Previous studies have suggested that exposure to polychlorinated biphenyls (PCBs) may alter thyroid function, but data on effects of PCB exposure on other endogenous hormones has been lacking. The current study is ancillary to a larger investigation of the effects of Great Lakes fish consumption on PCBs and reproductive function. In the current study we examine associations of PCBs, 1,1-bis (4-chlorophenyl)-2,2-dichloroethene (DDE), and fish consumption with thyroid and steroid hormones in 178 men and PCBs, DDE, and fish consumption with thyroid hormones in 51 women from the original study. Serum PCB level and consumption of Great Lakes fish are associated with significantly lower levels of thyroxine (T(4)) and free thyroxine index (FTI) in women and with significantly lower levels of T(4) in men. Fish consumption, but not PCB level, is significantly and inversely associated with triiodothyronine (T(3)) in men. Results for thyroid-stimulating hormone (TSH) are inconsistent. Among men, there are significant inverse associations of both PCB and fish consumption with sex hormone-binding globulin (SHBG)-bound testosterone, but no association with SHBG or free testosterone. There are no significant overall associations of PCB, DDE, or fish consumption with estrone sulfate, follicle-stimulating hormone, luteinizing hormone, or dehydroepiandrosterone sulfate. The results of this study are consistent with previous studies showing effects of fish consumption and PCB exposure on thyroid hormones and suggest that PCBs may also decrease steroid binding to SHBG. Elucidation of specific mechanisms must await future investigations.

OBJECTIVE

Morbid obesity (body mass index (BMI>> or =40 kg/m(2)) is associated with thyroid function disturbances, with a high rate of subclinical hypothyroidism (SH) being the most consistently reported. We evaluated the circulating thyroid function parameters in morbid obese patients and related the results to the presence of circulating thyroid antibodies (Thyr-Ab).

METHODS

Morbid obese patients were consecutively enrolled (n=350). Two control groups were used: control group (CG)1, healthy normo-weight subjects (n=50); CG2, normo-weight patients with SH (n=56) matched for TSH with the obese patients with SH. Serum levels of free triiodothyronine (FT(3)), free thyroxine (FT(4)), TSH, antithyroglobulin antibodies, and antithyroperoxidase antibodies were measured in all patients.

RESULTS

i) Compared with CG1, obese patients having thyroid function parameters in the normal range and negative Thyr-Ab showed significantly higher serum TSH and lower free thyroid hormones levels, but a similar FT(4)/FT(3) ratio; ii) SH was recorded in 13.7% obese patients; iii) compared with CG2, obese patients with untreated SH had a significantly lower rate of positive Thyr-Ab (32.1 vs 66.1%; P<0.005); iv) no gender prevalence was observed in SH obese patients with negative Thyr-Ab; and v) the comparison of the untreated SH patients (obese and normo-weight) with CG1 demonstrated that in SH obese subjects, unlike normo-weight SH patients, the FT(3) levels were significantly lower. This resulted in a normal FT(4)/FT(3) ratio in SH obese patients.

CONCLUSIONS

Thyroid autoimmunity is not a major cause sustaining the high rate of SH in morbid obese patients. In these patients, the diagnosis of SH itself, as assessed by a raised TSH alone, appears questionable.

To determine the prevalence and significance of abnormal thyroid hormone metabolism in congestive heart failure, free thyroxine (T4) index, free triiodothyronine (T3) index, reverse T3 and thyrotropin levels were obtained in 84 hospitalized patients with chronic advanced heart failure. Free T4 index was normal in all patients. Free T3 index was reduced or reverse T3 elevated, or both, leading to a low free T3 index/reverse T3 ratio in 49 (58%) of the 84 patients. A low free T3 index/reverse T3 ratio was associated with higher right atrial, pulmonary artery and pulmonary capillary wedge pressures and lower ejection fraction, cardiac index, serum sodium, albumin and total lymphocyte count. In multivariate analysis, the free T3 index/reverse T3 ratio was the only independent predictor of poor 6 week outcome (p less than 0.001); the actuarial 1 year survival rate was 100% for patients with a normal ratio and only 37% for those with a low ratio (p less than 0.0001). A low free T3 index/reverse T3 ratio is associated with poor ventricular function and nutritional status and is the strongest predictor yet identified for short-term outcome in patients with advanced heart failure.

An 18-yr-old woman with clinical and laboratory features of hyperthyroidism had persistently elevated serum levels of immunoreative thyrotropin (TSH). During 11 yr of follow-up there had been no evidence of a pituitary tumor. After thyrotropin-releasing hormone (TRH), there was a marked increase in TSH and secondarily in triiodothyronine (T3), the latter observation confirming the biologic activity of the TSH. Exogenous T3 raised serum T3 and several measurements of peripheral thyroid hormone effect, while decreasing serum TSH, thyroxine (T4), and thyroidal radioiodine uptake. After T3, the TRH-stimulated TSH response was decreased but was still inappropriate for the elevated serum T3 levels. Dexamethasone reduced serum TSH but did not inhibit TRH stimulation of TSH. Propylthiouracil reduced serum T4 and T3 and raised TSH. This patient represents a new syndrome of TSH-induced hyperthyroidism, differing from previous reports in the absence of an obvious pituitary tumor and in the responsiveness of the TSH to TRH stimulation and thyroid hormone suppression. This syndrome appears to be caused by a selective, partial resistance of the pituitary to the action of thyroid hormone. This case is also compared with previous reports in the literature of patients with elevated serum levels of immunoreactive TSH in the presence of elevated total and free thyroid hormones. A classification of these cases, termed "inappropriate secretion of TSH," is proposed.

BACKGROUND

We evaluated the association of central versus overall adiposity on levels of thyroid stimulating hormone (TSH), free triiodothyronine (fT(3)), and free thyroxine (fT(4)) among euthyroid subjects taken from a cross-sectional, representative sample of the adult non-institutionalized U.S. population.

METHODS

The National Health and Nutrition Examination Survey 2007-2008 included 1,623 men and 1,491 women who were 20 years and older, with no history of thyroid or liver disease, kidney failure, diabetes, or thyroid function-altering prescription medication use (based on self-report), and having TSH, fT(3), and fT(4) levels between 0.5-4.49 mIU/L, 2.5-3.9 pg/mL, and 0.6-1.6 ng/dL, respectively. Associations between body mass index (BMI) and waist circumference (measures of overall and central adiposity, respectively) and TSH, fT(3), and fT(4) levels were estimated using multivariable linear regression models stratified by sex and adjusted for age, race, smoking status, and alcohol intake.

RESULTS

An increase in serum TSH levels was observed for every 1-quartile increase in BMI in euthyroid men (3.8% [95% CI 0.8%, 6.8%]) and euthyroid women (4.0% [95% CI 1.6%, 6.5%]). Similar, albeit slightly weaker, associations were observed with waist circumference. We also found increases in fT(3) levels with every 1-quartile increase in BMI (1.0% in men and 1.3% in women) and waist circumference (1.2% in men and 1.2% in women). No associations were observed with fT(4.)

CONCLUSIONS

Our results provide support that BMI and waist circumference are positively associated with levels of serum TSH and f T(3) but not fT(4) among euthyroid adults. Longitudinal studies are needed to define the temporality of these associations and their potential health implications.

BACKGROUND

Huntington's disease (HD) is a severe inherited neurodegenerative disorder characterized, in addition to neurological impairment, by weight loss suggesting endocrine disturbances. The aims of this study were to look for neuroendocrine disturbances in patients with Huntington's disease (HD) and to determine the relationship with weight loss seen in HD METHODS AND FINDING: We compared plasma levels of hormones from the five pituitary axes in 219 patients with genetically documented HD and in 71 sex- and age-matched controls. Relationships between hormone levels and disease severity, including weight-loss severity, were evaluated. Growth hormone (GH) and standard deviation score of insulin-like growth factor 1 (SDS IGF-1) were significantly higher in patients than in controls (0.25 (0.01-5.89) vs. 0.15 (0.005-4.89) ng/ml, p = 0.013 and 0.16+/-1.02 vs. 0.06+/-0.91, p = 0.039; respectively). Cortisol was higher (p = 0.002) in patients (399.14+/-160.5 nmol/L vs. 279.8+/-130.1 nmol/L), whereas no differences were found for other hormone axes. In patients, elevations in GH and IGF-1 and decreases in thyroid-stimulating hormone, free triiodothyronine and testosterone (in men) were associated with severity of impairments (Independence scale, Functional score, Total Functional Capacity, Total Motor score, Behavioral score). Only GH was independently associated with body mass index (beta = -0.26, p = 0.001).

CONCLUSIONS

Our data suggest that the thyrotropic and in men gonadotropic axes are altered in HD according to the severity of the disease. The somatotropic axis is overactive even in patients with early disease, and could be related to the weight loss seen in HD patients.

The role of liver in the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) was studied in normal subjects and patients with alcoholic liver disease by measurement of thyrotrophin (TSH) and total and free T4 and T3 in randomand serial serum samples. Also, T4 to T3 conversion rates and T3 disposal rates were compared by noncompartmental analysis. While the mean total serum T4 values were similar for the two groups, 8.6 and 8.1 mug/kl, the mean free T4 value was significantly higher in the cirrhotic patients (3.3 ng/dl) than in the normal subjects (2.1 ng/dl, P less than 0.001). The mean serum T3 value, 85 ng/dl, was significantly reduced in the hepatic patients as compared to a mean serum T3 value of 126 ng/dl in the normal subjects (P less than 0.001), while the free T3 value was 0.28 ng/dl in both groups. The reduction of the serum total and free T3 values were closely correlated with the degree of liver damage, as indicated by elevation of serum bilirubin (r equal -0.547) and reduction of serum albumin (r equal 0.471). The mean serum TSH level was 3.1 muU/ml in the normals and 7.1 muU/ml in the cirrhotic aptients ( less than 0.001). 15% of the hepatic patients had serum TSH values above 10 muU/ml, which, however, did not correlate with any of the four liver function tests studied. Serial blood sampling from two convalescing patients with alcoholic hepatitis showed a gradual normalization of serum TSH and T3 levels as the liver function improved. After oral T4 administration, 0.25 mg/day for 10 days, three of four cirrhotic patients studied failed to raise their serum T3 values. The mean T4 to T3 conversion rate of seven normal subjects was 35.7%. The mean T4 to T3 conversion rate of four cirrhotic patients studied was significantly reduced to 15.6% (P less than 0.001). The mean disposal rates of T4 and T3 of the normal subjects were 114 and 34 mug/day, respectively. The ratio of T4 disposal to T3 disposal was 3.5. In contrast, the mean T4 disposal rate, 82 mug/day, and the mean T3 disposal rate, 10 mug/day, were both reduced in the cirrhotic patients. Their ratio of T4 disposal to T3 disposal was 7.9. These findings suggest that impairment of T4 conversion in patients with advanced hepatic cirrhosis may lead to reduced T3 production and lowered serum T3 level. Therefore, the liver is one of the major sites of T4 conversion to T3.

OBJECTIVE

The aim of the present study was to analyze the current status of morphologic and functional thyroid abnormalities in a previously iodine-deficient area.

METHODS

The population based Study of Health in Pomerania (SHIP) comprised 4310 participants, aged 20-79 years. Thyroid function (thyrotropin [TSH] free triiodothyronine [FT(3)], and free thyroxine [FT(4)]) and serum autoantibodies to thyroperoxidase (TPOAb) were evaluated from blood samples. Thyroid structure and size were measured by ultrasound. Data from 3941 participants with no known thyroid disorders were analyzed.

RESULTS

The median iodine urine excretion was 12.4 microg/dL. The rate of decreased serum TSH levels (<0.3 mIU/L) was 11.3%; 2.2% of participants had suppressed serum TSH levels (<0.1 mIU/L). The prevalence of subclinical hyperthyroidism was 1.8%, the prevalence of overt hyperthyroidism 0.4%. Elevated TSH levels were found in 1.2% of individuals. Subclinical hypothyroidism was observed in 0.5%, overt hypothyroidism in 0.7% of the sample. Elevated TPOAb were detected in 7% of subjects, 4.1% of participants had TPOAb greater than 200 IU/mL. The prevalence of goiter was 35.9%. An inhomogeneous echo pattern was detected in 35.2% and nodules in 20.2% of participants. Diffuse autoimmune thyroiditis was diagnosed in 47 subjects (1.2%).

CONCLUSIONS

There are a number of thyroid disorders in this previously iodine-deficient region. Further studies are required to investigate the change of thyroid disorders during iodine supplementation programs.

The goal of eliminating iodine deficiency worldwide was successfully achieved in China after the implementation of a mandatory universal salt iodization program for the last 16 years. Thus, China has been assessed as a country with more than adequate iodine levels. This survey aimed to investigate the current iodine status in China and the effects of an increased iodine intake on the spectrum and prevalence of thyroid disorders.

A total of 15,008 adult subjects from 10 cities in eastern and central China were investigated. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and urine iodine concentration (UIC) were measured, and an ultrasonography of the thyroid was performed in all subjects. Free thyroxine (fT4) and free triiodothyronine (fT3) levels were only measured if the serum TSH was outside the normal range.

The median UIC values were 197 μg/L in school-age children (SAC) and 205 μg/L in a cohort population. Six cities were classified as regions with adequate iodine intake (AII), and four cities as regions with more than adequate iodine intake (MTAII), according to median SAC UIC. The prevalence of clinical hypothyroidism, subclinical hypothyroidism, and positive thyroid antibodies was significantly higher in MTAII cities than it was in AII cities. Moreover, the prevalence of clinical hyperthyroidism (1.1% vs. 0.8%, p = 0.033) and Graves' disease (0.8% vs. 0.5%, p = 0.019) also significantly increased in MTAII cities. Compared with a five-year prospective study conducted in 1999, the prevalence of goiter significantly decreased (2.9% vs. 5.02%, p = 0.001), but there was a significant increase in thyroid nodules (12.8% vs. 2.78%, p = 0.001). The prevalence of subclinical hypothyroidism (16.7% vs. 3.22%), positive TPOAb (11.5% vs. 9.81%), and positive TgAb (12.6% vs. 9.09%) significantly increased, while no changes were seen in clinical hyperthyroidism, subclinical hyperthyroidism, or Graves' disease.

The goal of eliminating iodine deficiency has been successfully achieved in China. However, the prevalence and spectrum of thyroid disorders has increased, reflecting possible adverse effects of increased iodine intake.

OBJECTIVE

To characterize children at risk for nonalcoholic fatty liver disease (NAFLD) and to explore possible mechanisms underlying the development of NAFLD in Hispanic youth with a body mass index>> or =95th percentile.

METHODS

Hispanic nonoverweight (n = 475) and overweight (n = 517) children, ages 4 to 19 y, were characterized in terms of body composition (dual-energy x-ray absorptiometry), maturation (Tanner stage), diet (24-h recall), physical activity (accelerometry), fitness (maximal oxygen uptake), and biochemical profile (fasting alanine aminotransferase [ALT], glucose, insulin, and lipids; inflammation markers such as adiponectin, leptin, C-reactive protein, and soluble intercellular adhesion molecule-1; and total antioxidants) using standard laboratory techniques. Risk for NAFLD was defined by fasting serum ALT values >97.5th percentile for age- and sex-specific reference values.

RESULTS

Fasting serum ALT was elevated in 24% of overweight children and in only 4% of nonoverweight children. Therefore, to identify risk factors associated with elevated ALT, the remaining statistical analysis was restricted to the overweight group. The percentage of overweight children with elevated ALT did not differ by sex, age, or Tanner stage. Weight, body mass index, z score, waist-to-hip ratio, fat-free mass, fat mass, and percent truncal fat mass were higher in the overweight children with elevated ALT. Fasting insulin, glucose, and homeostasis model-insulin resistance were higher in the overweight children with elevated ALT, as were triglycerides, total cholesterol, low-density lipoprotein, thyroid-stimulating hormone, and triiodothyronine. Fasting serum leptin, C-reactive protein, and soluble intercellular adhesion molecule-1 were significantly higher and adiponectin was lower in the overweight children with elevated ALT.

CONCLUSIONS

The risk for developing NAFLD was high in the overweight Hispanic children. The proportion of "at risk" children was not influenced by gender, age, or maturation. The risk for elevated ALT was predicted by the severity of obesity, central adiposity, hyperinsulinemia, hypertriglyceridemia, elevated thyroid-stimulating hormone, and systemic inflammation.

BACKGROUND

The aim of our present study was to establish new reference intervals for thyrotropin (TSH) and thyroid hormones based on National Academy of Clinical Biochemistry (NACB) criteria and regular thyroid ultrasonography. We also assessed the effect of potentially confounding factors to modulate the limits of these intervals.

METHODS

We investigated 870 apparently healthy persons and excluded, step by step, those with a family history of thyroid disease, pathologic thyroid ultrasonography results, and increased anti-thyroid peroxidase or anti-thyroglobulin antibodies. Accordingly, only 453 of the 870 persons in the entire group were finally included as reference collective. We measured serum concentrations of TSH, total and free thyroxine (T(4) and FT(4)), and total and free triiodothyronine (T(3) and FT(3)) of the whole and the reference collective on the ELECSYS system assays (Roche Diagnostics) and calculated the 2.5th and 97.5th percentiles for comparison.

RESULTS

The calculated lower limit for TSH differed significantly between the reference intervals for healthy persons with an assessed normal thyroid gland vs the nonselected group of healthy blood donors. Age was the only independent factor and was significantly inversely associated with TSH (P <0.0001). Use of oral contraceptives was a significant predictor for variation in T(4) concentrations (P <0.001). Age and oral contraceptives were independently associated with T(3) variations (P <0.05). For FT(4) vs FT(3) variation, gender and (inversely) age (P <0.01) were independent modulating factors.

CONCLUSIONS

The selection of healthy persons according to NACB criteria combined with sonographic confirmation of a normal thyroid gland provide a valid basis for the reference interval for TSH. Factors indicating a preclinical disease state, such as family history, pathologic ultrasonography result, or increased anti-thyroid peroxidase and anti-thyroglobulin antibodies, can be associated with normal hormone concentrations. Additionally, patient age and gender as well as use of contraceptives should be considered in diagnostic evaluation of thyroid diseases.

Acute and chronic critical conditions are associated with reduced serum levels of free triiodothyronine (FT(3)), free thyroxine FT(4), and thyrotropin, known as nonthyroidal illness syndrome (NTIS). It is still controversial whether these changes reflect a protective mechanism or a maladaptive process during prolonged illness. However, larger studies to determine the prevalence of the NTIS and its association with outcome in medical intensive care units (ICUs) are missing. Complete thyroid hormone levels from 247 of 743 patients admitted to our ICU between October 2002 and February 2004 were retrospectively evaluated. From these patients, Acute Physiology and Chronic Health II scores, ICU mortality, length of stay, mechanical ventilation, and concomitant medication were recorded. Ninety-seven patients (44.1%) had low FT(3) levels indicating an NTIS, either with normal (23.6%) or reduced (20.5%) serum thyrotropin levels. Of 97 patients with NTIS, 24 (23.3%) also showed reduced serum FT(4) levels. The NTIS was significantly associated with Acute Physiology and Chronic Health II scores, mortality, length of stay, and mechanical ventilation. In a multivariate Cox regression analysis, the combination of low FT(3) and low FT(4) was an independent risk factor for survival. Nonthyroidal illness syndrome is frequent at a medical ICU. A reduction of FT(4) together with FT(3) is associated with an increase in mortality and might reflect a maladaptive process, thereby worsening the disease.

BACKGROUND

Interpretation of thyroid function tests during pregnancy needs trimester-related reference intervals from pregnant populations with minimal risk for thyroid dysfunction. While India has become iodine sufficient after two decades of salt iodisation, there is no normative data for thyroid function from healthy pregnant women of this country.

OBJECTIVE

To determine trimester-specific reference ranges for free triiodothyronine (FT(3)), free thyroxine (FT(4)) and thyrotropin (TSH) from healthy pregnant Indian women.

METHODS

Cross-sectional study in a reference population of pregnant women.

METHODS

Primary care level obstetric department in India.

METHODS

Women with uncomplicated pregnancy in any trimester.

METHODS

Five hundred and forty-one apparently healthy pregnant women with uncomplicated single intrauterine gestations reporting to the Armed Forces Clinic in any trimester were consecutively recruited. Clinical examination, thyroid ultrasound for echogenicity and nodularity and estimation of FT(3), FT(4), TSH and antithyroid antibodies (antithyroperoxidase [anti-TPO] and antithyroglobulin [anti-Tg]) using electrochemiluminescence technique were carried out. From this entire sample, a disease- and risk-free reference population was obtained by excluding those with any known factor that could affect thyroid function or those who were being treated for thyroid dysfunction.

METHODS

None.

RESULTS

Of the 541 consecutive pregnant women in different trimesters enrolled for the study, 210 women were excluded. The composition of reference population comprising 331 women was 107 in first trimester, 137 in second trimester and 87 in third trimester. The 5th and 95th percentiles values were used to determine the reference ranges for FT(3), FT(4) and TSH. The trimester-wise values in the first, second and third trimesters were: FT(3) (1.92-5.86, 3.2-5.73 and 3.3-5.18 pM/l), FT(4) (12-19.45, 9.48-19.58 and 11.32-17.7 pM/l) and TSH (0.6-5.0, 0.44-5.78 and 0.74-5.7 iu/ml), respectively. Analysis of mean, median values for FT(3), FT(4) and TSH between each trimester showed no significant difference in FT(3) and TSH values (95% CI). However, FT(4) showed significant variation between trimesters with values decreasing with advancing gestational age (P value: first versus second = 0.015, first versus third = 0.003 and second versus third = not significant). Women with antibody positivity and hypoechogenicity of thyroid gland had significantly higher TSH values when compared with women with antibody negativity and normoechogenicity.

CONCLUSIONS

Reference ranges of FT(3), FT(4) and TSH have been established for pregnant Indian women using 5th and 95th percentiles.

A survey of thyroid function in 95 patients with primary biliary cirrhosis revealed the presence of thyroid antibodies in 24 females and 1 male. Thirteen (52%) of this thyroid antibody positive group (all female) had biochemical evidence of thyroid disease: 8 (32%) were hypothyroid (7 of whom showed signs of myxedema), 2 had elevated thyroid stimulating hormone (TSH) levels, and 3 had abnormal responses to stimulation with thyrotropin releasing hormone (TRH). In contrast, only 3 (4%) of the thyroid antibody negative patients had reduced serum thyroxine (T4) levels and none were clinically hypothyroid. Evidence of an increase in thyroid hormone binding, as reported by other workers, was not found, and both the resin uptake of radioactive triiodothyronine and the free thyroxine indices were normal in both groups. The presence of thyroid antibodies showed a highly significant association with lacrimal gland dysfunction but not with liver histologic staging or liver function tests.

Of 344 relatively healthy persons older than 60 years, 22 (5.9%) had a clearly elevated level of serum thyrotropin (TSH) (greater than 10 muU/mL), a finding more common in women than in men. Ten of the 22 had low values for serum thyroxine (T4) and free T4 (FT4) index, but only one had a low value for serum triiodothyronine (T3) or free T3 (FT3) index. A further 14.4% had a slightly elevated level of serum TSH (greater than 5 less than or equal to 10 muU/mL), but none had low values for serum T4 or FT4 index. Age alone has little effect on the measurements of T4; age is associated with slightly lower T3 levels, but only in men 60 years or older or in women 80 years or older. Longitudinal studies should determine if a slightly elevated serum TSH rises further with age and if there is a causal relationship between a high level of serum TSH and cardiovascular disease.

BACKGROUND

Data on human fetal thyroid function have largely been derived from histologic studies or studies of cord-blood samples obtained at hysterotomy or delivery. These data may not represent true normal values. Cordocentesis (ultrasound-guided blood sampling from the umbilical cord) is a technique that allows investigation of physiologic processes in fetuses not under stress.

METHODS

We measured serum thyroid-stimulating hormone, total and free thyroxine (T4), total and free triiodothyronine (T3), and thyroxine-binding globulin in blood samples from 62 fetuses. The samples were obtained by cordocentesis (n = 58) or cardiocentesis (n = 4) at 12 to 37 weeks of gestation. Maternal serum samples were obtained immediately before fetal blood sampling.

RESULTS

Fetal serum thyroid-stimulating hormone, thyroxine-binding globulin, and total and free T4 and T3 concentrations increased significantly with the length of gestation (P less than 0.001). The only significant association among these variables, independent of the length of gestation, was between thyroid-stimulating hormone and free T4 (P less than 0.0001). Maternal serum concentrations of these variables did not change during gestation, and there was no significant relation between fetal and maternal values. Most fetal serum concentrations of thyroid-stimulating hormone were higher, whereas most serum total and free T3 concentrations were lower than the respective values for normal adults. The fetal serum total T4, free T4, and thyroxine-binding globulin values reached the level of the mean adult values at approximately 36 weeks of gestation.

CONCLUSIONS

The increases in fetal serum concentrations of thyroid-stimulating hormone, thyroxine-binding globulin, and total and free T4 and T3 during gestation reflect increasing maturation of the pituitary, thyroid, and liver. The finding of increasing fetal serum concentrations of thyroid-stimulating hormone in the presence of increasing thyroid hormone concentrations suggests that the sensitivity of the fetal pituitary gland to negative feedback is limited or is counterbalanced by increasing stimulation by thyrotropin-releasing hormone from the hypothalamus.

Polychlorinated biphenyls (PCBs) and some organochlorine pesticides, which continue to be measurable in a high proportion of blood samples from the general population, have been found to alter thyroid hormone levels in animals and humans. However, studies of these relationships in adult men are limited and results across studies have been inconsistent. In the present study, we measured serum levels of 57 PCB congeners, dichlorodiphenyldichloroethylene (p,p(')-DDE, a stable metabolite of DDT), and hexachlorobenzene (HCB), as well as free T(4), total T(3), and TSH, in 341 adult men recruited from an infertility clinic from 2000 to 2003. In multivariate linear regression, there were positive associations between p,p(')-DDE and both free T(4) and total T(3), and an inverse association between p,p(')-DDE and TSH. Conversely, for PCBs there was only a suggestive inverse association between PCB 153 and total T(3) when potential confounding variables were considered. However, when results were additionally adjusted for p,p(')-DDE, inverse associations with T(3) were significant for PCB 138, PCB 153, sum of PCBs and three different PCB groupings, and HCB, while the positive associations between p,p(')-DDE and T(3) also remained. In conclusion, serum concentrations of PCBs, p,p(')-DDE, and HCB were associated with circulating thyroid hormone levels in adult men.

BACKGROUND

BMI, body mass index; CYP, cytochrome P450; DDT, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane; HCB, hexachlorobenzene; MDL, method detection limit; NHANES, national health and nutrition examination survey: p,p(')-DDE, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene; PCB, polychlorinated biphenyl; T(3), triiodothyronine; T(4), thryoxine; TSH, thyroid stimulating hormone (thyrotrophin); US, United States.

The development of oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum-free medium in the presence of platelet-derived-growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into oligodendrocytes. T3 also induces morphological differentiation of oligodendrocytes as indicated by the marked increase in the length of oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24-48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis. Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in oligodendrocyte maturation and that these two T3-regulated events are independent.

OBJECTIVE

We undertook the present study to establish reference data for serum thyroid function tests in a previously iodine-deficient area.

METHODS

Data from 4298 individuals, 20-79 years of age were available for the present analysis. Thyroid function (thyrotropin [TSH], free triiodothyronine [FT(3)], and free thyroxine [FT(4)]) and serum autoantibodies to thyroperoxidase (anti-TPOAb) were evaluated from blood samples. Thyroid structure and size were measured by ultrasound.

RESULTS

A reference population was selected comprising 1488 persons (825 men) by excluding subjects with known thyroid diseases, and with yet unknown thyroid disorders such as goitre, inhomogeneous thyroid pattern, nodules, hypoechogenicity and anti-TPOAb seropositivity. Reference intervals for serum TSH, FT(3), and FT(4) were 0.25-2.12 mIU/L, 3.8-7.0 pmol/L, and 8.3-18.9 pmol/L, respectively. Reference serum TSH levels were not comparable to the reference values that were recently established for the U.S. population and most reference values slightly differed from the reference values provided by the manufacturers.

CONCLUSIONS

The reference ranges of thyroid function tests in this formerly iodine-deficient region are distinct from the reference ranges that were established in areas with iodine sufficiency. Creating a reference population in the present setting should include thyroid ultrasound in order to exclude yet undiagnosed thyroid disorders.

Northern elephant seal (Mirounga angustirostris) pups rely on the oxidation of fat stores as their primary source of energy during their 8- to 12-wk postweaning fast; however, potential endocrine mechanisms involved with this increased fat metabolism have yet to be examined. Therefore, 15 pups were serially blood sampled in the field during the first 7 wk of their postweaning fast to examine the changes in plasma concentrations of cortisol and thyroid hormones (TH), which are involved in fat metabolism in other mammals. Cortisol increased, indicating that it contributed to an increase in lipolysis. Increased total triiodothyronine (tT(3)) and thyroxine (tT(4)) may not reflect increased thyroid gland activity, but rather alterations in hormone metabolism. tT(3)-to-tT(4) ratio decreased, suggesting a decrease in thyroxine (T(4)) deiodination, whereas the negative correlation between total proteins and free T(4) suggests that the increase in free hormone is attributed to a decrease in binding globulins. Changes in TH are most similar to those observed during hibernation than starvation in mammals, suggesting that the metabolic adaptations to natural fasting are more similar to hibernation despite the fact these animals remain active throughout the fasting period.

BACKGROUND

Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones.

METHODS

We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation.

RESULTS

A SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels.

CONCLUSIONS

This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.

OBJECTIVE

Many hypothyroid subjects receiving L-thyroxine (L-T4) complain of psychological symptoms or cognitive dysfunction. However, there is limited validated information on these self-reports.

METHODS

Cross-sectional comparison of 20 euthyroid and 34 treated hypothyroid subjects, aged 20-45 years, with normal thyroid-stimulating hormone (TSH) levels. Subjects underwent the following validated measures: Short Form 36 (SF-36); Symptom Checklist 90-Revised (SCL-90-R); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, Digit Span Backwards), and motor learning (Pursuit Rotor).

RESULTS

L-T4-treated subjects had higher mean TSH and free T4 levels, but free triiodothyronine (T3) levels were comparable to controls. L-T4-treated subjects had decrements on SF-36 and SCL-90-R summary scales and subscales. These subjects performed slightly worse on N-Back and Pursuit Rotor tests. Neither TSH nor thyroid hormone levels were associated with performance on psychological or cognitive measures.

CONCLUSIONS

This group of L-T4-treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to euthyroid controls. Higher mean TSH levels suggest this may be related to suboptimal treatment, although there were no correlations between TSH levels and outcomes. These findings are limited by potential selection bias, and randomized studies targeting different TSH levels and memory subdomains would clarify these issues.

BACKGROUND

TSH is known to have a circadian rhythm, but the relationship between this and any rhythm in T(4) and T(3) has not been clearly demonstrated.

OBJECTIVE

With a view to optimizing thyroid hormone replacement therapy, we have used modern assays for free T(4) (FT4) and free T(3) (FT3) to investigate circadian rhythmicity.

METHODS

The study was performed at a university hospital.

METHODS

This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis.

RESULTS

Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH.

CONCLUSIONS

FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.

Hypothyroidism denotes deficient production of thyroid hormone by the thyroid gland and can be primary (abnormality in thyroid gland itself) or secondary/central (as a result of hypothalamic or pituitary disease). The term 'subclinical hypothyroidism' is used to define that grade of primary hypothyroidism in which there is an elevated thyroid-stimulating hormone (TSH) concentration in the presence of normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations. Subclinical hypothyroidism may progress to overt hypothyroidism in approximately 2-5% cases annually. All patients with overt hypothyroidism and subclinical hypothyroidism with TSH >10 mIU/L should be treated. There is consensus on the need to treat subclinical hypothyroidism of any magnitude in pregnant women and women who are contemplating pregnancy, to decrease the risk of pregnancy complications and impaired cognitive development of the offspring. However, controversy remains regarding treatment of non-pregnant adult patients with subclinical hypothyroidism and serum TSH values ≤10 mIU/L. In this subgroup, treatment should be considered in symptomatic patients, patients with infertility, and patients with goitre or positive anti-thyroid peroxidase (TPO) antibodies. Limited evidence suggests that treatment of subclinical hypothyroidism in patients with serum TSH of up to 10 mIU/L should probably be avoided in those aged >85 years. Other pituitary hormones should be evaluated in patients with central hypothyroidism, especially assessment of the hypothalamic-pituitary-adrenal axis, since hypocortisolism, if present, needs to be rectified prior to initiating thyroid hormone replacement. Levothyroxine (LT4) monotherapy remains the current standard for management of primary, as well as central, hypothyroidism. Treatment can be started with the full calculated dose for most young patients. However, treatment should be initiated at a low dose in elderly patients, patients with coronary artery disease and patients with long-standing severe hypothyroidism. In primary hypothyroidism, treatment is monitored with serum TSH, with a target of 0.5-2.0 mIU/L. In patients with central hypothyroidism, treatment is tailored according to free or total T4 levels, which should be maintained in the upper half of the normal range for age. In patients with persistently elevated TSH despite an apparently adequate replacement dose of LT4, poor compliance, malabsorption and the presence of drug interactions should be checked. Over-replacement is common in clinical practice and is associated with increased risk of atrial fibrillation and osteoporosis, and hence should be avoided.