Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis.

CONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously. DESIGN AND SETTING: We identified studies through a systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline TSH, free T4, and stroke outcomes were included, and we collected individual participant data from each study, including thyroid function measurements and incident all stroke (combined fatal and nonfatal) and fatal stroke. The applied reference range for TSH levels was between 0.45 and 4.49 mIU/L. RESULTS: We collected individual participant data on 43 598 adults with TSH within the reference range from 17 cohorts, with a median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449 908 person-years. Age- and sex-adjusted pooled hazard ratio for TSH was 0.78 (95% confidence interval [CI] 0.65-0.95 across the reference range of TSH) for all stroke and 0.83 (95% CI 0.62-1.09) for fatal stroke. For the free T4 analyses, the hazard ratio was 1.08 (95% CI 0.99-1.15 per SD increase) for all stroke and 1.10 (95% CI 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking, and prevalent diabetes. CONCLUSION: Higher levels of TSH within the reference range may decrease the risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.

Low Thyroid Hormone in Early Pregnancy Is Associated With an Increased Risk of Gestational Diabetes Mellitus.

CONTEXT: Although thyroid dysfunction in early pregnancy may have adverse effects on pregnancy outcome and offspring, few prospective studies have evaluated these effects. OBJECTIVE: Our aim was to evaluate the correlations between different thyroid hormone levels in early pregnancy and the incidence of gestational diabetes mellitus (GDM). SETTING AND PARTICIPANTS: The study comprised 27 513 mothers who provided early pregnancy serum samples for analyses of thyroid function. GDM was diagnosed using a 2 hours, 75-g oral glucose tolerance test, and the mothers were grouped and compared according to the results. MAIN OUTCOME MEASURES: We focused on GDM during the index pregnancy. RESULTS: The incidence of GDM in pregnant women tended to increase with age (5.83%, 10.18%, 14.95%, and 22.40%; P < .0001). The incidence of GDM increased with increasing prepregnancy body mass index (P < .0001). Pregnant women with a family history of diabetes had a much higher incidence of GDM than those without a family history of diabetes (21.09% vs 12.92%; P < .0001). The level of free T4 (FT4) in early pregnancy in GDM women was lower than that in non GDM women (P < .0001). With increasing early pregnancy FT4, the rate of incident GDM was decreasing (P < .0001). CONCLUSIONS: Low thyroid hormone levels in early pregnancy are a risk factor for GDM incidence.

Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study.

CONTEXT: Perturbations in thyroid function are common in older individuals but their significance in the very old is not fully understood. OBJECTIVE: This study sought to determine whether thyroid hormone status and variation of thyroid hormones within the reference range correlated with mortality and disability in a cohort of 85-year-olds. DESIGN: A cohort of 85-year-old individuals were assessed in their own homes (community or institutional care) for health status and thyroid function, and followed for mortality and disability for up to 9 years. SETTING AND PARTICIPANTS: Six hundred and forty-three 85-year-olds registered with participating general practices in Newcastle and North Tyneside, United Kingdom. MAIN OUTCOMES: All-cause mortality, cardiovascular mortality, and disability according to thyroid disease status and baseline thyroid hormone parameters (serum TSH, FT4, FT3, and rT3). Models were adjusted for age, sex, education, body mass index, smoking, and disease count. RESULTS: After adjustment for age and sex, all-cause mortality was associated with baseline serum rT3 and FT3 (both P < .001), but not FT4 or TSH. After additional adjustment for potential confounders, only rT3 remained significantly associated with mortality (P = .001). Baseline serum TSH and rT3 predicted future disability trajectories in men and women, respectively. CONCLUSIONS: Our study is reassuring that individuals age 85 y with both subclinical hypothyroidism and subclinical hyperthyroidism do not have a significantly worse survival over 9 years than their euthyroid peers. However, thyroid function tests did predict disability, with higher serum TSH levels predicting better outcomes. These data strengthen the argument for routine use of age-specific thyroid function reference ranges.

Isolated hyperthyrotropinemia in childhood obesity and its relation with metabolic parameters.

PURPOSE: The aim of the presented study was to evaluate the prevalence of isolated hyperthyrotropinemia (IH) in obese children and the relation between anthropometric and metabolic parameters. METHODS: Hospital records of the children, who presented to the Pediatric Endocrinology outpatient clinic of our institution with obesity, and age and gender-matched healthy children, who had undergone thyroid function test for any reason were retrospectively reviewed. RESULTS: The prevalence of IH was significantly higher in the obese group than in the controls (9.2 and 3.8 %, respectively). Body mass index-standard deviation score (BMI-SDS), thyroid-stimulating hormone (TSH), lipid parameters were significantly different in the obese group than in the control group. A positive correlation between TSH and BMI-SDS and negative correlation between TSH and free T4 (fT4) levels were found in obese subjects. Stepwise multiple linear regression analysis confirmed that BMI-SDS, fT4 and triglyceride levels were the strongest independent variables correlated with TSH level in obese subjects (r (2) = 0.046, p = 0.001). CONCLUSIONS: IH prevalence is higher in obese children as compared to healthy children and the increase in TSH level correlates negatively with serum fT4 and positively with BMI-SDS and triglyceride levels in obese children.

Maintenance of brain thyroid hormone level during peripheral hypothyroid condition in adult rat.

Thyroid hormones are essential for normal functioning of adult mammalian brain. The present investigation deals with the understanding of the time course of thyroid hormone homeostasis in adult rat brain. Animals were rendered hypothyroid by PTU injections (2 mg/100 g bw) for 30 consecutive days. Serum and synaptosomal T3/T4 content, synaptosomal AChE and Na+-K+-ATPase activities were determined on alternate days. While serum T4 level initially increased on the second day compared to control, serum T3 declined in a triphasic pattern; the first phase lasting from the second day to the 6th day, the second phase ended on the 14th day and last phase continued till the 30th day. Cerebro-cortical synaptosomal T3 level increased on the 2nd day from the control, attained a peak on the 4th day, remained stable until the 18th day, and abruptly declined on the 20th day. Synaptosomal T4 content remained negligible or undetected throughout. Synaptosomal membrane Na+-K+-ATPase and AChE activity exhibited an inverse relationship during the experimental regime, being much more prominent on the 2nd, 18th and 20th day coinciding with the variations in brain T3 level. Thus, the study identifies the onset of central homeostasis between the first and second day, its continuation for about 16-18 days and its termination between the 18th and 20th day.

Stereospecific determination and in vivo monodeiodination of thyroxine enantiomers in euthyroid man.

To compare in man the absorption, serum disappearance, and peripheral monodeiodination of the thyroxine enantiomers, we studied six euthyroid subjects who, on separate occasions, orally ingested 3 mg of either dextrothyroxine (DT4) or levothyroxine (LT4). We measured the serum concentrations of total T4 (TT4), total T3, and reverse T3 (rT3) by nonstereospecific radioimmunoassay and we determined serum DT4 and LT4 by stereospecific chromatography. Mean serum TT4 levels from 4 hours were significantly greater after LT4 administration. After DT4 administration, stereospecific analysis of serum revealed two T4 peaks that persisted from 2 to 48 hours. The mean serum LT4 level did not significantly change during the 48 hours after DT4 administration. Increases in serum T3 and rT3 were seen from 2 hours after administration of either enantiomer. From 12 hours the levels of both triiodothyronines after LT4 were significantly higher than after DT4. In this short term study we found no evidence that in man DT4 is converted to LT4, nor is it preferentially deiodinated to rT3. The greater and more persistent increases in serum T4 and T3 observed after LT4 probably contribute to the known higher bioactivity of that enantiomer.

Stereospecific determination of D-thyroxin and L-thyroxin in serum.

A new method for separate determination of D-thyroxin and L-thyroxin in the serum was applied to study the response of serum levels of these isomers and of radioimmunologically determined total T3, total T4, free T4 and TSH upon administration of 2, 4 and 6 mg of a highly purified D-thyroxin preparation in six male patients with diffuse nontoxic goiter. D- and L-thyroxin are determined separately following extraction of the hormone from the serum and formation of diastereomeric dipeptides. The separation and final determination are accomplished by means of ion-pair chromatography on reversed-phase columns using an iodine-selective catalytic detector. A significant decrease in TSH takes place during the 3-days observation period. The values of D-T4, total T3 and free T4 are highest 4 hours after administration of the tablets and get to be to initial values after 24 hours. L-T4 shows no significant change. A direct suppressive effect of D-T4 on the pituitary gland may therefore be assumed as the cause of the suppression of TSH secretion.

Elevated triiodothyronine and dextrothyroxine levels: a potential cause of iatrogenic hyperthyroidism.

A woman in whom the use of dextrothyroxine was associated with clinical hyperthyroidism is described. She had a markedly elevated T3 level while receiving the drug, apparently resulting from conversion of the dextrothyroxine to triiodothyronine. The T3 levels fell to normal after withdrawal. Patients receiving dextrothyroxine should be examined for possible elevation of T4 and T3 thyrotoxicosis.

Influence of D-thyroxine on plasma thyroid hormone levels and TSH secretion.

Triiodothyronine (T3), thyroxine (T4), basal TSH and TSH after stimulation with TRH were determined in healthy subjects and patients treated with D-thyroxine (DT4). After a dosage of 6 mg DT4 the D/L T4 plasma concentration rose about 4-fold 4 hours after application and was only moderately elevated 14 hours later. To achieve constantly elevated T4 levels 3 mg DT4 were applied in the further experiment every 12 hours. The D/L T4 plasma concentration rose 2.5-4-fold and there was a small but significant increase of the D/L T3 plasma concentration. 74 hours after onset of treatment basal TSH was below detectable limits and the increase of TSH 30 min after injection of 200 mug TRH (TRH test) was only about 15% compared to zero time. The time course of TSH suppression was investigated after treatment with DT4 and LT4 (single dosage of 3 mg). TRH-tests were performed before, 10, 26, 50 and 74 hours after the first dosage of D or LT4. There was no difference in the time course of basal TSH and TSH stimulated by TRH. In 10 patients on DT4 long-term therapy, basal and stimulated TSH were found to be below the detectable limits of 0.4 mug/ml. Our results show that (1) plasma half-life of DT4 is less than 1 day, (2) TSH suppression after D and LT4 treatment is very similar, and (3) in patients on long-term DT4 treatment, TSH plasma concentration is below detectable limits even after stimulation with TRH.