Autoimmune thyroiditis in 18q deletion syndrome

Deletion of a segment of the long arm of chromosome 18 causes characteristic physical features and mental retardation. Autoimmune disorders have been described with this syndrome in a limited number of reports. We describe 2 cases of autoimmune hypothyroidism in children with 18q deletion syndrome.     

Generation of a transgenic animal model of hyperthyroid Graves' disease

Graves' disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism. Agonistic anti-thyrotropin receptor antibodies (thyroid-stimulating antibodies, TSAb), which mimic the thyrotropin (TSH) action, are thought to cause GD. The precise immunological mechanism of TSAb production, however, remains elusive. Previous immunization approaches using TSH receptor led to transient hyperthyroidism, but did not seem sufficient for comprehensive understanding of the development of autoimmune responses. To create GD-related autoimmunity in mice, we here generated TSAb-transgenic mice in which a patient-derived TSAb is expressed in B cells. Expression of the human TSAb in mice resulted in various manifestations of hyperthyroidism including increased free thyroxine levels with concomitantly decreased TSH levels, increased thyroid uptake of technetium pertechnetate, hyperthermia and thyroid hyperplasia. We found a correlation between the serum levels of human TSAb immunoglobulin and free thyroxine. In addition, conventional B cells expressing the TSAb were partially deleted in the periphery while B1 cells expressing the TSAb persisted and accumulated in the peritoneal cavity, a finding consistent with previous demonstrations that the maintenance of B1 cells plays an important role in the development of autoimmune diseases. Thus, our transgenic mouse may provide a novel and useful animal model for elucidating the pathogenesis and pathophysiology of GD.     

Cloning of cDNAs encoding the three pituitary glycoprotein hormone beta subunit precursor molecules in the Japanese toad,Bufo japonicus

Complementary DNAs encoding precursor molecules of the beta subunits of three pituitary glycoprotein hormones (LH, FSH, and TSH) of the Japanese toad (Bufo japonicus) were isolated and sequenced. Unexpectedly large numbers of single nucleotide substitutions were found in all three beta subunit cDNAs. The eight isolated LH beta precursor cDNA clones were classified into six forms of nucleotide sequence, with four nucleotide substitutions each in the apoprotein coding region and in the 3' untranslated region (UTR). In the deduced amino acid sequence, the LH beta subunit showed two forms with a single amino acid substitution. The seven isolated FSH beta subunit cDNAs were classified into two forms, which differed from each other at 11 positions in the 3' UTR. The six isolated TSH beta subunit clones were classified into four forms with 2 and 5 nucleotide substitutions in the signal peptide and apoprotein coding regions, respectively. However, all the substitutions in the apoprotein coding region were silent. The substitution in the signal peptide coding region could produce three forms of signal peptide. Amino acid sequence comparison revealed that the toad LH beta subunit is more similar to the fish GTH II beta subunit than to mammalian and avian LH beta subunits. We found that the toad LH beta subunit molecule is a partial chimera of LH and FSH; amino acid residues located in 36th to 42nd and 96th to 99th are identical or similar to those of not LH- but FSH-beta subunit in mammalian, whereas it is more similar to LH- than FSH-beta subunit in total. We also found that the toad FSH beta subunit is more similar to the fish GTH II beta subunit than to the fish GTH I beta subunit and that the toad TSH beta subunit is more similar to tetrapod TSH beta subunits than to fish TSH beta subunits.     

Alcohol decreases the nocturnal peak of TSH in healthy volunteers

Rationale Studies of ethanol's effects on TSH carried out during the daytime, when its secretion is at its nadir, do not reflect the true action of alcohol on TSH secretion since TSH peak occurs at night.Objective The present study investigated the effects of alcohol on the serum concentrations of TSH in healthy volunteers during a 26-h session.Methods The trial included a 26-h session during which alcohol was administered at a rate similar to that found in heavy drinkers, i.e. 256 g per day and a 26-h placebo session. Volunteers functioned as their own controls, and we controlled for masking effects in both sessions.Results The usual TSH circadian rhythm flattened during the alcohol session, and the usual peak in the middle of the night completely disappeared.Conclusion Alcohol dramatically decreased nocturnal TSH secretion in healthy volunteers.     

Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation.

Microsomal enzyme inducers that increase UDP-glucuronosyltransferase (UDP-GT) activity are suspected to affect the thyroid gland by increasing the glucuronidation of T(4), which reduces serum thyroxine (T(4)). In response to reduced serum T(4), serum thyroid-stimulating hormone (TSH) increases. However, not all microsomal enzyme inducers that reduce serum T(4) produce an increase in serum TSH. We have shown that serum TSH is increased the most in rats treated with the microsomal enzyme inducers phenobarbital (PB) or pregnenolone-16alpha-carbonitrile (PCN), whereas TSH is affected less in rats treated with 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB). It is unclear why serum TSH is differentially affected by various microsomal enzyme inducers. We propose that the glucuronidation of T(3) might be the reason serum TSH is increased by some microsomal enzyme inducers but not by others. Male Sprague-Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), PCN (at 200, 400, 800, or 1600 ppm), 3MC (at 50, 100, 200, or 400 ppm), or PCB (at 25, 50, 100, or 200 ppm) for 7 days; and T(4) and T(3) UDP-GT activities were then determined. T(4) UDP-GT activity was increased in rats treated with PB (120%), PCN (250 to 400%), 3MC (400 to 600%), or PCB (300 to 430%). In contrast, T(3) UDP-GT activity was increased in rats treated with PB (90%) or PCN (120 to 200%), whereas 3MC and PCB treatments did not have an appreciable effect. In conclusion, differential effects on T(3) glucuronosyltransferase activity were found in rats treated with microsomal enzyme inducers.     

Thyroid status in senile dementia of the Alzheimer type (SDAT)

Thyroid function was investigated in a group of 21 patients with severe senile dementia of the Alzheimer type (SDAT) and in a group of 17 age and sex matched normal controls. Free thyroid hormone levels (triiodothyronine (T3) and thyroxine (T4) were measured, as were also the thyrotrophin (TSH), prolactin (PRL) and growth hormone (GH) responses to thyrotrophin releasing hormone (TRH)). When compared to controls, patients demonstrated a significantly lower free T3 value (but not free T4), a blunted TSH response to TRH, slightly elevated basal PRL and GH values and a small GH response to TRH. However, all differences were small in biological terms and were within the laboratory's normal range. This emphasizes the relative normality of neuroendocrine function, particularly thyroid status, in SDAT.     

Influence of free thyroid hormone levels on the TSH response to TRH in endogenous depression

The TSH response to TRH (Δ_maxTSH) and the serum concentrations of free thyroxine (FT₄), 3,5,3′-, and 3,3′,5′-triiodothyronine (FT₃, and FrT₃) were studied in two groups of patients with endogenous depression before and after clinical recovery following electroconvulsive treatment (ECT). Before ECT, the patients from group 1 (n = 17) had a reduced Δ_maxTSH (p < 0.01), which after ECT rose to values not different from those found in controls. FT₄ levels were elevated before ECT (p < 0.01), and they decreased after ECT (p < 0.05) to levels similar to those found in controls. FT₃ and FrT₃ levels were not different from the control values, but FrT₃ decreased during ECT (p < 0.01). In group 2 (n = 19), Δ_maxTSH was reduced both before (p < 0.02) and after (p < 0.01) ECT. FT₄ levels were increased both before and after ECT (p < 0.02). Both parameters were unaffected by ECT.

The data are compatible with the assumption that the decreased TSH response to TRH found in patients with endogenous depression is secondary to an increase in circulating FT₄.     

Effect of flunarizine on pituitary secretion by healthy men and in woman with migraine

Summary Flunarizine is widely used in the prophylaxis of migraine. It is both a calcium blocker and a histamine antagonist at H₁-receptors and either of these effects could alter hormonal secretion. The effect of administration of flunarizine to 8 women with common migraine on pituitary secretion has been studied. The dopamine antagonist domperidone (10 mg) and gonadotropin releasing hormone (100 µg) were injected iv before and after one month of flunarizine therapy (10 mg orally at bed-time).The basal prolactin level was significantly increased by the drug, and the peak induced by domperidone stimulation was reduced. Basal TSH concentrations were not affected, but the increase after domperidone was blunted.After 90 days of therapy there were no significant differences from the baseline concentration. Neither basal nor gonadotropin releasing hormone — stimulated secretion of FSH and LH were affected by flunarizine. Twelve healthy men were given placebo and flunarizine (10 mg at bedtime) for 5 days in single-blind fashion. Flunarizine caused a significant increase in prolactin and TSH with no effect on basal gonadotropin and thyroid hormone levels.These results can be accounted for by the calcium blocking effect of the drug, although weak interference with dopaminergic transmission is a further possibility explanation.     

Low headache prevalence amongst women with high TSH values

The aim of this large cross‐sectional population‐based study was to examine a possible positive or negative association between thyroid dysfunction and headache. Between 1995 and 1997, all 92 566 adults in Nord‐Trøndelag County in Norway were invited to participate in a health survey. A total of 51 383 (56%) responded to a headache questionnaire, whereof thyroid‐stimulating hormone (TSH) was measured in 28 058 individuals. These included 15 465 women and 8019 men above 40 years of age, 1767 randomly selected individuals between 20 and 40 years of age, and 2807 (97%) with thyroid dysfunction. Associations between thyroid dysfunction and headache were assessed in multivariate analyses, estimating prevalence odds ratios (OR) with 95% confidence intervals (CIs). High TSH values were associated with low prevalence of headache. This was most evident amongst women with no history of thyroid dysfunction. Amongst these, headache was less probable (OR=0.5, 95% CI 0.3–0.7) if TSH ≥ 10 mU/l than in women with normal TSH (0.2–4 mU/l). In all age groups between 40 and 80 years, TSH was lower amongst headache sufferers, especially migraineurs, than in those without headache complaints.