We observed that the level of reverse triiodothyronine (rT3) was significantly increased after partial hepatectomy (PH) in both wild-type and constitutively active/androstane receptor (CAR) knockout (KO) mice, and treatment with phenobarbital (PB), a CAR activator, after PH decreased rT3 to restore its original level only in wild-type mice. On the other hand, no significant changes in the level of total T3 or free T3 in the serum were observed in either wild-type or CAR KO mice after PH or treatment with PB. Type 1 deiodinase (D1) activity and expression were significantly reduced by PH and up-regulated by PB in a CAR-dependent manner. In addition, known T3-regulated genes [tyrosine aminotransferase (TAT) and basic transcription element binding protein (BTEB)] were also significantly decreased by PH and induced by PB. Injection of rT3 into normal mice revealed that rT3 is capable of repressing the known thyroid hormone-regulated genes Tat, Bteb, and Cpt-1 in the liver. Our results suggest that PH decreases D1 activity leading to increased rT3 level, resulting in the repression of T3 target genes. Subsequent treatment with PB decreases rT3 in a CAR-dependent manner through the up-regulation of the D1 gene.

1. Eight women were studied under metabolic-ward conditions while consuming a constant diet throughout a single menstrual cycle. Basal body temperature, salivary and urinary hormone concentrations were used in monitoring the cycle and designing the study so that whole-body calorimetry for 36 h was conducted at four phases of the cycle in relation to the time of ovulation. 2. The metabolic rate during sleep showed cyclical changes, being lowest in the late follicular phase and highest in the late luteal phase. The increase amounted to 6.1 (SD 2.7)%. Energy expenditure (24 h) also increased but the change was not statistically significant (P greater than 0.05). Exercise efficiency did not change during the cycle. 3. There were no significant changes in plasma thyroxine, 3,5,3'-triiodothyronine or free 3,5,3'-triiodothyronine concentrations to explain the metabolic rate changes; nor did they relate to urinary luteinizing hormone, pregnanediol-3 alpha-glucuronide or oestrone-3-glucuronide excretion rates. No link with salivary cortisol or progesterone concentrations was observed, but there was a small inverse relation between the individual increase in sleeping metabolic rate and the subjects' falling ratio of urinary oestrone-3-glucuronide: pregnanediol-3 alpha-glucuronide.

Plasma levels of thyroid hormones - triiodothyronine (T 3 ), thyroxin (T 4 ), and thyroid-stimulating hormone (TSH) were measured in male and female rhesus monkeys (Macaca mulatta) fed either ad libitum or a 30 % calorie-restricted (CR) diet (males for 11 years; females for 6 years). The same hormones were measured in another group of young male rhesus monkeys during adaptation to the 30 % CR regimen. Both long- and shorter-term CR diet lowered total T 3 in plasma of the monkeys. The effect appeared to be greater in younger monkeys than in older counterparts. No effects of CR diet were detected for either free or total T 4, although unlike T 3, levels of this hormone decreased with age. TSH levels also decreased with age, and were increased by long-term CR diet in older monkeys only. No consistent effects of shorter-term CR diet were observed for TSH. In the light of the effects of the thyroid axis on overall metabolism, these results suggest a possible mechanism by which CR diets may elicit their well-known beneficial 'anti-aging' effects in mammals.

The arrhythmia profile and heart rate (HR) were analyzed by 24-hour Holter monitoring in 37 hyperthyroid patients before (triiodothyronine [T3] hormone level = 331 +/- 108 ng/dl), during (T3 level = 202 +/- 98 ng/dl) and after an antihyperthyroid therapy of 8 to 89 weeks' duration (T3 level = 149 +/- 41 ng/dl). The data were compared with those of 50 control subjects free from cardiac disease. Only 12 hyperthyroid patients (32%) had complex ventricular arrhythmias (Lown grade 3 or 4) as compared with 6 normal subjects (12%, p greater than 0.05). Three patients (8%) had repetitive ventricular arrhythmias (Lown grade 4A/B) as compared with 4 normal subjects (8%, p greater than 0.05). Supraventricular premature complexes occurred more often in hyperthyroid patients than in normal subjects before and after therapy (p less than 0.001). The prevalence of supraventricular tachycardia decreased from 8 patients to 1 during therapy (p less than 0.002). The HR decreased from 95 +/- 13 to 79 +/- 9 beats/min after therapy, but was still increased as compared with the normal subjects (72 +/- 8 beats/min, p less than 0.001). A day/night difference in HR greater than 10% was found in 32 patients (86%) and was more pronounced than in the normal group (p less than 0.001). Compared with the normal HR profile, the HR curve of hyperthyroid patients was shifted to a higher level (about 20 beats/min). Serum T3 level correlated best with HR at night in hyperthyroid patients (r = 0.74, p less than 0.001). Thus, hyperthyroid patients show frequent supraventricular arrhythmias that might be reversible during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

Various physiological changes occur in maternal thyroid economy during pregnancy. This review focuses on the events taking place during gestation that together strongly influence maternal thyroid function.

METHODS

Scientific reports on maternal thyroid physiology in pregnancy.

RESULTS

During the 1st trimester, human chorionic gonadotropin (hCG) induces a transient increase in free thyroxine (FT4) levels, which is mirrored by a lowering of thyroid-stimulating hormone (TSH) concentrations. Following this period, serum FT4 concentrations decrease of approximately 10 to 15%, and serum TSH values steadily return to normal. Also starting in early gestation, there is a marked increase in serum thyroxine-binding globulin (TBG) concentrations, which peak around midgestation and are maintained thereafter. This event, in turn, is responsible for a significant rise in total T4 and triiodothyronine (T3). Finally, significant modifications in the peripheral metabolism of maternal thyroid hormones occur, due to the expression and activity of placental types 2 and 3 iodothyronine deiodinases (D2 and D3, respectively).

CONCLUSIONS

In line with these variations, both free thyroid hormone and TSH reference intervals change throughout pregnancy, and most scientific societies now recommend that method- and gestation-specific reference ranges be used for interpreting results in pregnancy.The maternal iodide pool reduces during pregnancy because of increased renal clearance of iodine and transfer of iodine to the feto-placental unit. This results in an additional requirement of iodine during pregnancy of ~100% as compared to nonpregnant adults. In accordance, the recommended iodine intake in pregnancy is 250 μg/day. A daily iodine intake below this threshold poses risks of various degrees of thyroid insufficiency for both the mother and the fetus.

Automated immunoassays used to evaluate thyroid function are vulnerable to different types of interference that can affect clinical decisions. This review provides a detailed overview of the six main types of interference known to affect measurements of thyroid stimulating hormone (TSH), free thyroxine (T4) and free triiodothyronine (T3): macro-TSH, biotin, antistreptavidin antibodies, anti-ruthenium antibodies, thyroid hormone autoantibodies, and heterophilic antibodies. Because the prevalence of some of these conditions has been reported to approach 1% and the frequency of testing for thyroid dysfunction is important, the scale of the problem might be tremendous. Potential interferences in thyroid function testing should always be suspected whenever clinical or biochemical discrepancies arise. Their identification usually relies on additional laboratory tests, including assay method comparison, dilution procedures, blocking reagents studies, and polyethylene glycol precipitation. Based on the pattern of thyroid function test alterations, to screen for the six aforementioned types of interference, we propose a detection algorithm, which should facilitate their identification in clinical practice. The review also evaluates the clinical impact of thyroid interference on immunoassays. On review of reported data from more than 150 patients, we found that ≥50% of documented thyroid interferences led to misdiagnosis and/or inappropriate management, including prescription of an unnecessary treatment (with adverse effects in some situations), inappropriate suppression or modification of an ongoing treatment, or use of unnecessary complementary tests such as an I123 thyroid scan. Strong interaction between the clinician and the laboratory is necessary to avoid such pitfalls.

BACKGROUND

The long-term clinical effects of soy protein containing various concentrations of isoflavones on endogenous hormones are unknown.

OBJECTIVE

We examined the effects of ingestion of soy protein containing various concentrations of isoflavones on hormone values in postmenopausal women.

METHODS

Seventy-three hypercholesterolemic, free-living, postmenopausal women participated in a 6-mo double-blind trial in which 40 g protein as part of a National Cholesterol Education Program Step I diet was provided as casein from nonfat dry milk (control), isolated soy protein (ISP) containing 56 mg isoflavones (ISP56), or ISP containing 90 mg isoflavones (ISP90). Endogenous hormone concentrations were measured at baseline and at 3 and 6 mo.

RESULTS

The concentration of thyroxine and the free thyroxine index were higher in the ISP56 group, and the concentration of thyroid-stimulating hormone was higher in the ISP90 group than in the control group at 3 and 6 mo (P < 0.05). Triiodothyronine was significantly higher in the ISP90 group only at 6 mo. Thyroxine, free thyroxine index, and thyroid-stimulating hormone at 6 mo were inversely associated with measures of baseline estrogenicity. No significant differences were found for endogenous estrogens, cortisol, dehydroepiandrosterone sulfate, insulin, glucagon, or follicle-stimulating hormone after baseline hormone values were controlled for.

CONCLUSIONS

This study does not provide evidence that long-term ingestion of soy protein alters steroid hormone values, but it suggests that soy protein may have small effects on thyroid hormone values that are unlikely to be clinically important. The thyroid effects are, however, consistent with previous findings in animals and highlight the need for future research investigating possible mechanisms of action.

To determine the acute effect of calcium, we measured levothyroxine absorption after ingestion of thyroxine (T4) with and without simultaneous ingestion of calcium (as calcium carbonate) in seven volunteers without thyroid disease. Serum total T4, total triiodothyronine (T3), free T4, and thyrotropin (TSH) levels were measured after ingestion of 1,000 microg of levothyroxine on two separate visits at 4-week intervals: (1) levothyroxine alone and (2) levothyroxine together with 2.0 g of calcium as calcium carbonate. The amount of absorbed levothyroxine was calculated as the incremental rise in serum T4 level during the first 6 hours multiplied by the volume of distribution for the hormone. When 1,000 microg of levothyroxine alone was given to subjects, the maximum average total T4 absorption was 837 microg (83.7% of the dose ingested) at 120 minutes. When levothyroxine was coadministered with 2.0 g of calcium (as calcium carbonate), the maximum average T4 absorption decreased to 579 microg (57.9% of the dose ingested) at 240 minutes. The total levothyroxine absorption over 6 hours was significantly greater with thyroxine than that with thyroxine and calcium (p = 0.02). The administration of calcium and levothyroxine in these subjects was associated with a significant reduction in the peak increment in serum total T4 (p = 0.02) and free T4 levels (p = 0.03), as well as a significant reduction in the overall increment in serum total T4 (p = 0.003), free T4 (p = 0.002), and total T3 levels (p = 0.01) over four time points (120 minutes, 240 minutes, 360 minutes, 1,440 minutes). In summary, this pharmacokinetic study in seven volunteers indicates that calcium carbonate acutely reduces T4 absorption.

OBJECTIVE

Initial therapy of thyrotoxicosis usually includes beta-blockade for symptom relief and thionamides to block new thyroid hormone synthesis. In view of the increased enterohepatic circulation of thyroxine (T4) and triiodothyronine (T3) in thyrotoxicosis, we proposed that cholestyramine, an anion exchange resin which binds iodothyronines, when used adjunctively with thionamides and a beta-blocker, would lower serum iodothyronine levels faster than would standard therapy alone.

METHODS

A double blind placebo-controlled cross-over design was used with patients randomly assigned to either the treatment or control groups. They received their initial treatment for two weeks (Phase 1) followed by a one-week washout period, and then crossed to the opposite treatment for two weeks (Phase 2). Standard therapy included atenolol 50 mg daily, individualized dosages of methimazole and either 4 g of cholestyramine or 4 g of placebo powder four times per day.

METHODS

Fifteen patients with thyrotoxicosis (14 Graves' disease, 1 toxic adenoma) participated in this study.

METHODS

Total and free thyroxine and triiodothyronine, as well as thyroid-stimulating immunoglobulin and thyrotrophin-binding inhibitory immunoglobulin, were measured weekly.

RESULTS

Seven patients received cholestyramine and eight patients received placebo during Phase 1. A more rapid decline in all thyroid hormone levels was seen in the cholestyramine-treated group (F = 4-7, P < 0.01) than in the placebo group (F = 2-3.1, P = 0.05). In Phase 2, the eight patients who received cholestyramine showed an additional decline in free thyroxine from weeks one to two, but the overall rate of decline in hormone levels was not different between the groups. Immunoglobulin levels remained unaffected regardless of group, treatment, or time.

CONCLUSIONS

We conclude that cholestyramine is a safe and effective adjunctive agent in the treatment of thyrotoxicosis and that its greatest efficacy may be during the first few weeks of treatment.

Flux of amino acids across the leg was measured in malnourished cancer patients and three control groups: (a) malnourished patients without cancer; (b) well-nourished but acutely ill patients; and (c) well-nourished controls hospitalized for minor elective surgery. All patients were examined after an overnight fast, and some patients were reexamined 2 weeks later during enteral nutrition by gastric infusion of a formula diet. The efflux of amino acids did not differ qualitatively or quantitatively between malnourished cancer patients and malnourished patients without cancer. Well-nourished patients with acute illness had the greatest release of amino acids after an overnight fast. The leg efflux of amino acids did not correlate with plasma insulin levels in any of the patient groups, either in the fasting or in the fed state. Enteral nutrition decreased the efflux of amino acids from the leg in malnourished patients without cancer, but not in the malnourished cancer group. Enteral nutrition resulted in an increased peripheral uptake of energy precursors as glucose, free fatty acids, and the branched-chain amino acids. This was concomitant with increase in plasma level of triiodothyronine in malnourished patients without cancer. This study demonstrates that malnourished cancer patients do not differ from malnourished patients without cancer or from well-nourished patients after an overnight fast with respect to amino acid efflux from peripheral tissues, and thus shows normal adaptation for protein conservation. The results also suggest that conventional nasogastric tube-feeding was not sufficient alone to support normal replenishment of peripheral tissue in malnourished patients with and without cancer.

OBJECTIVE

Mutations in the selenocysteine insertion sequence binding protein 2 gene (SECISBP2 also known as SBP2) lead to a multisystemic disorder. Our objectives are to examine the clinical manifestations of the present patient and evaluate the effects of GH and triiodothyronine (T(3)) for longitudinal bone growth and maturation.

METHODS

A Japanese boy presented with unusual thyroid function tests (normal or slightly elevated TSH, low-normal or slightly decreased free T(3) (FT(3)), and elevated free thyroxine (FT(4))), short stature without GH deficiency, and delayed bone maturation. The entire coding region of the patient's SBP2 was analyzed. GH treatment was initiated when the patient was 4 years old, and combination therapy with GH plus T(3) was started when the patient was 10 years old. We monitored the patient's height and bone age until he was 11 years old.

RESULTS

The patient showed typical symptoms of SBP2 deficiency, and novel compound heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X). Six years of GH monotherapy improved the patient's height s.d. from -3.4 to -1.7 without accelerating bone maturation, whereas 6 months of T(3) treatment combined with GH almost normalized the thyroid function tests and improved both longitudinal bone growth and maturation.

CONCLUSIONS

In the growth plate, GH may compensate for decreased local T(3) effects on longitudinal bone growth; however, GH does not appear to compensate for the effects of T(3) on bone maturation. We believe that the present case has important implications for understanding the mechanism of thyroid hormone and GH on longitudinal bone growth and maturation.

BACKGROUND

Weight change affects resting energy expenditure (REE) and metabolic risk factors. The impact of changes in individual body components on metabolism is unclear.

OBJECTIVE

We investigated changes in detailed body composition to assess their impacts on REE and insulin resistance.

METHODS

Eighty-three healthy subjects [body mass index (BMI; in kg/m²) range: 20.2-46.8; 50% obese] were investigated at 2 occasions with weight changes between -11.2 and +6.5 kg (follow-up periods between 23.5 and 43.5 mo). Detailed body composition was measured by using the 4-component model and whole-body magnetic resonance imaging. REE, plasma thyroid hormone concentrations, and insulin resistance were measured by using standard methods.

RESULTS

Weight loss was associated with decreases in fat mass (FM) and fat-free mass (FFM) by 72.0% and 28.0%, respectively. A total of 87.9% of weight gain was attributed to FM. With weight loss, sizes of skeletal muscle, kidneys, heart, and all fat depots decreased. With weight gain, skeletal muscle, liver, kidney masses, and several adipose tissue depots increased except for visceral adipose tissue (VAT). After adjustments for FM and FFM, REE decreased with weight loss (by 0.22 MJ/d) and increased with weight gain (by 0.11 MJ/d). In a multiple stepwise regression analysis, changes in skeletal muscle, plasma triiodothyronine, and kidney masses explained 34.9%, 5.3%, and 4.5%, respectively, of the variance in changes in REE. A reduction in subcutaneous adipose tissue rather than VAT was associated with the improvement of insulin sensitivity with weight loss. Weight gain had no effect on insulin resistance.

CONCLUSIONS

Beyond a 2-compartment model, detailed changes in organ and tissue masses further add to explain changes in REE and insulin resistance.

Previous studies on thyroid hormones in hibernating bears have used very few sampling periods, so that the time course of any change is poorly understood. In this study, plasma sampled from pregnant and nonpregnant black bears before and during hibernation (16 samples each at 10-day intervals) was assayed by radioimmunoassay for concentrations of thyroxine (T4) and triiodothyronine (T3). Only free T4 showed a difference (P = 0.019) between females that produced cubs and those that did not, but this appeared to be due to higher preimplantation values. Free T3, total T3, and free T4 varied (P = 0.001, 0.038, 0.002, respectively) among sampling periods: during December, bears had depressed concentrations. These lowered concentrations were maintained during hibernation for the free hormones. Our data confirm previous work showing that food restriction and/or physiological preparation for hibernation is coincident with depressed plasma concentrations of thyroid hormones. Hormonal changes associated with pregnancy were minor.

Many clinically euthyroid patients with severe, chronic, non-throidal illnesses (i.e. sick euthyroid patients) have very low circulating concentrations of total and absolute free triiodothyronine (T3), low-normal concentrations of total thyroxine (T4), elevated concentrations of absolute free T4, and circulating concentrations of thyrotrophin (TSH) that are either normal or subnormal. This study was undertaken to elucidate the mechanism of the low circulating T3 concentrations. The disappearance rate of 125 I-T3 from the circulation of five representative sick euthyroid patients was studied and found to be slower, but not significantly so, compared with three control subjects, thus excluding an increased destruction rate as the cause of the low T3 levels. A selective decrease of T3 secretion from the thyroid gland of these patients was also excluded by the results of TSH stimulation tests. Inhibition of extra-thyroidal conversion of T4 to T3 was suggested by studies of the thyroid function in a hypothyroid woman with a Grade IV lymphoma on T4 replacement therapy. When the lymphoma was in remission, her circulating T3 concentration was 2-55 nmol/l but when it relapsed it fell to 0-55 nmol/l. The T4 concentrations were 124-7 nmol/l and 126 nmol/1 respectively. Decreased monodeiodination of T4 to T3 in sick euthyroid patients was confirmed by paper chromatography of extracted serum obtained 48 h after an i.v. injection of 125 I-T4 into two severely ill patients from the intensive therapy unit and a control subject. Peaks of radioactivity corresponding to 125 I-T4 and 125 I-T3 were detected in the control subject, but only a single peak corresponding to 125 I-T4 was detected in the ill patients.

To investigate cellular mechanisms involved in thyroid hormone stimulation of erythropoiesis, we studied the response of erythroid burst-forming unit (BFU-E) proliferation to L-triiodothyronine (L-T3) in a serum-free culture system. When added directly to culture, L-T3 stimulates erythroid burst formation by normal human bone marrow cells. In contrast, granulocyte-macrophage colony formation is unaffected. Enhancement of erythroid burst formation by L-T3 required the presence of nylon wool adherent and/or B-4 antigen-positive light-density marrow populations. Addition of other erythropoietic factors including platelet-derived growth factor and insulinlike growth factor II did not abrogate this apparent cellular requirement. Pulse exposure of marrow and peripheral blood mononuclear cells (greater than 95% lymphocytes) to L-T3 accelerates the release of a soluble factor that augments BFU-E proliferation into serum-free liquid culture medium. Time-course studies show that this factor appears in conditioned medium (CM) coincidentally with erythroid burst-promoting activity (BPA). Furthermore, incubation of CM with an antibody known to react with and adsorb BPA from solution removes the inducible mitogen. Biochemical analysis of CM prepared from unexposed and L-T3 pulse-exposed cells indicates that the rate of protein appearance is accelerated by L-T3 in a fashion that immediately precedes growth factor release and that several polypeptides are quantitatively increased. We conclude that unlike erythropoietin, which is mitogenic for progenitor cells directly, L-T3 enhances BFU-E proliferation indirectly by augmenting the release of soluble BPA-like molecules from accessory cells in culture.

OBJECTIVE

To test the hypothesis that, in older adults, living in a mildly iodine-deficient area, thyroid dysfunction may be associated with mortality independent of potential confounders.

METHODS

Longitudinal.

METHODS

Community-based.

METHODS

Nine hundred fifty-one individuals aged 65 and older.

METHODS

Plasma thyrotropin, free thyroxine, and free triiodothyronine concentrations and demographic features were evaluated in participants of the Invecchiare in Chianti Study aged 65 and older. Participants were classified according to thyroid function test. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis.

RESULTS

Eight hundred nineteen participants were euthyroid, 83 had subclinical hyperthyroidism (SHyper), and 29 had subclinical hypothyroidism (SHypo). Overt hypo- and hyperthyroidism were found in five and 15 subjects, respectively. During a median of 6 years of follow-up, 210 deaths occurred (22.1%), 98 (46.6%) of which were from cardiovascular causes. Kaplan-Meier analysis revealed higher overall mortality for SHyper (P = .04) than euthyroid subjects. After adjusting for multiple confounders, participants with SHyper (hazard ratio (HR) = 1.65, 95% confidence interval (CI) = 1.02-2.69) had significantly higher all-cause mortality than those with normal thyroid function. No significant association was found between SHyper and cardiovascular mortality. In euthyroid subjects, thyrotropin was found to be predictive of lower risk of all-cause mortality (HR = 0.76, 95% CI = 0.57-0.99).

CONCLUSIONS

SHyper is an independent risk factor for all-cause mortality in older adults. Low to normal circulating thyrotropin should be carefully monitored in elderly euthyroid individuals.

OBJECTIVE

To investigate the time course of thyroid function, factors that affect it, and its relationship to outcome in children surviving meningococcal septic shock.

METHODS

Observational cohort study in a university-affiliated pediatric intensive care unit (PICU).

METHODS

We divided the 44 children admitted to the PICU who survived meningococcal septic shock into those with short-stay (<7 days, n=33) or long-stay >>or=7 days, n=11).

RESULTS

Serum thyroid hormone concentrations were determined on PICU admission and after 24 and 48 h. The Pediatric Risk of Mortality score and selected laboratory parameters were used to assess disease severity. On admission all children showed signs of euthyroid sick syndrome: low total triiodothyronine (TT3) and high reverse triiodothyronine (rT3) without compensatory elevated thyrotropin (TSH). Admission rT3 levels and the TT3/rT3 ratio were correlated with C-reactive protein levels and with time from first petechia to admission. Short-stay children only had higher TT3 and lower interleukin 6 levels at admission than long-stay children; after 48 h they showed higher total thyroxin, free thyroxin, TT3, and TSH and lower rT3 than long-stay children. All changes in thyroid parameters within the first 24 h were related to length of PICU stay. In children receiving dopamine TSH levels and TT3/rT3 ratios remained unchanged, whereas both values increased in those who did not receive dopamine or in whom dopamine was discontinued.

CONCLUSIONS

All children surviving meningococcal septic shock showed signs of euthyroid sick syndrome on admission. Thyroid hormone level changes in the first 24 h were prognostic for length of PICU stay.

In this study we determined the time course of changes in body composition and of serum concentrations of some hormones in mature rats returning to "set point" following weight loss. Groups of six female rats were fed ad libitum for 10 days. Carcass composition of one group was determined. A control group continued to eat ad libitum. The others were restricted to 5 g per rat per day for 22 days. Carcass composition of groups of rats was determined after 0, 2, 6, 13 and 20 days of refeeding. Of 60 g of body weight lost during restriction, 21 g were fat and 12 g were protein. The fat was replaced by the sixth day of refeeding. Protein and body weight were recovered by the thirteenth day. Calculated efficiency of energy retention was increased until body fat was replete. This was not due to a decrease in metabolism of brown fat, measured in vitro. Serum thyroxine (T4), L-3,3',5'-triiodothyronine (rT3), insulin, corticosterone and free fatty acids did not change with body composition. T3 (L-3,3',5-triiodothyronine) decreased in restricted rats and returned to control levels when body weight, protein and food intake had been restored. These results do not support the concept that body weight is controlled by regulating body fat content.

Quantitative aspects and structure-activity relationships of the inducing effects of natural steroids on delta-aminolevulinic acid (ALA) synthase and porphyrins have been investigated in monolayer cultures of chick embryo liver cells maintained in a serum-free medium as well as in the chick embryo liver in ovo. Many 5 alpha and 5 beta metabolites of neutral C-19 and C-21 hormones and hormone precursors stimulated porphyrin formation and ALA-synthase induction in the cultured liver cells as we have previously described. In these inducing actions a number of 5 beta epimers (A:B cis) were found to be more potent than their corresponding 5 alpha epimers (A:B trans). The structure-activity relationship between 5 beta and 5 alpha steroid epimers with respect to ALA-synthase induction in culture was also found to prevail with respect to induction of this enzyme in chick embryo liver in ovo. Hemin in concentrations of 2 x 10(-7) M inhibited steroid induction of porphyrin formation, and CaMgEDTA enhanced the responsiveness of the cultured liver cells to steroids by approximately 10 times. The addition of insulin, or insulin plus hydrocortisone or insulin plus hydrocortisone plus triiodothyronine, was important for the maintenance of protein synthesis and essential for maximal expression of the ability of steroids to induce porphyrins and ALA-synthase in the "permissive" effect which insulin, hydrocortisone, and triiodothyronine exert on allylisopropylacetamide induction of porphyrins and ALA-synthase also extends to the induction process which is elicited by natural steroids. These findings also strongly suggest that the regulation of hepatic porphyrin-heme biosynthesis by endogenous as well as exogenous chemicals is significantly influenced by the internal hormonal milieu.

Angiotensinogen is regulated by both hormones and changes in cardiovascular and electrolyte status. We have used the Reuber H35 (H4IIE) rat hepatoma cell line to study the regulation of angiotensinogen mRNA levels by dexamethasone, aldosterone, L-T3, and 17 beta-estradiol. Using the Acc I (1097 basepairs) fragment of our angiotensinogen cDNA clone, we have studied, by Northern and slot blot analysis, the accumulation of angiotensinogen mRNA in this cell culture system. Angiotensinogen mRNA of approximately 1800 bases was identified in these cells. It was identical in size to angiotensinogen mRNA from rat liver. Cells grown in medium containing serum depleted of thyroid and steroid hormones for up to 72 h showed a progressive decrease in angiotensinogen mRNA. Dexamethasone treatment resulted in a time- and dose-dependent increase in angiotensinogen mRNA. The half-maximal response occurred at 10(-9) M dexamethasone, with a maximal response of approximately 4-fold (serum-free conditions). Aldosterone induced a dose-dependent increase in mRNA. Half-maximal levels were obtained at 5 X 10(-8) M. Competition studies using the glucocorticoid antagonist RU38486 (Roussel-UCLAF) confirmed that dexamethasone was acting through the glucocorticoid receptor and suggested that aldosterone was acting through the same receptor. L-T3 treatment caused a dose and time-dependent increase in angiotensinogen mRNA levels. The half-maximal response occurred at 5 X 10(-8) M, and the maximal response was a 2-fold increase. Combined treatment with dexamethasone and L-T3 triiodothyronine resulted in a synergistic increase in angiotensinogen mRNA levels. 17 beta-Estradiol failed to elicit a change in angiotensinogen mRNA levels consistent with the observation that these cells lack estrogen receptors. Our results indicate that hepatic angiotensinogen mRNA levels are regulated in a complex fashion by several hormones. These cells provide a useful system for studying the hormonal regulation of the angiotensinogen gene.

The benefits of using thyroxine (T4) plus triiodothyronine (T3) in combination in thyroid hormone replacement are unproven but many individuals continue to be treated with this regime. When T3 is used alone for hypothyroidism, it results in wide fluctuations of thyroid hormone levels. However, only limited data exists on combined T3/T4 therapy. In this study, we have compared 24-hour profiles of thyroid stimulating hormone (TSH), free T4 (fT4) and free T3 (fT3) and cardiovascular parameters in 10 hypothyroid patients who had been on once daily combined T3/T4 therapy for more than 3 months with 10 patients on T4 alone. Twenty patients, who were part of a larger study, investigating the long-term benefits of combined T3/T4 therapy, were recruited into this sub-study. Over 24-hours, 12 samples were taken for thyroid hormones. Their 24-hour pulse and BP is also monitored on a separate occasion. On T4 alone, a modest 16% rise in fT4 with no change in fT3 was seen in the first 4-hours post-dose. In contrast, on combined treatment, fT3 levels showed a marked rise of 42% within the first 4-hours post-dose (T3/T4:T4=6.24: 4.63 mU/L, p<0.001). Mean exposure to fT3 calculated by area under the curve (AUC) was higher (T3/T4:T4=1148:1062, p<0.0001) on T3. Circadian rhythm of TSH was maintained on both treatments. No difference in pulse or blood pressure over the 24-hours was seen between the groups. Our data suggests that despite chronic combined T3/T4 therapy, wide peak-to-trough variation in fT3 levels persists. Although no immediate cardiovascular effects were seen, the long-term consequences for patients on combined therapy are unknown.

Thyroid function tests were measured in 645 patients admitted to an acute psychiatric disorders unit. Thirty-three percent had elevated serum thyroxine (T4), and 18 percent had an elevated free T4 index (FTI). Serum triiodothyronine (T3) was low, normal, or minimally elevated in 77 patients, with a high initial free T4 index. Twenty-two patients with an initial elevation of their free T4 index were serially followed (study group). Serum T4, free T4 index, and free T4 fell in every patient: serum T4 from 13.95 +/- 1.93 micrograms/dl (mean +/- standard deviation: SD) to 9.33 +/- 2.4 micrograms/dl (p less than 0.001); free T4 index, from 6.15 +/- 0.83 to 3.79 +/- 1.1 (p less than 0.001); free T4, from 2.43 +/- 0.65 mg/dl to 1.38 +/- 0.35 ng/dl (p less than 0.001). Serum T3 was initially normal or low, and then fell in 17 patients, and rose in five. Serial testing of thyrotropin-releasing hormone (TRH) demonstrated both flat and normal responses in patients with a variety of psychiatric diagnoses and at varying stages of thyroid disease activity.

OBJECTIVE

Antiepileptic drugs (AEDs) may affect serum thyroid hormone concentrations. This study aimed to evaluate thyroid function in men taking carbamazepine (CBZ), oxcarbazepine (OCBZ), or valproate (VPA) for epilepsy.

METHODS

Ninety men with epilepsy (40 taking CBZ, 29 taking OCBZ, and 21 taking VPA monotherapy) and 25 control subjects participated in the study. After clinical examination, a blood sample for hormone, gamma-glutamyl-transferase (GGT) and antibody (ab) assays was obtained.

RESULTS

Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in men taking CBZ or OCBZ. Forty-five percent of men taking CBZ and 24% of men taking OCBZ had serum T4 and/or FT4 levels below the reference range. However, no correlations were found between T4 or FT4 and GGT concentrations in men taking CBZ or OCBZ. Thirteen percent of men taking CBZ, 17% of men taking OCBZ, and 6% of control men had increased levels of thyroid peroxidase (TPO)-ab and/or thyroglobulin (TG)-ab, but these were not associated with altered serum thyroid hormone concentrations. Serum triiodothyronine and thyrotropin levels in men taking CBZ or OCBZ were normal. In men taking VPA, the concentrations of thyroid hormones, thyrotropin, and antithyroid ab were normal.

CONCLUSIONS

Serum thyroid hormone concentrations are low in CBZ- or OCBZ-treated men. However, these low levels do not seem to be due to liver enzyme induction or activation of immunologic mechanisms. Therefore, interference with hypothalamic regulation of thyroid function by CBZ and OCBZ seems possible. VPA does not have any significant effects on thyroid function.

OBJECTIVE

It has been postulated that a decrease in thyroid size can be achieved by thyroxine treatment in patients with goitrous Hashimoto's thyroiditis but no objective data are available. We have therefore investigated the influence of thyroxine treatment on ultrasonically determined thyroid size. We also measured serum antithyroid peroxidase antibodies.

METHODS

Consecutive patients with goitrous Hashimoto's thyroiditis was studied.

METHODS

Thirteen women participated; all had goitrous thyroiditis.

METHODS

To render them euthyroid thyroxine was given for 24 months.

METHODS

Thyroid size was measured ultrasonically and antithyroid peroxidase antibodies were measured using a commercial radioimmunological method.

RESULTS

Concomitant with the gradual increase in serum free thyroxine and free triiodothyronine index values and a fall in serum thyrotrophin level, a gradual decrease in thyroid volume from 50.4 +/- 6.8 ml (mean +/- SEM) to 34.1 +/- 5.7 ml (32%), P less than 0.001 was demonstrated. Antithyroid peroxidase antibodies were present in high concentrations in all subjects but the mean serum level was not significantly changed at 24 months after initiation of treatment.

CONCLUSIONS

A clinically significant reduction in thyroid volume related to normalization of thyroid function but unrelated to changes in antithyroid peroxidase antibody can be achieved during L-thyroxine treatment of hypothyroid goitrous Hashimoto's thyroiditis.