T4 In Men Research Articles

Electrocardiography in euthyroid individuals: a Danish general population study

Thyroid hormones within the euthyroid range have been linked to mortality and differences in heart rate. However, some relations between thyroid hormone concentration and various electrocardiographic measurements remain unassessed. We aimed to investigate the association between thyroid hormone concentrations within the euthyroid range and different electrocardiographic markers in people free of thyroid disease.We obtained electrocardiograms (ECG) and blood samples of free T4, total T3, and thyrotropin (TSH) in 20,852 subjects from the general population (the GESUS study). Relations between concentrations of TSH, free T4, and total T3 and heart rate, QTc, QRS duration, PR interval, P-wave duration and T-wave morphology were assessed in a multivariate adjusted linear model stratified by sex.Roughly half of the 18,046 included participants with thyroid hormone measurements within euthyroid range were men, and the average age was 56 years. Heart rate increased with concentrations of T3 (6.4 bpm/nM, P<0.001 in women and 5.3 bpm/nM, P<0.001 in men) and T4 (3.7 bpm/10pM, P<0.001 in women and 3.1 bpm/10pM, P<0.001 in men). We found no relation between TSH and heart rate. PR interval and QRS duration decreased with higher concentrations of T3 (all P<0.01). QTc increased with higher concentrations of T4 in men (5 ms/10pM), and T waves were flatter, more asymmetric, and more often had notches with higher concentrations of T4 (all P≤0.01).Thyroid hormone concentrations within the euthyroid range in people free of thyroid disease were associated with changes in the electrocardiogram in a general population.

Electrocardiography in euthyroid individuals: a Danish general population study

Thyroid hormones within the euthyroid range have been linked to mortality and differences in heart rate. However, some relations between thyroid hormone concentration and various electrocardiographic measurements remain unassessed. We aimed to investigate the association between thyroid hormone concentrations within the euthyroid range and different electrocardiographic markers in people free of thyroid disease. We obtained electrocardiograms (ECG) and blood samples of free T4, total T3, and thyrotropin (TSH) in 20,852 subjects from the general population (the GESUS study). Relations between concentrations of TSH, free T4, and total T3 and heart rate, QTc, QRS duration, PR interval, P-wave duration and T-wave morphology were assessed in a multivariate adjusted linear model stratified by sex. Roughly half of the 18,046 included participants with thyroid hormone measurements within euthyroid range were men, and the average age was 56 years. Heart rate increased with concentrations of T3 (6.4 bpm/nM, P<0.001 in women and 5.3 bpm/nM, P<0.001 in men) and T4 (3.7 bpm/10pM, P<0.001 in women and 3.1 bpm/10pM, P<0.001 in men). We found no relation between TSH and heart rate. PR interval and QRS duration decreased with higher concentrations of T3 (all P<0.01). QTc increased with higher concentrations of T4 in men (5 ms/10pM), and T waves were flatter, more asymmetric, and more often had notches with higher concentrations of T4 (all P≤0.01). Thyroid hormone concentrations within the euthyroid range in people free of thyroid disease were associated with changes in the electrocardiogram in a general population.

Association between serum nitric oxide metabolites and thyroid hormones in a general population: Tehran Thyroid Study

ABSTRACTNitric oxide participates in the regulation of thyroid function. Aims: The purpose of this study was to determine whether there is an association between serum nitric oxide metabolites (NOx) and free thyroxine (free T4), anti-thyroid peroxidase (anti-TPO), and thyroid-stimulating hormone (TSH) levels. Methods: Study subjects were adults, aged ≥20 years, who participated in the Tehran Thyroid Study (TTS). In a cross-sectional study, in the third phase of TTS, serum NOx concentrations were measured in 1974 adult participants; pregnant women and subjects who had chronic diarrhea, cancer, weight loss, and hospitalization within the past 3 months were excluded, as were those taking medicines that affect thyroid function; the remaining 1771 subjects were grouped according to tertiles of free T4, anti-TPO, and TSH. Spearman’s correlation coefficients and multivariable linear regression analysis were used to determine the relationship between serum NOx levels and free T4, anti-TPO, and TSH. Results: Serum NOx levels were negatively correlated with free T4 in men (r = −0.083; p = 0.029). An inverse association between the third tertile of free T4 and NOx levels was found in both non-adjusted (β = −0.095, p = 0.031) and multivariable-adjusted (β = −0.094, p = 0.039) analyses, only in men. After multivariable adjustment, the third tertile of anti-TPO was significantly associated with NOx levels in women (β = −0.067, p = 0.050). Conclusions: Based on the result, serum NOx concentration was found to be associated with free T4 in men and anti-TPO in women.

Mechanisms of molecular recognition: crystal structure analysis of human and rat transthyretin inhibitor complexes.

Structure-activity data show that many pharmacological agents are strong competitive inhibitors for thyroxine (T4) binding to transthyretin (TTR) and that this competition can interfere with their normal pharmacological actions. TTR is a tetrameric serum protein responsible for the transport of 20% of the circulating T4 in man, while in lower vertebrates such as rats it is the only carrier. The sequence of rat TTR is 85% homologous to the human protein. Crystallographic analyses of ligand co-crystal complexes of human and rat TTR have been studied to understand the molecular basis for binding selectivity of competitor binding to TTR. Analysis of TTR crystal complexes with several classes of competitors (hormone metabolites, flavonoids, fluorescent probes, analgesics and cardiac agents) revealed multiple modes of binding with both forward and reverse ligand binding orientations. These ligands also have different binding positions along the length of the channel with the smallest ligands located deeper within the hormone domain. Data for the human TTR complex with the bromoflavone EMD21388 incubated at different times revealed variable binding positions and occupancies dependent upon incubation time. Comparison of the structures of T4 thyroacetic acid in complex with both human and rat TTR revealed forward and reverse binding, but also showed different modes of binding in the rat compared to the human complex. These data highlight the importance of hydrogen bonding with Lys-15 and Ser-117 and provide insight into ligand binding affinity and negative cooperativity.

A radioimmunoassay for measurement of thyroxine sulfate.

A highly sensitive, specific, and reproducible RIA has been developed to measure T4 sulfate (T4S) in ethanol extracts of serum. rT3 sulfate (rT3S) cross-reacted 7.1%, and T3S cross-reacted 0.59% in the RIA; T4, T3, rT3, and 3,3'-diiodothyronine cross-reacted 0.004% or less. The recovery of nonradioactive T4S added to serum averaged 95%. The detection threshold of the RIA was 18 pmol/L. The coefficient of variation averaged 6.9% within an assay and 12% between assays. T4S was bound by T4-binding globulin and albumin in serum. The free fraction of T4S in four normal sera averaged 0.06% compared to a value of 0.03% for T4 (P < 0.001). The serum concentration of T4S was (mean +/- SE) 19 +/- 1.2 pmol/L in normal subjects, 33 +/- 10 in hyperthyroid patients with Graves' disease, 42 +/- 15 in hypothyroid patients, 34 +/- 6.9 in patients with systemic nonthyroidal illnesses, 21 +/- 4.3 in pregnant women at 15-40 weeks gestation, and 245 +/- 26 in cord blood sera of newborns; the value in the newborn was significantly different from normal (P < 0.001). The mean concentration of T4S in amniotic fluid samples at 15-38 weeks gestation was 106 +/- 22 pmol/L (cf. normal adults; P < 0.001). Administration of sodium ipodate (Oragrafin; 3 g, orally) to hyperthyroid patients was associated with a transient increase in serum T4S. The T4S content of the thyroid gland was less than 1/4000th that of T4. We conclude that 1) T4S is a normal component of human serum, and its levels are markedly increased in newborn serum and amniotic fluid; and 2) the sulfation pathway plays an important role in the metabolism of T4 in man.

The hidden, nonexchangeable pool of 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in man: does it exist?

The validity of estimation of the production rates of T3 and rT3 in man based on noncompartmental analysis of blood-derived data has been questioned owing to incomplete exchangeability of T3 and rT3 between plasma and extrathyroidal tissues in which a local production of these iodothyronines takes place. The possible existence of a nonexchangeable or hidden pool of T3 and rT3 would result in an underestimation of the daily production. By contrast, the production rate of T4 can be estimated reliably using noncompartmental analysis. We have studied 16 women with pretreatment severe hypothyroidism on constant levothyroxine therapy. Simultaneous measurements of T4, T3 and rT3 production rates were performed using bolus injection of radiolabelled iodothyronines. The tracers were isolated from plasma using gel separation/antibody extraction, and production rates were calculated by noncompartmental analysis. Mean (+/- SD) production rate of T4, T3 and rT3 were: 119 +/- 43, 40.0 +/- 22.0 and 54.9 +/- 20.0 nmol.day-1.(70 kg)-1, respectively. Thus 79.5 +/- 7.0% of T4 was deiodinated into T3 and rT3. This leaves 20.5% to other metabolic pathways of T4 and to a possible underestimation of T3 and rT3 production rate. Based on conservative estimates from the literature, the other metabolic pathways of T4 amount: oxidative deamination 1.1%; ether link cleavage 0%; urinary excretion 2.5%; and fecal excretion 14%. Thus, the various metabolic pathways seem to explain 97% of daily produced and degradated T4 in man. Therefore the understimation of T3 and rT3 production rates in man using noncompartmental analysis seems of little if any importance, and existence of a hidden pool of these iodothyronines may be questioned.

Effects of rifampicin on the peripheral turnover kinetics of thyroid hormones in mice and in men.

The induction of mixed function hepatic oxygenases by rifampicin is known to increase the metabolic clearance rate (MCR) of T4. By performing T3 and rT3 kinetics we have shown that rifampicin also increases the MCR of T3 and rT3. Using the fall of serum T4 during TSH suppression as an indirect marker of the production rate (PR) of T4, we have demonstrated that there was no major change in monodeiodination nor any shift to either 5'- or 5-monodeiodination. Rifampicin stimulates in mice the mixed function hepatic oxygenases. However, we were unable to increase hepatic deiodinase activity (deiodinase type I) in this species. It is therefore possible that the increased MCR of T4 in man is not mediated by an increased conversion rate either. As mixed function hepatic oxygenases are known to increase hepatic conjugation it is suggested that rifampicin increases the biliary excretion of iodothyronine conjugates.

The nondeiodinative pathways of thyroxine metabolism: 3,5,3',5-tetraiodothyroacetic acid turnover in normal and fasting human subjects.

Complete turnover studies of T4, T3, rT3, and 3,5,3',5-tetriodothyroacetic acid (TA4) were carried out in normal subjects given T4 (0.2 mg, by mouth daily) by the integration method. When compared to the five fed controls, the four fasting subjects showed a decrease of mean T3 disposal from 41 to 18 micrograms/day, an increase of mean rT3 disposal from 49 to 61 micrograms/day. The mean serum TA4 concentration rose from 53 to 112 ng/dl, while the TA4 metabolic clearance remained unchanged. The fraction of T4 metabolized by deiodination changed from 79.0% to 77.5% in the fasting subjects as the fraction of T4 metabolized by deamination changed from 1.1% to 2.2%. Therefore, fasting induces a significant shunting of T4 away from T3 production into rT3 and TA4 production. However, oxidative deamination remains a minor metabolic pathway of T4 in man during both normal and fasting conditions. Given its low disposal rate and low biological potency, the increased TA4 production during fasting is probably not the inhibitory factor of TSH response to the lowered T3 production during fasting.

Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man.

Serum triiodothyronine (T(3)) kinetics in man have been difficult to define presumably due to the interference of iodoproteins generated during the peripheral metabolism of T(3). The use, in the present study, of an anion-column chromatographic method for separation of serum T(3) as well as thyroxine (T(4)) from these iodoproteins has overcome this technical handicap. Simultaneous measurement of serum (125)I-T(3) and (131)I-T(4) kinetics were performed in 31 subjects from the clinical categories of euthyroid, primary hypothyroid, thyrotoxic and posttreatment hypothyroid Graves' disease, factitial thyrotoxic, and idiopathically high and low thyroxinebinding globulin states. The normal mean T(3) fractional turnover rate (kT(3)) was 0.68 (half-life = 1.0 days), increased in toxic Graves' disease patients to 1.10 (half-life = 0.63 days), and decreased in primary hypothyroid patients to 0.50 (half-life = 1.38 days). The mean T(3) equilibration time averaged 22 hr except in hypothyroid and high thyroxine-binding globulin (TBG) patients where the equilibration period was delayed by 10 hr. The mean T(3) distribution space in normal subjects was 38.4 liters. This was reduced in subjects with high TBG levels (26 liters) and increased in patients with low TBG and in all hyperthyroid states (53-55 liters). The normal serum T(3) concentration was estimated by radioimmunoassay to be 0.106 mug/100 ml. Combined with the mean T(3) clearance value of 26.1 liters/day, the calculated T(3) production rate was 27.6 mug/day. The mean T(3) production rate increased to 201 mug/day in thyrotoxic Graves' disease patients and was reduced to 7.6 mug/day in primary hypothyroid subjects. T(3) production rate was normal in subjects with altered TBG states. The ratio of T(3) to T(4) production rate in normal subjects was 0.31 and was unchanged in patients with altered TBG values. This ratio was increased in all Graves' disease patients with the highest value being 0.81 in the posttreatment hypothyroid Graves' disease group. This apparent preferential production of T(3) may have been responsible for the retention of rapid turnover kinetics for T(3) and T(4) observed in treated Graves' disease patients. The finding that factitial thyrotoxic patients also displayed similar rapid T(3) and T(4) turnover kinetics indicates that these alterations are not a unique feature of Graves' disease per se. When comparing the peripheral turnover values for T(3) and T(4) in man, it is apparent that alterations in metabolic status and serum TBG concentration influence both hormones in a parallel manner; however, changes in metabolic status seem to have a greater influence on T(3) kinetics while alterations in TBG concentrations have a greater effect on T(4). These observations probably relate to the differences in TBG binding affinity and peripheral tissue distribution of these two hormones.