OBJECTIVE

To evaluate the effects of liquid (drops) and tablet formulations of levothyroxine in homogeneous groups of infants with congenital hypothyroidism (CH) as diagnosed through neonatal screening.

METHODS

Forty-two consecutive infants with CH were subdivided into 2 groups consisting of infants with the severe or the moderate/mild form. For each form, the infants with CH were randomly assigned to receive liquid (group 1) or tablet (group 2) formulation. In all patients, thyroid function tests were performed before the beginning of therapy and at 15 and 30 days and at 3 and 6 months after the beginning of therapy.

RESULTS

In the severe form, after 15 days of treatment, serum thyrotropin (TSH) levels became normal in 8 of 9 patients in group 1 and in 5 of 9 patients in group 2; serum free triiodothyronine (fT3) levels were significantly higher in group 1 than in group 2; and serum fT4 levels were higher than the upper limit of the normal range in all patients in both groups. During the follow-up, there were significantly more patients with suppressed TSH concentrations in group 1 than in group 2. In the moderate/mild form, the patients of group 1 and group 2 showed median values of TSH, fT3, and fT4 that were not significantly different. No clinical or electrocardiographic signs of heart disease were found. There were no significant differences in the developmental quotient between group 1 and group 2 patients with severe and moderate/mild CH.

CONCLUSIONS

Our data seem to indicate that there is not complete bioequivalence between drops and tablets, especially in infants with severe CH.

OBJECTIVE

To evaluate the changes in serum sex hormones of gonadal or adrenal origin, the gonadotropic hormones, and sex hormone-binding globulin (SHBG) in men and women with chronic temporal lobe epilepsy (TLE), who are undergoing monotherapy with carbamazepine or receiving carbamazepine in combination with other anticonvulsant drugs.

METHODS

Gonadal hormones (estradiol, testosterone, free testosterone, and inhibin B), adrenal hormones [cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17alpha-hydroxyprogesterone], and gonadotropic hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) were measured in 22 women and 26 men with TLE. The study also measured prolactin; human growth hormone and its major mediator, insulin-like growth factor-I; thyroid hormones (free thyroxine and free triiodothyronine); thyroid-stimulating hormone (TSH); and SHBG. The results were compared with those obtained from 60 healthy women and 106 healthy men.

RESULTS

In the female patients, TSH, DHEAS, follicular-phase LH, and luteal-phase estradiol were significantly lower than in the control groups, with prolactin and SHBG significantly higher. In the male patients, DHEAS, 17alpha-hydroxyprogesterone, free testosterone, inhibin B, and the testosterone/LH ratio were significantly lower than in the control group, with LH, FSH, and SHBG significantly higher. Increased FSH in 31% of the men indicates an impairment of spermatogenesis; lowered inhibin B in 12% indicates an impaired Sertoli's cell function; and the decreased testosterone/LH ratio in 50% indicates an impaired Leydig's cell function.

CONCLUSIONS

The case patients had endocrine disorders, mainly concerning the gonadotropic and gonadal functions in both sexes; the adrenal function, with lowered DHEAS levels in both sexes; and lowered 17alpha-hydroxyprogesterone levels in the men. SHBG levels were increased in patients taking anticonvulsant medications.

The concentrations of thyroid hormones were measured in 14 pediatric patients before, during, and after cardiopulmonary bypass. The ages of the patients ranged between 18 months and 14 years. Patients were kept normothermic, or moderate or deep hypothermia was induced depending on the specific pathologic condition involved. A marked reduction in the levels of total triiodothyronine, total thyroxine, free triiodothyronine, and thyroid-stimulating hormone, and in the ratio of free triiodothyronine to free thyroxine was detected during the time frame of the study. The minimum levels of each hormone were reached between 12 and 48 hours after cardiopulmonary bypass, indicating that changes in thyroid function and in the conversion of thyroxine to triiodothyronine are triggered by cardiopulmonary bypass and represent specific phenomena, and that these changes are progressively exacerbated during the post-operative period. The thyroid-stimulating hormone level was markedly reduced versus its baseline values (24% +/- 0.13%), despite low levels of both total (40% +/- 18%) and free (39% +/- 20%) triiodothyronine: it returned to its preoperative level by the third postoperative day, but both the total (75% +/- 10%) and free (74% +/- 3%) triiodothyronine levels remained below their baseline values for 7 days postoperatively. Neither hemodilution nor hypothermia was responsible for the alteration observed. We conclude that pediatric patients undergoing cardiopulmonary bypass manifest changes in hormone metabolism similar to those seen in adult patients. These changes increase progressively during the postoperative period, and are still present 7 days postoperatively. The exact mechanism responsible for causing these changes is not thoroughly understood. Whether triiodothyronine replacement therapy is beneficial or deleterious remains controversial.

OBJECTIVE

Cardiopulmonary bypass suppresses circulating thyroid hormone levels. Although acute triiodothyronine repletion has been evaluated in adult patients after cardiopulmonary bypass, triiodothyronine pharmacokinetics and effects have not previously been studied in infants undergoing operations for congenital heart disease. We hypothesized that triiodothyronine deficiency in the developing heart after bypass may adversely affect cardiac function reserve postoperatively.

METHODS

Infants less than 1 year old undergoing ventricular septal defect or tetralogy of Fallot repair were randomized into 2 groups. Group T (n = 7) received triiodothyronine (0.4 microg/kg) immediately before the start of cardiopulmonary bypass and again with myocardial reperfusion. Control (NT, n = 7) patients received saline solution placebo or no treatment.

RESULTS

These groups underwent similar ischemic and bypass times and received similar quantities of inotropic agents after the operation. The NT group demonstrated significant depression in circulating levels, compared with prebypass levels, for free triiodothyronine and total triiodothyronine at 1, 24, and 72 hours after bypass. Group T demonstrated similar low thyroxine values, but free and total triiodothyronine levels were maintained at prebypass levels for 24 hours and remained elevated over those of group NT (P <.05) at 72 hours. Heart rate was transiently elevated in group T compared with group NT (P <.05), and peak systolic pressure-rate product increased after 6 hours.

CONCLUSIONS

These data imply that (1) triiodothyronine in the prescribed dose prevents circulating triiodothyronine deficiencies and (2) triiodothyronine repletion promotes elevation in heart rate without concomitant decrease in systemic blood pressure. Elevation of peak systolic pressure-rate product implies that triiodothyronine repletion improves myocardial oxygen consumption and may enhance cardiac function reserve after cardiopulmonary bypass in infants.

To evaluate developmental exposure effects of two brominated flame retardants, tetrabromobisphenol A (TBBPA) and 1,2,5,6,9,10-hexabromocyclododecane (HBCD), pregnant Sprague-Dawley rats were administered either chemical at doses of 100, 1000 or 10,000 ppm in a soy-free diet from gestation day 10 until the day 20 after delivery. Offspring exposed to TBBPA showed dose-unrelated slight decreases of serum triiodothyronine (T(3)) concentration at postnatal day 20, and there was no evidence of hypothyroidism-related neuronal mismigration and impaired oligodendroglial development as judged by morphometric analyses of NeuN-immunoreactive neuronal distribution in the hippocampal CA1, and area of corpus callosum as well as density of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-immunoreactive oligodendrocytes in the cingulate deep cortex at the adult stage. On the other hand, HBCD exerted a weak hypothyroidism evident with increases in thyroid weight, thyroid follicular cell hypertrophy and serum concentrations of thyroid-stimulating hormone as well as decreases of serum T(3) concentrations in offspring at 10,000 ppm at weaning. Increased thyroid weights and decreased serum T(3) concentrations were also observed in the adult stage from 1000 ppm. With regard to the effect on brain development, HBCD reduced density of CNPase-positive oligodendrocytes at 10,000 ppm, suggesting an impaired oligodendroglial development. Results thus suggest that TBBPA did not exert developmental brain effects, while HBCD did, and 100 ppm was determined to be the no-observed-adverse-effect level of HBCD from changes in thyroid parameters at the adult stage by maternal exposure, translating into 8.1-21.3mg/kg-d.

The effect of six perfluoroalkyl acids (PFAAs), namely, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDE), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamide) acetic acid (MPAH), and perfluorononanoic acid (PFNA) on the levels of six thyroid function variables, namely, thyroid stimulating hormone (TSH), free and total thyroxine (FT4, TT4), free and total triiodothyronine (FT3, TT3), and thyroglobulin (TGN) was evaluated. Data from National Health and Nutrition Examination Survey for the years 2007-2008 were used for this evaluation. TSH levels increased with increase in levels of PFOA (p<0.01). There were no statistically significant associations between the levels of FT3, and FT4 with the levels of any of the six PFAAs. Levels of TT3 were found to increase with the levels of PFOA (p=0.01) and TT4 levels were found to increase with increase in PFHxS levels (p<0.01). Males had statistically significantly higher levels of FT3 than females and females had statistically significantly higher levels of TT4 than males. As compared to non-Hispanics whites and Hispanics, non-Hispanic blacks had lower levels of TSH, FT3, TT3, and TT4 but Hispanics had the lowest levels of TGN. Age was negatively associated with FT3 and TT3 but positively associated with FT4 and TT4. Non-smokers had higher levels of TSH and TT4 than smokers and smokers had higher levels of FT3 and TGN than non-smokers. Iodine deficiency was associated with increased levels of TSH, TT3, TT4, and TGN.

OBJECTIVE

The aim was to study whether functional impairment of the pituitary, thyroid, testes, and adrenal glands of humans occupationally exposed to mercury (Hg) vapour can be shown as a result of accumulation of Hg in these glands.

METHODS

Basal concentrations of thyrotrophin (TSH), prolactin, free thyroxine (free T4), free 3,5,3'-triiodothyronine (free T3), antibodies against thyroperoxidase, and testosterone in serum, as well as cortisol in morning urine were measured in 41 chloralkali workers exposed (10 years on average) to Hg vapour, and in 41 age matched occupationally unexposed referents. The chloralkali workers had a mean urinary Hg concentration (U-Hg) of 15 nmol/mmol (27 micrograms/g) creatinine, and a mean blood Hg concentration (B-Hg) of 46 nmol/l. For the reference group U-Hg and B-Hg were 1.9 nmol/mmol (3.3 micrograms/g) creatinine and 17 nmol/l respectively.

RESULTS

The serum free T4 concentration and the ratio free T4/free T3 were slightly, but significantly, higher in the subgroups with the highest exposure, and the serum free T3 was inversely associated with cumulative Hg exposure. This indicates a possible inhibitory effect of mercury on 5'-deiodinases, which are responsible for the conversion of T4 to the active hormone T3. Serum total testosterone, but not free testosterone, was positively correlated with cumulative Hg exposure. Prolactin, TSH and urinary cortisol concentrations were not significantly associated to exposure.

CONCLUSIONS

Apart from inhibition of the deiodination of T4 to T3, the endocrine functions studied seem not to be affected by exposure to Hg vapour at the exposure levels of the present study. Growth hormone secretion was not studied.

OBJECTIVE

To attempt to confirm a previous report of superior effectiveness of using two thyroid hormones rather than one hormone to treat hypothyroidism.

METHODS

This trial attempted to replicate prior findings, which suggested that substituting 12.5 microg of liothyronine (LT(3)) for 50 microg of levothyroxine (LT(4)) might improve mood, cognition, and physical symptoms in patients with primary hypothyroidism. Additionally, this trial aimed to extend the previous findings to fatigue and to assess for differential effects in subjects with low fatigue and high fatigue at baseline. A randomized, double-blind, two-period, crossover design was used. At an endocrinology and diabetes clinic, 30 adult subjects with primary hypothyroidism stabilized on LT(4) were recruited. Patients randomly assigned to treatment sequence 1 received their standard LT(4) dose in one capsule and placebo in another. Patients assigned to sequence 2 received their usual LT(4) dose minus 50 microg in one capsule and 10 microg of LT(3) in the other. At the end of the first 6 weeks, subjects were crossed over to receive the other treatment. Carryover and treatment effects were assessed by t tests.

RESULTS

Of the 30 enrolled study subjects, 27 completed the trial. The mean LT(4) dose was 121 +/- 26 microg/day at baseline. No significant differences in fatigue and symptoms of depression were found between treatments. Measures of working memory were unchanged. During substitution treatment, the free thyroxine index was reduced by 0.7 (P<0.001), total serum thyroxine was reduced by 3.0 microg/dL (P<0.001), and total serum triiodothyronine was increased by 20.5 ng/dL (P = 0.004).

CONCLUSIONS

With regard to the outcomes measured, substitution of LT(3) at a 1:5 ratio for a portion of baseline LT(4) yielded no better results than did treatment with the original dose of LT(4) alone.

OBJECTIVE

To determine whether thyroxine treatment is effective in patients with symptoms of hypothyroidism but with thyroid function tests within the reference range, and to investigate the effect of thyroxine treatment on psychological and physical wellbeing in healthy participants.

METHODS

Randomised double blind placebo controlled crossover trial.

METHODS

Outpatient clinic in a general hospital.

METHODS

25 patients with symptoms of hypothyroidism who had thyroid function tests within the reference range, and 19 controls.

METHODS

PARTICIPANTS were given thyroxine 100 microgram or placebo to take once a day for 12 weeks. Washout period was six weeks. They were then given the other to take once a day for 12 weeks. All participants were assessed physiologically and psychologically at baseline and on completion of each phase.

METHODS

Thyroid function tests, measures of cognitive function and of psychological and physical wellbeing.

RESULTS

22 patients and 19 healthy controls completed the study. At baseline, patients' scores on 9 out of 15 psychological measures were impaired when compared with controls. Patients showed a significantly greater response to placebo than controls in 3 out of 15 psychological measures. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo (mean (SD) 60 (17) v 73 (16), P<0.01). However, patients' scores from psychological tests when taking thyroxine were no different from those when taking placebo except for a poorer performance on one visual reproduction test when taking thyroxine. Serum concentrations of free thyroxine increased and those of thyroid stimulating hormone decreased in patients and controls while they were taking thyroxine, confirming compliance with treatment. Although serum concentrations of free triiodothyronine increased in patients and controls taking thyroxine, the difference between the response to placebo and to thyroxine was significant only in the controls.

CONCLUSIONS

Thyroxine was no more effective than placebo in improving cognitive function and psychological wellbeing in patients with symptoms of hypothyroidism but thyroid function tests within the reference range. Thyroxine did not improve cognitive function and psychological wellbeing in healthy participants.

OBJECTIVE

There is current controversy on the association between subclinical hyperthyroidism and hypertension. Data from cohort studies have not been available yet. The present study was designed to longitudinally investigate possible associations of subclinical hyperthyroidism with blood pressure, pulse pressure and the risk of hypertension.

METHODS

We used data from the population-based, prospective cohort Study of Health in Pomerania and included 2910 subjects (1469 women) aged 20-79 years with completed 5-year examination follow-up. Subjects with increased serum TSH levels or overt hyperthyroidism were excluded. Serum TSH levels below 0.25 mIU/l with free triiodothyronine and free thyroxine levels within the reference range were defined as subclinical hyperthyroidism. Blood pressure was measured according to standard methods.

RESULTS

Multivariable analyses adjusted for age, sex, overweight, obesity, smoking status and time between the examinations did not reveal any statistically significant association between subclinical hyperthyroidism and any of the blood pressure-related variables in the whole study population. Although the 5-year hypertension incidence was higher in subjects with subclinical hyperthyroidism compared with those without (31.4 vs 19.2%; risk ratio 1.64; 95% confidence interval (CI) 1.17-2.28, P=0.006), both groups did not differ with respect to the risk of hypertension, after analyses were adjusted for confounders (relative risk 1.23, 95% CI 0.91-1.68, P=0.182). Analyses yielded similar results in subjects without thyroid disease and in those who took no antihypertensive medication.

CONCLUSIONS

Subclinical hyperthyroidism is not associated with changes in blood pressure, pulse pressure or incident hypertension.

OBJECTIVE

Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients.

METHODS

We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy.

METHODS

Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout.

RESULTS

After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm.

CONCLUSIONS

GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.

Thyroid gland function develops and matures during fetal life, with production of serum thyroxine (T4) concentrations beginning around 12 weeks gestation and increasing to term. Infants born prior to term have lower cord serum T4 concentrations that correlate with gestational age or birth weight. This is partially the result of lower thyroxine-binding globulin (TBG) concentrations. The cord serum free thyroxine (FT4) concentrations also correlate with gestational age, but they are not proportionately as low as the cord T4 concentration. Preterm infants have a postnatal thyrotropin (TSH) surge and rise in serum T4 and triiodothyronine (T3), which is qualitatively similar to, but quantitatively smaller than, term infants. In contrast to term infants, preterm infants often experience a fall in serum T4 and T3 in the first week of life to below birth levels. This drop appears to be the result of many factors, including nutritional problems and decreased hepatic TBG production, immaturity of hypothalamic-pituitary control of the thyroid gland, immaturity of the thyroid gland itself, and increased tissue utilization of T4. These changes are impacted by complications of prematurity, such as respiratory distress syndrome (RDS), which result in nonthyroidal illness-like changes. Again, serum FT4 seems less affected, and when measured by equilibrium dialysis may be in the normal range for age. Several studies have correlated different measures of morbidity and mortality in the preterm infant with lower serum T4 concentrations. However, as with adults, it may be that low serum T4 concentrations are a marker of the sickest preemies. Also, as with adults, this has led to speculation that T4 treatment might be beneficial in improving these complications of prematurity, in particular the neurological outcome. While some studies appear to show improvement in some facet of medical complications with T4 treatment, most show no effect. Regarding neurological outcome, the 2 best controlled trials do not show improvement in neuropsychiatric testing outcome assessed up to 2 years of age. One study, however, showed an IQ that was 18 points higher in the T4-treated subgroup less than 27 weeks gestational age. It may be that the most preterm infants, eg, those less than 27 weeks of age, are at a disadvantage compared with their intrauterine counterparts, in that they lack the maternal thyroid hormone contribution and are forced to adapt to extrauterine life before their hypothalamic-pituitary-thyroid axis is mature enough to deal with tissue thyroxine demands. Further controlled studies are needed to determine if this subgroup of infants indeed may benefit from transient thyroid hormone supplementation.

OBJECTIVE

In recent years, there has been increasing focus on thyroid function in pediatric obese patients. Our aims were to investigate whether there is an association between serum thyroid-stimulating hormone (TSH) within the normal range and body mass index (BMI), and to determine if TSH levels correlate with metabolic risk factors in children.

METHODS

A retrospective cross-sectional analysis was carried out on 528 euthyroid, age- and sex-matched lean, overweight, or obese children. Anthropometric indices, blood pressure, fasting blood glucose, hepatic enzymes, lipid profiles, TSH, free triiodothyronine (fT3), and free thyroxine (fT4) were assessed from medical records and compared among groups. Subjects with known presence of diabetes, using medications altering blood pressure and glucose or lipid metabolism, with TSH levels >97.5 or <2.5 percentile, or with autoimmune thyroid disease were excluded.

RESULTS

Hypertension, dyslipidemia, and elevated levels of hepatic enzymes were found to be more common in overweight and obese children (p<0.001), and those metabolic changes were significantly correlated with the increase in BMI (p<0.05). Serum concentrations of TSH and fT3 within the normal range were higher in overweight and obese children (p<0.01), and TSH was positively correlated with total cholesterol, triglycerides, and systolic blood pressure (p<0.05).

CONCLUSIONS

Our findings suggest that obese children have higher serum TSH and fT3 levels even within the normal range, and that an increase in TSH is associated with dyslipidemia and higher systolic blood pressure. It remains to be seen whether TSH might serve as a potential marker of metabolic risk factors in obese pediatric patients.

In neonates, infants, children and adolescents serum concentrations of the thyroid hormones show a clear age dependency. Currently, age-dependent thyroid hormone reference ranges for the new ADVIA Centaur immunoanalyzer are not available. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), total thyroxine (T4), free triiodothyronine (FT3) and total triiodothyronine (T3) were determined in the sera of 460 healthy children aged 0 daysto 18 years from an inland (n=308) and a seaside city (n=152) using the Bayer ADVIA Centaur analyzer. Square root functions defining the upper and lower limit of the continuous age-dependent reference range and the median line for each thyroid hormone were estimated applying a parametric regression technique. Continuous age-dependent reference ranges show a better fit to the obtained data than discontinuous reference ranges. The median TSH and FT4 concentrations decrease within the first year of life and are nearly constant until 18 years of age. The median T4 decreases within the entire age interval, whereas the median FF3 is constant. The median T3 increases within the first year of life and decreases afterwards. The calculated continuous reference ranges for T4, T3 and partly FT4 are consistent with published reference ranges. However, the reference ranges obtained for FT3 and partly TSH differed considerably, compared to published reference ranges. No significant residence- or sex-specific effects on age-adjusted hormone concentrations were found except for a slight residence-specific effect on age-adjusted FT4, which was probably due to assay imprecision. Due to the lack of international standardization, the assay-specific evaluation of reference ranges is very important. Continuous age-dependent reference ranges comply better with the biological reality and are more reliable than discontinuous reference ranges.

The essential micronutrient selenium (Se) occurs in the form of the amino acid selenocysteine in selenoproteins which exert various effects, while maintaining the cell reduction-oxidation balance. The discovery that all three deiodinases that convert thyroxine (T4) into triiodothyronine (T3) contain selenocysteine illustrates how the production of the active thyroid hormone is dependent on Se status. The selenoenzyme families of glutathione peroxidases (GPx) and thioredoxin reductases (TRx) possess powerful antioxidant properties and form a complex defense system that protects thyrocytes from oxidative damage. Se supplementation in patients with autoimmune thyroiditis seems to modify the immune response, probably by enhancing plasma GPx activity and decreasing excess levels of hydrogen peroxide. However, the enhancement of immunocompetence may also be the result of the synergistic action of various selenoproteins and not exclusively of GPx. There is evidence supporting considerable oxidative stress in Graves' disease where Se supplementation, because of its free radical scavenging properties, may increase the enzymatic antioxidant activity. TRx has been found significantly elevated in GD revealing its involvement in the pathogenesis of this condition and representing a potential future target for therapeutical intervention. Low Se serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis. It is noteworthy, that the Food and Drug Administration has recently determined that there is sufficient evidence to warrant a qualified health claim for Se and cancer. Furthermore, the recent discovery that defects in the SECIS-binding protein 2 (SBP2), which is an indispensable protein for the incorporation of Se into the selenoproteins, result in thyroid dysfunction, together with the recognition of the many roles of selenoprotein P in Se distribution and storage in the human body, reveal not only the indispensability of Se and the selenoproteins as essential factors in thyroid metabolism and pathogenesis, but open up new prospects for enhanced treatment.

Subclinical thyroid dysfunction is defined as an abnormal serum thyroid-stimulating hormone level (reference range: 0.45 to 4.50 microU per mL) and free thyroxine and triiodothyronine levels within their reference ranges. The management of subclinical thyroid dysfunction is controversial. The prevalence of subclinical hypothyroidism is about 4 to 8.5 percent, and may be as high as 20 percent in women older than 60 years. Subclinical hyperthyroidism is found in approximately 2 percent of the population. Most national organizations recommend against routine screening of asymptomatic patients, but screening is recommended for high-risk populations. There is good evidence that subclinical hypothyroidism is associated with progression to overt disease. Patients with a serum thyroid-stimulating hormone level greater than 10 microU per mL have a higher incidence of elevated serum low-density lipoprotein cholesterol concentrations; however, evidence is lacking for other associations. There is insufficient evidence that treatment of subclinical hypothyroidism is beneficial. A serum thyroid-stimulating hormone level of less than 0.1 microU per mL is associated with progression to overt hyperthyroidism, atrial fibrillation, reduced bone mineral density, and cardiac dysfunction. There is little evidence that early treatment alters the clinical course.

OBJECTIVE

To compare the effects of pregnancy on the serum free thyroxine (FT4) levels in two cohorts of primary hypothyroid women treated with different levothyroxine (L-T4) doses before gestation.

METHODS

Twenty-five women with compensated hypothyroidism of different aetiology (thyroidectomized and Hashimoto's thyroiditis) were enrolled in this prospective study. The women were receiving substitutive doses of L-T4 and were anticipating pregnancy. They were assigned to two groups: 14 patients (group I) were switched to partially suppressive treatment while 11 patients (group II) continued the same therapeutic regimen.

RESULTS

Pre-conceptional thyroid function evaluation demonstrated significantly higher FT4 and lower TSH in group I (P<0.001, for both hormones) and comparable free 3,5,3'-triiodothyronine (FT3) levels. The first post-conception thyroid function evaluation occurred at a median time of 6 (5-8) and 7 (5-9) weeks of gestation, for groups I and II respectively (P<0.05); all women in group I showed adequate serum FT4 levels while three patients in group II showed low-normal FT4 levels and one case was below normal levels. Statistical analysis demonstrated significantly higher frequencies (0% vs 36.4%; P<0.05) of low-normal FT4 levels in patients receiving substitutive doses of L-T4. None of the Hashimoto's-affected patients showed low or low-normal serum FT4 levels regardless of their therapeutic regimen.

CONCLUSIONS

Our results suggest that in hypothyroid women anticipating pregnancy (with serum TSH in the lower quartile of normal range), the pre-conception adjustment of L-T4 doses may result in adequate maternal thyroid function up to the first post-conception evaluation. The procedure seems safe and inexpensive; it may be a worthwhile treatment, at least in thyroidectomized women, in view of the well-known potential effects of even marginal maternal thyroid hypofunction on the subsequent IQ of the progeny.

OBJECTIVE

To study the prevalence of autoimmune thyroiditis (AT) in Sardinian children with celiac disease (CD) and the effects of a gluten-free diet (GFD) on thyroid function.

METHODS

Children with biopsy-proven CD (n = 324; female:male 2:1; mean age, 6.6 years) followed from 1 to 15 years, were retrospectively evaluated for AT at onset of CD and during GFD. Serum thyroid peroxidase and thyroglobulin antibodies (AbTPO, AbTG), thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), and thyroid ultrasonography were considered. Age-matched Sardinian schoolchildren (n = 8040), previously evaluated for antithyroid antibodies and thyroid function, were used as controls.

RESULTS

Thirty-four patients with CD (10.5%) developed AT (female:male 4,5:1; mean age, 10.5 years), 11 at onset of CD and 23 during GFD, with a higher prevalence than controls (P = 2.9(-13)). Twenty-eight patients were euthyroid and 6 hypothyroid. AbTPO and/or AbTG persisted elevated for 2 to 9 years despite the GFD in 9 of 11 patients with AT at onset of CD.

CONCLUSIONS

AT is strongly associated with CD in Sardinian children, has an age of onset of 10.5 years, and appears to be gluten-independent. In children with CD with AT, the female:male bias reported in adult AT is present before puberty.

OBJECTIVE

Vitamin D deficiency is reportedly linked to a variety of autoimmune diseases. However, the relationship between thyroid autoimmunity in Graves disease (GD) and vitamin D deficiency is unclear. The goal of this study was to determine whether increased thyroid hormone autoantibody titer is associated with vitamin D deficiency in GD patients.

METHODS

A total of 70 patients with GD and 70 matched control subjects were recruited to our study. The levels of 25-hydroxyvitamin D (25[OH]D), calcium, parathyroid hormone (PTH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyrotropin-receptor antibody (TRAb), thyroid-peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) in serum collected from these patients and controls were examined.

RESULTS

The level of 25(OH)D in serum from TRAb-positive GD patients was significantly lower than that in serum of healthy controls or TRAb-negative patients. However, compared with control subjects, the level of PTH in serum was increased in TRAb-positive GD patients. The rate of vitamin D deficiency (defined as serum 25[OH]D <50 nmol/L) in TRAb-positive GD patients was significantly higher than in healthy controls or TRAb-negative GD patients. The level of 25(OH)D in serum was inversely correlated with TRAb titer in serum of TRAb-positive GD patients. However, our results did not show a correlation between 25(OH)D level and the levels of TPOAb, TGAb, FT3, FT4, or TSH.

CONCLUSIONS

Low vitamin D status is associated with increased TRAb titer in GD, suggesting a possible link between vitamin D status and increased thyroid autoimmunity in GD patients.

Circulating thyroglobulin antibodies (TgAb) and thyroperoxidase antibodies (TPOAb) were measured in 143 iodine-deficient children, 5 to 15 years of age, from the Region of Tula, Russia, who had been moderately contaminated after the Chernobyl disaster (37-185 GBq/km2 of caesium-137, [group A]) and in 40 sex- and age-matched subjects from an uncontaminated neighboring area (<3.7 GBq/km2 of caesium-137, [group B]). Increased thyroid size at sonography was found in 41% and in 45% subjects from group A and group B, respectively, associated with supranormal thyrotropin (TSH) values in 7.7% of group A and 7.5% of group B, without differences in average serum free thyroxine (FT4), free triiodothyronine (FT3) and TSH. Serum thyroperoxidase antibody (TPOAb)-associated or not with thyroglobulin-antibody (TgAb) as detected in 18.9% of children and adolescents from group A, about four-fold higher than in group B (5%, Fischer's exact test p<0.05). A 24% frequency was found in subjects whose age, at the moment of the disaster was 0-72 months or were in utero, but the frequency was about 7%, similar to that in group B, in those who had not yet been conceived at that time. Less than half of antibody-positive group A children were hyperthyrotropinemic, whereas no group B subclinical hypothyroid subject was antibody-positive, thus excluding the autoimmune etiology of the subclinical thyroid failure; more likely it is attributable to iodine malnutrition. The high prevalence of humoral thyroid autoimmunity phenomena in the investigated area suggests a combined role of iodine malnutrition in enhancing the effects of short lived iodine isotopes, particularly evident in pubertal individuals conceived or born immediately before the Chernobyl disaster.

To investigate the influence of exercise on thyroid metabolism, 46 healthy young regularly menstruating sedentary women were randomly assigned to a 3 x 2 experimental design of aerobic exercise and energy availability treatments. Energy availability was defined as dietary energy intake minus energy expenditure during exercise. After 4 days of treatments, low energy availability (8 vs. 30 kcal.kg body wt-1.day-1) had reduced 3,5,3'-triiodothyronine (T3) by 15% and free T3 (fT3) by 18% and had increased thyroxine (T4) by 7% and reverse T3 (rT3) by 24% (all P < 0.01), whereas free T4 (fT4) was unchanged (P = 0.08). Exercise quantity (0 vs. 1,300 kcal/day) and intensity (40 vs. 70% of aerobic capacity) did not affect any thyroid hormone (all P>> 0.10). That is, low-T3 syndrome was induced by the energy cost of exercise and was prevented in exercising women by increasing dietary energy intake. Selective observation of low-T3 syndrome in amenorrheic and not in regularly menstruating athletes suggests that exercise may compromise the availability of energy for reproductive function in humans. If so, athletic amenorrhea might be prevented or reversed through dietary reform without reducing exercise quantity or intensity.

To investigate the relationship between energy availability (dietary energy intake minus energy expended during exercise) and thyroid metabolism, we studied 27 untrained, regularly menstruating women who performed approximately 30 kcal.kg lean body mass (LBM)-1.day-1 of supervised ergometer exercise at 70% of aerobic capacity for 4 days in the early follicular phase. A clinical dietary product was used to set energy availability in four groups (10.8, 19.0, 25.0, 40.4 kcal.kg LBM-1.day-1). For 9 days beginning 3 days before treatments, blood was sampled once daily at 8 A.M. Initially, thyroxine (T4) and free T4 (fT4), 3,5,3'-triiodothyronine (T3) and free T3 (fT3), and reverse T3 (rT3) were in the normal range for all subjects. Repeated-measures one-way analysis of variance followed by one-sided, two-sample post hoc Fischer's least significant difference tests of changes by treatment day 4 revealed that reductions in T3 (16%, P < 0.00001) and fT3 (9%, P < 0.01) occurred abruptly between 19.0 and 25.0 kcal.kg LBM-1.day-1 and that increases in fT4 (11%, P < 0.05) and rT3 (22%, P < 0.01) occurred abruptly between 10.8 and 19.0 kcal.kg LBM-1.day-1. Changes in T4 could not be distinguished. If energy deficiency suppresses reproductive as well as thyroid function, athletic amenorrhea might be prevented or reversed by increasing energy availability through dietary reform to 25 kcal.kg LBM-1.day-1, without moderating the exercise regimen.

48 weaned male Sprague-Dawley rats with an initial average body weight of 41 g were divided into 4 groups of 12 animals (zinc-deficient; zinc-adequate, pair-fed with zinc-deficient group; selenium-deficient; selenium-adequate) for 40 days. All groups were fed a semisynthetic diet with casein being the source of protein. In the selenium-deficient diet, there was a selenium concentration of 0.038 mg/kg. The other diets were supplemented with Na-selenite in order to adjust the selenium concentration to 0.3 mg/kg. In the zinc-deficient diet, there was a zinc concentration of 4.1 mg/kg. The zinc concentrations in the other diets were adjusted to 45 mg/kg by the addition of zinc-sulfate heptahydrate. Zinc-deficient rats were characterized by a markedly reduced alkaline phosphatase activity in their serum, whilst selenium-deficient rats showed a markedly reduced glutathione peroxidase in serum proving their respective zinc-deficient and selenium-deficient states. Zinc deficiency decreased concentrations of triiodothyronine (T3) and free thyroxine (fT4) in serum by approximately 30% when compared with zinc-adequate controls. The concentration of thyroxine (T4) in serum was not affected by zinc deficiency. Selenium-deficient animals had lower concentrations of T3 and T4 than selenium-adequate animals. The concentration of fT4 in serum was not affected by selenium deficiency. The activity of hepatic type I 5'deiodinase was decreased by 67% by zinc deficiency and by 47% by selenium deficiency compared to adequate controls. The study data show that both zinc and selenium deficiency affect the metabolism of thyroid hormones.

Seaweeds and soy are two commonly eaten foods in Asia. Both have been reported to affect thyroid function, seaweed because of its iodine content and soy because of its goitrogenic effect. Twenty-five healthy postmenopausal women (mean age 58 years) completed a double-blinded randomized crossover study. Ten capsules (5 g/day) of placebo or seaweed (Alaria esculenta), providing 475 microg of iodine/day, were consumed daily for 7 weeks. A powdered soy protein isolate (Solae Co., St. Louis, MO), providing 2 mg of isoflavones/kg of body weight, was given daily during the last week of each treatment arm. On average, this provided 141.3 mg of isoflavones/day and 67.5 g of protein/day. Blood samples and 48-hour urine samples were collected before and after each intervention period, and urinary I/C (microg of iodine/g of creatinine) and serum thyroxine, free thyroxine index, total triiodothyronine, and thyroid stimulating hormone (TSH) were measured. Seaweed ingestion increased I/C concentrations (P < .0001) and serum TSH (P < .0001) (1.69 +/- 0.22 vs. 2.19 +/- 0.22 microU/mL, mean +/- SE). Soy supplementation did not affect thyroid end points. Seven weeks of 5 g/day seaweed supplementation was associated with a small but statistically significant increase in TSH. Soy protein isolate supplementation was not associated with changes in serum thyroid hormone concentrations.