamine[Symbol: see text]HCl, or Long(TM)R(3)IGF-I. On the other hand, in the cultivation of rCHO-B cell which was more sensitive to its environmental changes, hormones such as Long(TM)R(3)IGF-I and triiodothyronine (T(3)) as well as various vitamins involving choline chloride, i-inositol, niacinamide, pyridoxine HCl, and thiamine[Symbol: see text]HCl enhanced the cell growth and antibody production. Particularly, when concentration of consuming amino acid was doubled, remarkable increase in specific productivity was served, resulting in high final antibody concentration. These results were believed to provide a fundamental strategy of medium fortification useful for improvement of recombinant antibody production in serum-free medium.

To determine the role of tumor necrosis factor (TNF) in endotoxin-induced changes in plasma thyroid hormone and thyroid-stimulating hormone (TSH) concentrations, 24 healthy postabsorptive humans were studied on a control study day (n = 6), after infusion of a recombinant TNF receptor IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) after intravenous injection of endotoxin (2 ng/kg; n = 6), or after administration of endotoxin with TNFR:Fc (n = 6). Administration of TNFR:Fc alone did not affect thyroid hormone or TSH levels when compared with the control day. Endotoxin induced a transient rise in plasma TNF activity (1.5 h: 219 +/- 42 pg/ml), which was completely prevented by TNFR:Fc (P < 0.05). After endotoxin administration, plasma L-thyroxine (T4), free T4, 3,5, 3'-triiodothyronine (T3), and TSH were lower and 3,3', 5'-triiodothyronine was higher than on the control day (all P < 0. 05). Coinfusion of TNFR:Fc with endotoxin did not influence these endotoxin-induced changes. Our results suggest that endogenous TNF does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

High-fluoride (100 and 200 ppm) water was administered to rats orally to study the fluoride-induced changes on the thyroid hormone status, the histopathology of discrete brain regions, the acetylcholine esterase activity, and the learning and memory abilities in multigeneration rats. Significant decrease in the serum-free thyroxine (FT4) and free triiodothyronine (FT3) levels and decrease in acetylcholine esterase activity in fluoride-treated group were observed. Presence of eosinophilic Purkinje cells, degenerating neurons, decreased granular cells, and vacuolations were noted in discrete brain regions of the fluoride-treated group. In the T-maze experiments, the fluoride-treated group showed poor acquisition and retention and higher latency when compared with the control. The alterations were more profound in the third generation when compared with the first- and second-generation fluoride-treated group. Changes in the thyroid hormone levels in the present study might have imbalanced the oxidant/antioxidant system, which further led to a reduction in learning memory ability. Hence, presence of generational or cumulative effects of fluoride on the development of the offspring when it is ingested continuously through multiple generations is evident from the present study.

OBJECTIVE

Amiodarone-induced thyrotoxicosis (AIT) is a challenging management problem, since patients treated with amiodarone invariably have underlying heart disease. Consequently, thyrotoxicosis can significantly contribute to increased morbidity and mortality. The aim of this study was to compare the clinical outcome and hormone profiles of patients with AIT (n = 60) with those with Graves' thyrotoxicosis (n = 49) and toxic multinodular goitre (MNG, n = 40).

METHODS

A retrospective study of patients with AIT in a single institution was conducted.

METHODS

Data from patients with AIT over 12 years were collected.

RESULTS

Mean TSH levels were significantly suppressed in all three groups. However, there was no intergroup significant difference. Free thyroxine (T4) levels were significantly higher in AIT (45.6 +/- 3.5 pmol/l) and Graves' disease (44.6 +/- 4.0 pmol/l) compared with toxic MNG (31.5 +/- 5.1 pmol/l, P < 0.05). In contrast, free triiodothyronine (T3) levels were only significantly higher in Graves' disease (14.7 +/- 1.5 pmol/l, P = 0.002) compared with AIT (8.6 +/- 0.7 pmol/l) and toxic MNG (7.4 +/- 0.5 pmol/l). Six deaths occurred in the patients with AIT (10.0%, P < 0.01) and no deaths occurred in the other groups. Amiodarone treatment (P = 0.002) was the most significant predictor of death, whereas free T4, free T3 and age did not affect outcome. Within the amiodarone-treated group severe left ventricular dysfunction (P = 0.0001) was significantly associated with death.

CONCLUSIONS

(i) AIT differs from other forms of thyrotoxicosis, and (ii) severe left ventricular dysfunction is associated with increased mortality in AIT.

L-Triiodothyronine in vitro increased the uptake of the non-metabolizable amino acid, alpha-aminoisobutyrate, into isolated rat thymocytes. This effect was evident at extracellular free hormone concentrations of 10-7 to 5 times 10-8M and was due to a marked inhibition of amino acid efflux. In contrast, insulin and dibutyryl cyclic AMP, which also increased uptake in these cells, acted to stimulate amino acid influx. When L-triiodothyronine was added to maximally effective concentrations of either insulin or dibutyryl cyclic AMP, the resultant effect was the sum of the effect of each hormone added individually. These studies extended previous observations which indicate that thyroid hormones stimulate the cellular uptake of amino acids, and they provide a convenient system for the study of thyroid hormone action in vitro.

These studies evaluated the influence of an initial exposure of thyroid slices to thyroid-stimulating hormone (TSH) on the subsequent responsiveness to the hormone. Bovine thyroid slices were incubated with or without 50 mU/ml TSH for varying periods and then incubated in hormone-free medium for varying periods. Subsequently, slices were incubated for 20 min with 10 mM theophylline and with or without TSH. Cylic AMP was measured after the third incubation. Phosphodiesterase and adenylate cylase were assayed in homogenates prepared from slices after the second incubation. In some experiments prostaglandin E1, puromycin, thyroxine, and triiodothyronine and propylthiouracil were included in the media. In other experiments, low does of TSH (1 AND 10 mU/ml) were used instead of 50 mU/ml. Slices previously exposed to TSH have decreased responsiveness of the adenylate cyclase-cylic AMP system. Such refractoriness is hormone specific since initial exposure to prostaglandin E1 decreases the subsequent response to this substance but not to TSH. Refractoriness to TSH develops only when the first incubation is at least 30 min. It is not reversed by 5 h of incubation without hormone. Incubation of thyroid slices with puromycin does not eliminate refractoriness. The decreased response to TSH cannot be explained by release of thyroxine, triiodothyronine, or iodide from the slices. Phosphodiesterase activity is not increased during the refractory period. The decreased cyclic AMP response to TSH is associated with diminished response of adenylate cyclase activity to the hormone. Guanosine triphosphate (1 mM) increased adenylate cyclase activity in both control and TSH treated tissue, but the effect was significantly less in the latter. Although with guanosine triphosphate, TSH increased adenylate cyclase activity in TSH treated tissue, the enzyme activity was still less than that present in control tissue incubated with guanosine triphosphate and TSH. NaF caused an equivalent stimulation of adenylate cyclase in both control and TSH treated tissue. These results suggest that the refractoriness represents an alteration in hormone binding or the coupling of the bound hormone to the adenylate cyclase activity rather than any modification of the catalytic site of the enzyme.

Thyroid hormone resistance (THR) is a rare syndrome of reduced end organ sensitivity. Patients with THR have elevated serum free thyroxine (FT4), free triiodothyronine (FT3), but normal or slightly elevated serum thyrotropin values. The characteristic clinical feature is goitre without symptoms and metabolic consequences of thyroid hormone excess. THR can be classified on the basis of tissue resistance into pituitary, peripheral or generalised (both pituitary and peripheral) types. Mutations in the TRbeta gene, cell membrane transporter and genes controlling intracellular metabolism of thyroid hormone have been implicated. THR is differentiated from thyroid stimulating hormone (TSH) secreting pituitary adenoma by history of THR in the family. No specific treatment is often required for THR; patients with features of hypo- or hyperthyroidism are appropriately treated with levo-triiodothyronine (L-T3), levo-thyroxine (L-T4), dextro-thyroxine(D-T4) or 3,3,5 triiodo-thyroacetic acid (TRIAC). The diagnosis helps in appropriate genetic counselling of the family.

Primary cultures of astrocytes from newborn rat brain showed evidence of a substrate-saturable process for glucose transport. The system shows a relatively high affinity for the substrate, with an apparent Km of approximately 1 mM. Maintenance of the cells in medium containing thyroid-hormone-free serum for 3, 6, or 9 days resulted in significantly reduced rates of hexose transport. Addition of exogenous triiodothyronine to the transport incubation medium of these "hypothyroid" cells markedly increased the net rate of 2-deoxyglucose uptake within 60 s to values equal to or above those of control cultures (cells maintained in normal serum). These findings support a key role for thyroid hormone in the transport of glucose across plasma membranes of brain cells and demonstrate the presence of this regulatory system in astrocytes.

The THORN trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial to test the hypothesis that administration of triiodothyronine (T(3)) and hydrocortisone would decrease mortality and respiratory morbidity in preterm infants of less than 30 wk gestation. Two hundred fifty-three infants were randomized to receive either 6 micro g.kg(-1).d(-1) of T(3) with 1 mg.kg(-1).d(-1) of hydrocortisone or 5% dextrose (placebo) as a continuous i.v. infusion for 7 d. The dose was halved on d 5. Our first primary outcome was death or ventilator dependence at 1 wk, and the second was death or oxygen dependence at 2 wk. The overall mortality rate for both groups was 11.4%. Relative risk of death or ventilator dependence at 1 wk, treated versus placebo, was 0.87, p = 0.2, and death or oxygen dependence at 2 wk, 1.00, p = 0.9. We examined the relationship between free T(3) (FT(3)) and free thyroxine (FT(4)) levels in the first 7 d and the primary outcome death or ventilator dependence at 1 wk in all 253 babies. We found significant positive correlations of p = 0.05 for FT(3) and p = 0.002 for FT(4). Thus the higher the FT(3) and FT(4) levels, the better the outcome. No beneficial effects of T(3) and hydrocortisone were shown. In this study, although FT(3) levels were doubled by the treatment infusion, FT(4) levels were significantly suppressed. The lack of any beneficial effect of T(3) in our study may be explained by suppression of FT(4) in the treatment group.

In this cross-sectional study, we evaluated 15 premenopausal women to elucidate whether bone turnover is increased and bone mineral density is reduced due to endogenous subclinical hyperthyroidism. Each patient had normal free thyroxine (FT4) and free triiodothyronine (FT3) levels associated with a stable suppression (<0.1 mU/L) of serum thyrotropin (TSH) levels during a period ranging between 6 and 11 months. Metabolic parameters of bone turnover (serum osteocalcin, bone specific alkaline phosphatase, procollagen I C-terminal peptide reflecting bone formation; urinary deoxypyridinoline and calcium excretion reflecting bone resorption) were assessed. Bone mineral density was measured at lumbar 1-4 vertebrae, femoral neck, and the forearm (midshaft radius and distal radius) by dual energy x-ray absorptiometry. All measurements were compared with 15 healthy age-, height-, and weight-matched premenopausal women who served as control group. Our findings suggest that endogenous subclinical hyperthyroidism is not associated with increased bone turnover, and bone mineral density is not reduced in premenopausal women, at least in the short term.

Thyroid function and serum levels of triiodothyronine (T3) and thyroxine (T4) were investigated in 79 euthyroid geriatric patients. Of the 59 inpatients and 20 outpatients 35 (59%) and 2, respectively, had low T3 levels. In contrast, 7 (12%) and 6 (30%), respectively, had raised T4 levels. Two further patients were excluded from the study because of raised levels of thyroid-stimulating hormone. Thyroxine-binding globulin was greatly increased in both groups of patients, but low serum albumin levels were present in 31 (39%). Despite these changes free T3 and T4 indices closely followed total T3 and T4 levels. The difference between the two groups of patients did not correlate with body weight, diagnostic categories, age, drug treatment, or duration of stay in hospital.

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on thyroid hormone parameters, cortisol, aldosterone, endothelin-1 and angiotensin II was investigated. Four groups composed of 25 volunteers each (ages between 18 and 35 years) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken by venipuncture after at least 12 h fasting on Day 21-26 of the control cycle and on Day 18-21 of the first, third and sixth treatment cycle. There was a significant increase in triiodothyronine (T3) and thyroxine (T4) by 20-40% in all treatment cycles, while thyroid-stimulating hormone was significantly increased only with EE/EV/DNG. Treatment with the DNG-containing OCs caused no change in free T4 (FT4) and a transitory reduction in free T3 (FT3) levels during the first cycle. During intake of EE/LNG, FT4 rose slightly, while FT3 was not altered. The pronounced rise in the serum concentrations of cortisol appeared to be related to the EE dose. During the first three cycles of treatment, no effect on angiotensin II levels was observed, while in the sixth cycle a significant decrease was measured in all treatment groups. The four OCs did not influence the serum concentrations of endothelin-1 and no consistent effects were found concerning those of aldosterone. The results suggest that the three DNG-containing and the LNG-containing low-dose OCs may increase T3, T4 and cortisol due to an elevated binding to serum globulins, while the free proportion of the hormones is not or only slightly changed. Therefore, these OCs have only minor effects on thyroid function, adrenal and blood pressure serum parameters.

BACKGROUND

Polychlorinated dioxins and -furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.Influences of brominated flame retardants, PCDD/F's and dioxin like-PCBs (dl-PCB's) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3', 5,5'tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3',5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort.

METHODS

Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels.

RESULTS

The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group.

CONCLUSIONS

Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.

Activation of glycogen synthase in the perfused rat liver is defective in severely diabetic rats. In the present study, activation of glycogen synthase by glucose and increased incorporation of [14C]glucose into glycogen by insulin are defective in hepatocytes isolated from alloxan diabetic rats. Acute activation of glycogen synthase in hepatocytes isolated from diabetic rats was restored by treatment of the rats with insulin in vivo. Restoration of synthase activation was not achieved by incubation of hepatocytes in the presence of insulin in vitro for up to 12 h. When isolated hepatocytes from diabetic rats were placed in primary culture in a serum-free defined medium over a 3-day period, glycogen synthesis was partially restored by cortisol and triiodothyronine and dramatically increased by insulin. Concomitant with restoration of [14C]glycogen synthesis was an insulin-mediated increase in glycogen synthase I and synthase phosphatase activity. Restoration of regulation of glycogen synthesis in primary cultures of hepatocytes from diabetic rats by insulin required the presence of cortisol and triiodothyronine. Primary cultures of hepatocytes from normal rats did not require triiodothyronine for insulin to effect glycogenesis over a 3-day period. These data demonstrate that insulin acts in a chronic manner in concert with other hormones to control synthase phosphatase activity, an effect which may be influencing acute control of hepatic glycogen synthesis.

Differentiation of human neural progenitors into neuronal and glial cell types offers a model to study and compare molecular regulation of neural cell lineage development. In vitro expansion of neural progenitors from fetal CNS tissue has been well characterized. Despite the identification and isolation of glial progenitors from adult human sub-cortical white matter and development of various culture conditions to direct differentiation of fetal neural progenitors into myelin producing oligodendrocytes, acquiring sufficient human oligodendrocytes for in vitro experimentation remains difficult. Differentiation of galactocerebroside(+) (GalC) and O4(+) oligodendrocyte precursor or progenitor cells (OPC) from neural precursor cells has been reported using second trimester fetal brain. However, these cells do not proliferate in the absence of support cells including astrocytes and neurons, and are lost quickly over time in culture. The need remains for a culture system to produce cells of the oligodendrocyte lineage suitable for in vitro experimentation. Culture of primary human oligodendrocytes could, for example, be a useful model to study the pathogenesis of neurotropic infectious agents like the human polyomavirus, JCV, that in vivo infects those cells. These cultured cells could also provide models of other demyelinating diseases of the central nervous system (CNS). Primary, human fetal brain-derived, multipotential neural progenitor cells proliferate in vitro while maintaining the capacity to differentiate into neurons (progenitor-derived neurons, PDN) and astrocytes (progenitor-derived astrocytes, PDA) This study shows that neural progenitors can be induced to differentiate through many of the stages of oligodendrocytic lineage development (progenitor-derived oligodendrocytes, PDO). We culture neural progenitor cells in DMEM-F12 serum-free media supplemented with basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF-AA), Sonic hedgehog (Shh), neurotrophic factor 3 (NT-3), N-2 and triiodothyronine (T3). The cultured cells are passaged at 2.5e6 cells per 75cm flasks approximately every seven days. Using these conditions, the majority of the cells in culture maintain a morphology characterized by few processes and express markers of pre-oligodendrocyte cells, such as A2B5 and O-4. When we remove the four growth factors (GF) (bFGF, PDGF-AA, Shh, NT-3) and add conditioned media from PDN, the cells start to acquire more processes and express markers specific of oligodendrocyte differentiation, such as GalC and myelin basic protein (MBP). We performed phenotypic characterization using multicolor flow cytometry to identify unique markers of oligodendrocyte.

Twenty toluene-exposed rotogravure printers, without signs of solvent-induced toxic encephalopathy, had lower median plasma levels of follicle stimulating hormone (FSH) (3.2 vs. 4.9 IU/L; p = .02) and luteinizing hormone (LH) (6.4 vs. 7.2 IU/L; p = .05) and also lower serum levels of free testosterone (7.8 vs. 86.8 pmol/L; p = .05), respectively, than 44 unexposed referents. The individual time-weighted toluene levels in air were 36 (median; range 8-111) ppm. The printers' median toluene levels in blood were 1.7 (1.0-6.6) mumol/l, and in subcutaneous adipose tissue 5.7 (2.5-21) mg/kg fat. There was a negative association between blood toluene and plasma levels of prolactin. In eight printers, the levels of FSH and LH increased during a 4 week vacation, while the levels of thyroid stimulating hormone, free triiodothyronine, and free thyroxine decreased during the same period. The results indicate a slight, reversible effect of toluene on the cortical level or on the hypothalamic-pituitary axis at exposures well below the permissible levels, possibly mediated through an effect on catecholamine neurotransmission.

Multiple endocrine determinations were carried out on 101 patients with anorexia nervosa. Ninety-five percent of the patients studied were female, and in 94% of patients the anorexia nervosa began before 30 years of age. Evidence of gonadal dysfunction was the predominant manifestation, both clinically and by laboratory studies. Amenorrhea occurred before or concurrent with onset of weight loss in 65% of the women. The average weight loss was 28% of the weight before illness began. In an additional 11%, the disease began before menarche. The mean age of menarche in patients with secondary amenorrhea was 13 years. Urinary excretion of pituitary gonadotropin was undetectable in 44 of 65 patients and was below 19 rat units per 24 hours in the remaining patients. Serum luteinizing hormone level was below 8 microgram/dl in 15 of 27 patients studied and serum follicle-stimulating hormone was below 10 microgram/dl in 7 of 27 patients studied. Mean serum or urinary estrogens, or both, were low in more than 50% of the patients. Elevation of serum corticosteroids or loss or reversal of diurnal variation, or both, was noted in 50% of patients. Fasting serum growth hormone levels were elevated in 45% of the patients. Mean total and free serum thyroxine, thyroid-stimulating hormone, and triiodothyronine levels were low. These hormonal alterations in the hypothalamic-pituitary axis in patients with anorexia nervosa probably represent adaptive and protective mechanisms for chronic starvation and weight loss.

Experimental evidence for the physiological effects of secondhand smoke (SHS) is limited, although it affects millions of people globally and its prevalence is increasing, despite currently adopted antismoking measures. Also, scarce evidence suggests that the effects of SHS may be more pronounced in men. We conducted a randomized single-blind crossover study to investigate the sex-specific SHS effects in a controlled simulated bar/restaurant environment on gonadal and thyroid hormones, inflammatory cytokines, and vascular function. Twenty-eight (women = 14) nonsmoking adults underwent a 1-h exposure to moderate SHS and a 1-h control trial. Serum and urine cotinine, gonadal and thyroid hormones, inflammatory cytokines, heart rate, and arterial blood pressure were assessed before exposure and immediately after in both trials. Results showed that testosterone (P = 0.019) and progesterone (P < 0.001) in men and 17beta-estradiol (P = 0.001) and progesterone (P < 0.001) in women were significantly decreased after SHS. In men, SHS was accompanied by increased free thyroxine (P < 0.001), triiodothyronine (P = 0.020), and decreased the triiodothyronine-to-free thyroxine ratio (P = 0.033). In women, significant SHS-induced change was observed only in free thyroxine (P = 0.010), with considerable sex variation in free thyroxine and triiodothyronine and a decrease in luteinizing hormone (P = 0.026) and follicle-stimulating hormone (P < 0.001). After SHS, IL-1beta (P = 0.001) and systolic blood pressure (P = 0.040) were increased in men but not women. We concluded that a 1-h SHS exposure at bar/restaurant levels is accompanied by decrements in gonadal hormones in both sexes and marked increases in thyroid hormone secretion, IL-1beta production, and systolic blood pressure in men.

OBJECTIVE

To determine the frequency of thyroid dysfunction in patients of chronic hepatitis C during treatment with interferon alpha-2b and ribavirin therapy.

METHODS

A cohort study.

METHODS

Army Medical College and Military Hospital, Rawalpindi, from February 2006 to January 2007.

METHODS

One hundred and sixty seven non-cirrhotic chronic hepatitis C patients were grouped into treatment group (n=107) and control group (n=60) awaiting treatment. Baseline serum(s.) Alanine Transferase (ALT) and S. Aspartate Transferase (AST) were measured by IFCC method. Serum Thyroid Stimulating Hormone (S. TSH), serum free thyroxine (S. Free T4) and serum total triiodothyronine (S.T3) level were determined by chemiluminescence. Study group patients underwent 24 weeks IFN and ribavirin therapy and were followed-up for thyroid dysfunction at weeks 0, 12 and 24. Control group patients underwent the same tests at weeks 0, 12 and 24. Statistical analysis was done on SPSS 15.

RESULTS

Out of 107 patients of treatment group, 20 patients (18.69%) developed thyroid dysfunction. Females were at higher risk with Relative Risk (RR) of 11.25 and Attributable Risk (AR) of 91%. Hypothyroidism was more common than hyperthyroidism.

CONCLUSIONS

Interferon-alpha and ribavirin therapy induces thyroid dysfunction in chronic hepatitis C patients. Hypothyroidism was more common. Females are at a higher risk of developing thyroid dysfunction.

Among the factors influencing weight loss and maintenance, psychobehavioral, nutritional, metabolic, hormonal and hereditary predictors play an important role. Psychobehavioral factors influence adherence to lifestyle changes and thus weight loss maintenance. The outcome of short-term weight reduction treatment is mainly affected by changes in energy and nutrient intake and physical activity and thus the impact of hormones can possibly be obscured. In order to reveal hormonal determinants of weight loss, a 4-week in-patient comprehensive weight reduction program was introduced in which food intake and physical activity were under the strict control. Women (n = 67, BMI: 32.4+/-4.4 kg; age: 48.7+/-12.2 years) who exhibited stable weight on a 7 MJ/day diet during the first week of weight management were given a hypocaloric diet yielding daily energy deficit 2.5 MJ over the subsequent 3-week period. This treatment resulted in a mean weight loss of 3.80+/-1.64 kg. Correlation analysis revealed that baseline concentrations of several hormones were significantly associated either with a higher (free triiodothyronine, C-peptide, growth hormone, pancreatic polypeptide) or with a lower (insulin-like growth factor-I, cortisol, adiponectin, neuropeptide Y) reduction of anthropometric parameters in response to weight management. In a backward stepwise regression model age, initial BMI together with baseline levels of growth hormone, peptide YY, neuropetide Y and C-reactive protein predicted 49.8 % of the variability in weight loss. Psychobehavioral factors (items of the Eating Inventory, Beck Depression score) did not contribute to weight change induced by a well-controlled short-term weight reduction program.

Changes in circulating triiodothyronine (T3), thyroxine (T4), binding of thyroid hormones to plasma proteins (resin-T3 test), cortisol, and glucose were evaluated in sixteen patients undergoing abdominal hysterectomy. In eight of the patients afferent neurogenic impulses from the surgical area were blocked during and after operation by epidural analgesia. These patients were pain-free, and the normal stress-induced increase in cortisol and glucose was abolished. During epidural analgesia and general anesthesia plasma-T3 fell rapidly and values in the hypothyroid range were found 6 hours after skin incision. Similarly, an increase in the resin-T3 test reflected decreased binding of T3 to plasma proteins. Plasma-T4 decreased slightly during surgery and epidural analgesia (as it does when other anaesthetics are given), but increased during general anaesthesia. These results indicated that the alterations in thyroid hormones and their binding to plasma proteins after surgery are not caused by a stress-induced increase in plasma-cortisol or by neurogenic afferent stimuli from the surgical area, factors which are both known to affect concentrations of other hormones.

The effect of three different live microsomal enzyme inducing drugs on thyroid hormone metabolism was investigated. Seven volunteers were randomly allocated in a crossover design to either antipyrine (1200 mg), phenobarbital (100 mg) or rifampicin (1200 mg) daily for 14 days. Before and after each treatment the following parameters of enzyme induction were measured: antipyrine clearance, gamma-glutamyltranspeptidase, d-glucaric acid and 6-beta-hydroxycortisol urinary excretion. In addition, thyroxine-binding globulin (TBG), T3-resin uptake (RT3U), thyroxine (T4), free thyroxine (FT4), triiodothyronine (T3), reverse T3 (rT3), and thyroid stimulating hormone were estimated. Following antipyrine and phenobarbital antipyrine clearance increased by about 45%, while with rifampicin an increase of 125% was observed. The indices of thyroid function did not change following phenobarbital and antipyrine, but after rifampicin T4, FT4 and rT3 decreased by about 14%, and T3 increased by 25%. In addition, the impact of rifampicin on the clearance of injected 125I-T4 was investigated in six additional volunteers by blocking thyroid iodine uptake. The 125I-T4 halflife decreased from 155 to 106 h and its clearance increased from 25 to 50 ml/h, while a fall in T4, FT4 and rT3 by about 40% and no rise but a decrease in T3 by 25% occurred. Therefore an increased clearance of T4 and rT3 but not of T3 seems likely following rifampicin, which might be due to enhanced hepatic metabolism and biliary excretion.