N-acetyltransferase activity in the Harderian glands of the Syrian hamster, Mesocricetus auratus, is regulated by androgens and by hormones of the pituitary-thyroid axis

This study tested the hypothesis that activity of the enzyme N-acetyltransferase (NAT) in the Harderian gland of the Syrian hamster is regulated both by androgens and by hormones of the pituitary-thyroid axis. To test the effects of castration and hypothyroidism, intact or castrated male hamsters were given either tap water or methimazole in their drinking water for 3 weeks. Methimazole suppresses iodination of thyroglobulin, thereby decreasing circulating levels of thyroid hormones and increasing TSH levels. Hypothyroidism or castration caused elevated or depressed Harderian gland NAT activities respectively, compared with euthyroid controls. When castration and hypothyroidism were combined, the animals exhibited high NAT activity compared with castrated euthyroid males. To test the effects of castration and hyperthyroidism, male hamsters were given daily injections of thyroxine (T4) or diluent and were either castrated or left intact for 4 weeks. Intact animals given T4 had depressed Harderian NAT activity; serum thyroid hormone levels were elevated and TSH levels were depressed compared with those of intact controls. Castrated animals had depressed NAT activity below that of intact controls; serum thyroid hormone levels were normal but TSH levels were depressed. Castrated animals given T4 injections had NAT activity similar to that of euthyroid castrated hamsters; thyroid hormone levels were elevated but TSH levels were similar to those seen in euthyroid castrated hamsters. In another experiment, both T4 and tri-iodothyronine (T3) were equally effective in decreasing NAT activity in intact males. To determine the effects of the removal of pituitary influences, male hamsters were hypophysectomized. NAT activity in the Harderian glands of these animals was reduced compared with intact controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal thyroid function tests in children on ethionamide treatment

Ethionamide (ETH) treatment may cause hypothyroidism. Clinical data, serum thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were retrospectively assessed in 137 children receiving anti-tuberculosis treatment including ETH. Abnormal thyroid function tests (TFTs) were recorded in 79 (58%) children: elevated serum TSH and suppressed fT4 (n = 30), isolated elevated serum TSH (n = 20), isolated low serum fT4 (n = 28) and isolated low TSH (n = 1). The risk for biochemical hypothyroidism was higher for children on regimens including para-aminosalicylic acid and in human immunodeficiency virus infected children. TFT abnormalities are frequent in children on ETH and are mainly due to primary hypothyroidism or euthyroid sick syndrome.     

Thyroid hormone in hypopituitarism,Graves’ disease,congenital hypothyroidism,and maternal thyroid disease during pregnancy

Although measurement of serum thyroid-stimulating hormone (TSH) is the single best test to diagnose thyroid disorders and monitor treatment, there are certain situations in which the TSH level cannot be used as a guideline. In the diagnosis of children with hypopituitary hypothyroidism, TSH is often “inappropriately” normal. Treatment is aimed at adjusting the l-thyroxine dose to maintain the serum free thyroxine (T4) in the upper half of the normal range for age. In children with Graves’ disease, serum TSH can be suppressed for several months after a euthyroid state is restored, so the clinician must rely on serum free T4 and triiodothyronine (T3) levels. Up to 30% of infants and 10% of children with congenital hypothyroidism have a mildly elevated TSH level despite other indications that the thyroid hormone dosage is correct. Such resistance to thyroid hormone at the pituitary gland diminishes with age. Pregnancy is another condition in which serum TSH levels are altered (slightly lower); in this situation, it is the result of elevated human chorionic gonadotropin levels that cross-react with the TSH receptor. This alteration must be taken into account when diagnosing or treating maternal thyroid disorders during pregnancy.     

Inhibition of TSH activation of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness?

Thyroidal economy in systemic nonthyroidal illness (the sick euthyroid syndrome) is marked by reductions in both thyroid function and peripheral T4 to T3 conversion, presumed to reflect a homeostatic mechanism to conserve energy. TSH levels tend to be normal in these patients, and the mechanism underlying reduced thyroidal secretion is unknown. Since increased blood levels of tumor necrosis factor (TNF) are found in many of the conditions associated with the sick euthyroid syndrome, we hypothesized that TNF might affect the function of the thyroid gland. We, therefore, explored the effects of TNF on TSH stimulation of the thyroid, employing a human thyrocyte cell culture model. Cells were incubated with various concentrations (0-1000 pg/mL) of recombinant human TNF-alpha and bTSH (1 mU/mL), with measurement of secreted thyroglobulin (Tg) and cyclic AMP (cAMP) as the end points of stimulation. TNF had no effect on either basal or TSH-stimulated cAMP generation, but significantly blunted TSH-stimulated Tg secretion. No loss of cell viability and growth was observed based on trypan blue exclusion and thymidine incorporation by cells. These studies demonstrated an inhibitory effect on TNF on human thyrocytes in concentrations comparable to blood levels seen in humans during systemic illness. We conclude that increases in serum TNF may be responsible for reduced thyroid function in patients with the sick euthyroid syndrome.     

Effect of endogenous thyroid stimulating hormone levels on the secretion of thyroid hormones in man.

The effect of endogenous thyroid stimulating hormone (TSH) on the thyroid secretion of triiodothyronine (T3) and thyroxine (T4) was evaluated by serial determinations of serum T3. T4 and TSH concentrations in the following groups of patients: a) three patients submitted to surgical removal of a solitary, autonomous thyroid nodule which had completely inhibited the extranodular tissue; b) five subjects, with the same disease, in whom functional recovery of the extranodular tissue was induced by increased circulating TSH levels, produced by treatment with methimazole; c) one patient submitted to hemithyroidectomy for multinodular goitre; d) two hyperthyroid patients who had been treated with methimazole. In all these patients serum T3 and T4 levels progressively decreased, with a consequent progressive increase in serum TSH concentrations, leading to stimulation of the thyroid gland. During this TSH-induced stimulation of thyroid tissue, a significant positive correlation was found between the serum TSH concentrations and the corresponding ratio between the serum levels of T3 and T4 (T3/T4), both within each patient group (P less than 0.001) and among all patients (P less than 0.001). The same correlation also governs the relationship between the TSH and the T3/T4 values of 34 euthyroid control subjects and one patient with incipient hypothyroidism. These data strongly suggest that endogenous TSH can induce a preferential secretion of T3 over T4 by the human thyroid.     

Thyroid resistance to TSH complicated by autoimmune thyroiditis

In this report we describe a 47-yr-old woman who was referred to our department for elevated serum TSH associated with normal free thyroid hormone levels, suggesting subclinical hypothyroidism. When first seen she was clinically euthyroid, and her thyroid gland was normal in size both at palpation and by ultrasound. The ultrasound of the thyroid showed a normoechogenic pattern. Serum thyroid hormone levels were confirmed to be within the normal range, whereas the serum TSH concentration was moderately elevated (13.4 microU/ml). Tests for antithyroperoxidase, antithyroglobulin, and anti-TSH receptor antibodies gave negative results. The only son of the proband, a clinically euthyroid 23-yr-old man, had a slightly elevated serum TSH concentration (5.2 microU/ml) with normal free thyroid hormone levels. The entire coding regions of the TSH receptor gene were sequenced in the proband, the son, and the father of the son. Genetic analysis in the proband showed a homozygous inactivating mutation of the TSH receptor. The mutation consisted of the substitution of an alanine in place of proline at position 162 in the extracellular portion of the receptor. The son was heterozygous for Pro(162)Ala. Only the wild-type sequence was found in the father. Both the proband and her son were considered to have compensated TSH resistance and were not treated. After 2 yr of follow-up, new thyroid tests were performed in the proband and showed a marked increase in the serum TSH concentration (61 microU/ml) compared with the initially observed value; serum free T(4) and T(3) levels were in the low normal range. At that time, tests for antithyroglobulin and antithyroperoxidase antibodies gave positive results, and thyroid echography showed a gland of normal size, but with a diffuse hypoechogenic pattern. In conclusion, we describe the first case of compensated TSH resistance evolving to mild hypothyroidism due to the appearance of a chronic autoimmune thyroiditis.     

Dopamine and the sick euthyroid syndrome in critical illness

OBJECTIVE The Sick euthyroid syndrome is a poorly understood hallmark of critical illness. Dopamine is a natural catecholamine with hypophysiotrophic properties, that is used as an inotropic agent of first choice in intensive care medicine. We explored the effect of dopamine infusion (5μg/kg/min) on the sick euthyroid syndrome of critically ill patients. PATIENTS AND DESION In a prospective, randomized, controlled and open-labelled study of critically ill, adult polytrauma patients (n= 12), we evaluated the effect of prolonged (83–296 hours) dopamine Infusion (5 μg/kg/min i.v.) on the thyroid axis. The effect of brief (15–21 hours) dopamine administration was documented in an additional randomized, controlled, cross-over study involving 10 patients. The median age of the studied patients was 29 (16–83) years. MEASUREMENTS Serum TSH concentrations were measured by IRMA. The TSH profiles were obtained by blood sampling every 20 minutes for 9 hours during two consecutive nights. Serum T4, T3 and reverse T3 concentrations were measured by RIA once per study night. RESULTS Withdrawal of prolonged dopamine infusion was found to elicit a tenfold increase of serum thyrotrophin concentrations, a 57 and 82% rise of T4 and T3 respectively, and an Increase of the T3/rT3 ratio, resulting in virtual normalization of the thyroid axis within 24 hours. The brief dopamine infusion was documented to have a suppressive effect on the thyroid axis within 24 hours. CONCLUSIONS Dopamine infusion appears to induce or aggravate the sick euthyroid syndrome in critical illness. As a consequence, the sick euthyroid syndrome of severely ill patients receiving dopamine may be not an adaptive mechanism, but a condition of latrogenic hypothyroidism.     

Changes in circulating thyroid hormone levels and systolic time intervals in acute hypothyroidism

OBJECTIVE: We have previously reported that, in thyrotoxic patients treated with carbimazole, serum T4 and T3 levels are the first parameters to return to normal, followed by the systolic time interval (STI, a marker of thyroid function at tissue level) and then the serum TSH. The aim of this study was to compare the rate of change of thyroid hormones, TSH and STI in treated hypothyroid patients after the sudden withdrawal of thyroxine. DESIGN AND PATIENTS: Serum T4, T3 (free and total) and TSH were measured in 12 patients taking thyroxine for primary hypothyroidism; seven were biochemically euthyroid and five were over-replaced, as defined by an elevated free T4 and a sub-normal TSH. Thyroxine was withdrawn and the measurements repeated three times a week until the STI rose above the euthyroid range (0.26-0.32). RESULTS: After stopping thyroxine, the serum TSH and STI left the normal range, in advance of the free T4 and T3, after 9.5 +/- 0.95 and 12.2 +/- 1.5 days respectively (mean +/- SEM). The TSH was the first parameter to leave the euthyroid range in all subjects except one in whom the serum TSH was fully suppressed (less than 0.05 mU/l) initially. In the euthyroid group the TSH and STI increased rapidly after stopping thyroxine (time to leave euthyroid range 7.4 +/- 0.8 and 9.4 +/- 0.7 days respectively). In contrast, in the over-replaced group serum TSH and STI became elevated after 12.4 +/- 1.0 days (P less than 0.005 vs euthyroid group) and 16.0 +/- 2.7 days (P less than 0.05 vs euthyroid group) respectively. There was no delay in the fall in serum T4 or T3 in the over-replaced group when compared with the euthyroid group. CONCLUSIONS: In the evolution of primary hypothyroidism, markers of thyroid function at a tissue level (TSH and STI) become abnormal in advance of thyroid hormones. After stopping thyroxine therapy in treated hypothyroid patients, there is a delayed rise in STI and serum TSH levels in subjects with a subnormal TSH level, as compared with those with a normal TSH on treatment. This suggests mild tissue thyrotoxicosis in these individuals.     

Thyroid hormone indices during illness in six hypothyroid subjects rendered euthyroid with levothyroxine therapy.

PURPOSE: We wanted to evaluate changes in the natural course of serum thyroxine (T4), tri-iodothyronine (T3), reverse tri-iodothyronine (rT3), and thyroid stimulating hormone (TSH) concentrations during hospitalization for an acute illness, in subjects rendered euthyroid with Levothyroxine (LT4) replacement therapy. METHODS: Six male subjects ranging in age 30 - 65 years with a history of primary hypothyroidism were included. They were euthyroid prior to hospitalization. LT4 continued to be administered orally in the same pre-admission daily dose. Serum, T4, T3, rT3, and TSH concentrations were determined on day of admission to the intensive care unit (ICU) for an acute illness. These were repeated during the first week on alternate days and again during a follow-up visit 1 week after discharge. Student's t-test, analysis of variance, and linear regression were used to analyze the data. RESULTS: Serum T4, T3 declined to a nadir and serum rT3 rose to its peak by day 3 of hospitalization before returning to pre admission euthyroid levels. Serum TSH declined initially but rose to supernormal levels on day 7 before normalization. Significant correlations were noted between TSH on one hand and T3/T4 (r = 0.76, p < 0.001) and rT3/T4 (r= - 0.64, p < 0.001) ratios. CONCLUSIONS: Alterations ensuing during a short stay in the hospital due to an acute illness in subjects with primary hypothyroidism rendered euthyroid with appropriate replacement therapy with Levothyroxine (LT4) are almost identical to those in normal subjects. These changes are probably secondary to altered thyroid hormone metabolism. The altered levels of thyroid hormones and TSH noted in these subjects are transient and therefore providers should refrain from initiating frequent changes in daily LT4 replacement dose during the acute illness in these subjects.     

Structural analysis of the thyrotropin receptor in four patients with congenital hypothyroidism due to thyroid hypoplasia.

Sporadic congenital hypothyroidism is most commonly caused by developmental abnormalities of the thyroid gland. More rarely, it is due to defects in gene products involved in the regulation of the hypothalamic-pituitary-thyroid axis or thyroid hormone synthesis. Loss of function mutations in the thyrotropin (TSH) receptor have been shown to result in resistance to biologically active TSH. In complete resistance to TSH, the thyroid gland is hypoplastic and unable to synthesize and secrete sufficient amounts of thyroid hormones. In partial resistance, referred to as euthyroid hyperthyrotropinemia, the size of the gland and the thyroid hormone levels are normal at the expense of an elevated TSH. Four patients with sporadic congenital hypothyroidism and properly located hypoplastic thyroid glands were included in this study. Serum TSH concentrations were 150 mU/L or higher, serum thyroglobulin levels were within normal limits (6.1 to 8.2 ng/mL; normal range: 2.1 to 32 ng/mL), and thyroid autoantibodies were absent. The coding region of the TSHbeta subunit gene, the TSH receptor gene, and exons 8 and 9 of Gsalpha were analyzed by direct sequencing and found to be normal in all patients. One patient was heterozygous for a G to A transition in the TSHbeta gene resulting in a substitution of alanine by threonine at position -7 of the signal peptide. This substitution was also found in her euthyroid father. In addition, Southern analysis of the TSH receptor gene excluded major structural alterations. These findings support previous reports that indicate that TSH resistance is genetically heterogeneous. In addition to mutations in the TSH receptor or the Gsalpha genes, other genetic defects can lead to an identical phenotype. These observations also suggest that TSH receptor mutations might be a relatively rare cause of congenital thyroid hypoplasia.     

Natural course of autoimmune thyroiditis in Thai children

Forty-seven pediatric patients with autoimmune thyroiditis were followed for an average of 5.18+/-2.89 years. The diagnosis was based on a firm goiter and a positive test for antithyroid antibodies. Initially, 23 patients had euthyroidism, 11 overt hypothyroidism, 6 compensated hypothyroidism and 7 with low TSH. All patients had clinical euthyroidism, except two who had overt hypothyroidism. The thyroid function tests, the size of the thyroid gland and the thyroid antibodies were regularly evaluated. After the follow-up, 26 patients had untreated euthyroidism, 12 with overt hypothyroidism received eltroxin for maintenance of euthyroidism, while 4 had compensated hypothyroidism and 5 low TSH levels. All had clinical euthyroid. The thyroid size was reduced in 12 patients (26%) while 4 (9%) had normal-sized gland. The goiter size in 35 patients (74%) remained unchanged. The antithyroglobulin and antimicrosomal antibody titers fluctuated higher in patients with overt hypothyroidism. Eltroxin was given only to those having overt hypothyroidism with diminished goiter size in 8 patients (73%).     

Familial thyroid hormone resistance

Eight patients with thyroid hormone resistance were found in four generations of a kindred containing 19 members. Results of studies in this family are consistent with an autosomal dominant mode of inheritance for this disorder. The affected family members were clinically euthyroid but all had goiters and markedly increased serum thyroid hormone levels: thyroxine (T4) = 21.1 +/- 2.1 microgram/dl; triiodothyronine (T3) = 323 +/- 60 ng/dl; free T4 = 5.4 +/- 0.9 ng/dl; and free T3 = 1,134 +/- 356 pg/dl (mean +/- SD). Serum thyrotropin (TSH) levels were normal or slightly elevated in six patients and responded normally to the administration of thyrotropin-releasing hormone (TRH) and L-triiodothyronine. Two patients who had previously undergone subtotal thyroidectomy had elevated baseline serum TSH levels and exaggerated TSH responses to the administration of TRH suggesting subclinical hypothyroidism despite elevated total and free thyroid hormone levels. The absence of thyrotoxicosis and normal serum TSH levels despite elevated serum free T3 and T4 levels in the untreated members of this family are consistent with resistance of pituitary and peripheral tissues to the actions of thyroid hormones. In addition, the absence of hypothyroidism and normal responsiveness of serum TSH to TRH and L-triiodothyronine administration in untreated family members suggest that the thyroid has compensated for the hormone resistance by increased secretory activity under the control of pituitary TSH secretion.     

Leptin and the pituitary-thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects

OBJECTIVE: To study interactions between leptin and the pituitary-thyroid axis, both in euthyroid and dysthyroid states. SUBJECTS AND MEASUREMENTS: We investigated the relationships of plasma leptin to levels of free thyroid hormones and TSH in 18 patients with newly diagnosed hyperthyroidism, 22 with newly diagnosed primary hypothyroidism, and 32 lean (body mass index [BMI] < 30) and 37 obese (BMI > 30 kg/m2) euthyroid subjects. Hypothyroid patients were restudied during thyroxine replacement treatment. RESULTS: Median [interquartile range] plasma leptin concentrations were highest in obese euthyroid subjects (31.5 [19.0-48.0] and in untreated hypothyroid patients (19.2 [11.5-31.5]), and lowest levels in untreated hyperthyroid patients (8.9 [5.5-11.1]) and lean euthyroid control subjects (6.6 [3.9-14.4] micrograms/l (Kruskall-Wallis one-way analysis of variance; P < 0.0001). In euthyroid subjects, plasma leptin levels were higher in obese than in lean subjects (P < 0.00001). In obese subjects plasma levels of TSH correlated with percentage body fat (r = 0.67; P < 0.001) and plasma leptin (r = 0.61; P < 0.001). In untreated hyperthyroid subjects plasma leptin was unrelated to free T3, and in untreated hypothyroidism plasma leptin was unrelated to either free T3 or TSH concentrations (all P = NS). In untreated hyperthyroid, but not hypothyroid, patients plasma leptin concentrations correlated with BMI (r = 0.57; P = 0.02). Treatment of hypothyroidism with thyroxine resulted in a significant reduction in plasma leptin concentrations from 20.8 (11.8 to 31.6) to 12.9 (4.6-21.2) micrograms/l (P = 0.005), but BMI did not change significantly in the hypothyroid subjects being studied prospectively. CONCLUSIONS: (i) In euthyroid subjects, plasma leptin and TSH levels correlate, and both are positively correlated with adiposity. (ii) Plasma leptin was significantly elevated in hypothyroid subjects, to levels similar to those seen in obese euthyroid subjects. (iii) Treatment of hypothyroidism resulted in a reduction in the raised plasma leptin levels. The data are consistent with the hypothesis that leptin and the pituitary-thyroid axis interact in the euthyroid state, and that hypothyroidism reversibly increases leptin concentrations.     

The site of the molecular defect in the thyroid gland of the hyt/hyt mouse: abnormalities in the TSH receptor-G protein complex.

The hyt/hyt mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T4, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the hyt/hyt thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the hyt/hyt thyroid gland. In order to evaluate the potential site of the defect in the hyt/hyt mouse, we have studied the hyt/hyt gland and hyt/hyt TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of hyt/hyt serum in the McKenzie bioassay, this reduced responsiveness to TSH in the hyt/hyt mouse is not due to reduced bioactivity of hyt/hyt TSH or a major structural abnormality in the hyt/hyt TSH molecule. In comparison to hyt/ + euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the hyt/hyt mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However, hyt/hyt cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE1, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the hyt/hyt thyroid gland. Specifically, these findings suggest that the hyt/hyt mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the hyt/hyt gland makes T3 and T4 but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both hyt/hyt and euthyroid hyt/ + littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the hyt/hyt thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the hyt/hyt thyroid gland may underlie the significant decrease in thyroid hormone production by the hyt/hyt mouse.     

Thyroid function in humans with morbid obesity.

Morbidly obese subjects may present with abnormal thyroid function tests but the reported data are scarce. Therefore, we studied the thyroid parameters in 144 morbidly obese patients, 110 females and 34 males, to assess the prevalence of hypothyroidism. Eleven percent (11.8%) carried the diagnosis of hypothyroidism and were undergoing levothyroxine (LT4) replacement therapy, 7.7% had newly diagnosed subclinical hypothyroidism, 0.7% had subclinical hyperthyroidism and 7.7% were euthyroid with positive antibodies (anti-thyroid peroxidase antibodies [TPOAb]). From the 144 subjects, we selected a cohort of 78 euthyroid subjects with negative TPOAb, who did not receive LT4 replacement or suppression therapy (the experimental group) and compared them to 77 normal-weight euthyroid subjects, TPOA-negative, matched for age and gender who served as controls. The experimental group had higher serum levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and thyrotropin (TSH) compared to the control group. Serum TSH concentration was associated with fasting serum insulin levels and insulin resistance but not with serum leptin levels, body mass index (BMI), fat mass, and lean body mass. In conclusion, in morbidly obese individuals, the prevalence of overt and subclinical hypothyroidism was high (19.5%). The morbidly obese subjects have higher levels of T3, FT3, T4, and TSH, probably the result of the reset of their central thyrostat at higher level.     

Do iodine-containing contrast media induce clinically relevant changes in thyroid function parameters of euthyroid patients within the first week?

Little is known about the reaction of normal thyroid glands to the iodine load given by x-ray dyes. We have therefore investigated the short-term effects of high doses of iodine on thyroid parameters in euthyroid patients. We measured free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) serum concentrations before and daily for 1 week after parenteral application of x-ray dyes (coronary angiography: n = 16; computed tomography [CT] of either thorax or abdomen: n = 6; iodine dose range from 300-1221 mg of iodine per kilogram). Inclusion criteria were as follows: normal FT4, normal TSH, negative thyroid antibodies, urinary iodine excretion below 30 microg/dL, no palpable goiter and no euthyroid sick syndrome. All but one patient reacted with a TSH increase. Mean TSH values increased significantly 3-5 days after the iodine load within the normal range. Four patients (18%) had a TSH increase above normal, the maximal observed value being 6.4 microU/mL. Basal TSH values of these four patients were above 2 microU/mL. The day peak TSH concentrations were reached varied from day 1 to day 7, the majority (32%) having the peak on day 3. Peak TSH was significantly correlated with basal TSH values (r = 0.794, p < 0.0001). FT4 and FT3 remained unchanged and there was no significant correlation between the dose of iodine and the TSH reaction. In conclusion, iodine-containing contrast media can induce transiently subclinical hypothyroidism even in euthyroid patients. The TSH reaction seems to depend on the preexisting state of thyroid function.     

The paraventricular nucleus of the hypothalamus has a major role in thyroid hormone feedback regulation of thyrotropin synthesis and secretion

The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.     

Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man

Tumor necrosis factor-alpha (TNF) is believed to be an important mediator in many diseases that are associated with the sick euthyroid syndrome. To investigate the effect of TNF on thyroid hormone metabolism, we performed a controlled study in six healthy postabsorptive males, in whom plasma thyroid hormones and TSH were sequentially measured after iv bolus injections of recombinant human TNF (50 micrograms/m2) and isotonic saline. During the 10.5-h study TNF produced the characteristic changes in circulating thyroid hormones and TSH observed in the sick euthyroid syndrome. Compared with the control experiment, TNF induced significant decreases in T3 (-36 +/- 2%; saline, -20 +/- 3%; P less than 0.05) and TSH levels (-68 +/- 3%; saline, -44 +/- 8%; P less than 0.05) and a significant increase in rT3 values (+48 +/- 11%; saline, -12 +/- 7%; P less than 0.05). T4 and free T4 index were not affected by TNF. Free T4 showed a mean transient increase of 18% in five subjects (nonsignificant), which occurred synchronically with a transient 3.5-fold rise in circulating FFA levels. Our results suggest that TNF is involved, either directly or indirectly, in the pathogenesis of the sick euthyroid syndrome.     

The influence of dexamethasone on serum thyrotrophin and thyrotrophin synthesis in the rat

Glucocorticoid hormones suppress circulating concentrations of thyrotrophin (TSH), but their effect on synthesis of TSH in the pituitary gland is unclear. We have examined the influence of the glucocorticoid dexamethasone on serum TSH, pituitary TSH content and TSH beta- and alpha-subunit mRNA concentrations in pituitary cytoplasm in both the euthyroid and hypothyroid rat, and following triiodothyronine (T3) treatment in the hypothyroid rat. The rise in serum TSH in hypothyroidism was attenuated in animals treated with dexamethasone; in addition the suppression of serum TSH 6 h after T3 administration to hypothyroid rats was enhanced by dexamethasone. In contrast to the changes in serum TSH, pituitary TSH content was unaffected by dexamethasone. Furthermore dexamethasone had no significant effect on changes in pituitary cytoplasmic TSH beta- and alpha-subunit mRNA levels with thyroid status. These findings demonstrate that dexamethasone exerts differential effects on serum TSH levels and TSH biosynthesis which contrast with those of thyroid hormones.     

AN ASSESSMENT OF PLASMA TSH RADIOIMMUNOASSAY AND OF THE TSH STIMULATION TEST IN THE DIAGNOSIS OF 100 CONSECUTIVE PATIENTS WITH SUSPECTED HYPOTHYROIDISM

A plasma TSH estimation and a TSH stimulation test were performed on each of 100 consecutive patients seen at a thyroid clinic in whom it was necessary to exclude a diagnosis of hypothyroidism. None of the patients had received replacement therapy. The normal response to 10 i.u. bovine TSH administered intramuscularly on three consecutive days was shown to be an absolute increment in the 4 hr uptake of ¹³²I by the thyroid gland of at least 13%. The mean plasma TSH in twenty-five untreated euthyroid patients, who had neither goitres nor thyroid antibodies, whose TSH stimulation tests were normal and in whom there was no evidence of hypopituitarism, was 3.8 μU/ml+3.6 (2 S.D.). All forty-nine patients with primary hypothyroidism had plasma TSH levels in excess of 25 μU/ml. In eighty-nine of the 100 patients, the radioimmunoassay of plasma TSH and the TSH stimulation test gave similar information about the reserve of thyroid function and in five euthyroid patients the plasma TSH was > 7.4 μU/ml while the TSH stimulation test was normal. The remaining six subjects (including one patient with hypopituitarism and three who had been treated with radioiodine for thyrotoxicosis) were euthyroid with an abnormal TSH stimulation test and a plasma TSH of <7.4 μU ml. For clinical purposes a plasma TSH of <7.4 μU/ml indicates a normal reserve of thyroid function, a plasma TSH between 7.4 and 25 μU/ml is equivocal, and a plasma TSH >25 μU/ml indicates an impaired or absent reserve of thyroid function with or without hypothyroidism. It is concluded that a single plasma TSH estimation should replace the time-consuming TSH stimulation test in the assessment of thyroid reserve.