Regulation of thyroid hormone metabolism in rat liver fractions.

The nature of the conversion of thyroxine (T4) to triiodothyronine (T3) and reverse triiodothyronine (rT3) was investigated in rat liver homogenate and microsomes. A 6-fold rise of T3 and 2.5-fold rise of rT3 levels determined by specific radioimmunoassays was observed over 6 h after the addition of T4. An enzymic process is suggested that converts T4 to T3 and rT3. For T3 the optimal pH is 6 and for rT3, 9.5. The converting activity for both T3 and rT3 is temperature dependent and can be suppressed by heat, H2O2, merthiolate and by 5-propyl-2-thiouracil. rT3 and to a lesser degree iodide, were able to inhibit the production of T3 in a dose related fashion. Therefore the pH dependency, rT3 and iodide may regulate the availability of T3 or rT3 depending on the metabolic requirements of thyroid hormones.     

Peripheral autoregulation of thyromimetic activity in man

This study describes an extrathyroidal mechanism for regulating serum concentration of triiodothyronine (T3) in thyroxine (T4) deficiency or excess. Serum levels of T3, T4, reverse T3 (rT3), and thyrotropin were determined in two series of athyreotic patients (n = 22 and n = 16, respectively) during various doses of T4 substitution therapy. The patients were followed from the severe hypothyroid state up to the modest hyperthyroid state, induced by stepwise increasing doses of administered T4. The periods of constant T4 replacement doses were 1 week (group I) and 5 weeks (group II), respectively. As serum T4 levels rose from less than 0.5 micrograms/dl to 18.9 micrograms/dl, serum T3 levels showed a curvilinear increase, which was pronounced in the very low T4 range while it was flattened at the higher end of the spectrum of T4 levels. As to rT3, an analogous course did not occur. The different character of the relationships between T4 and its conversion products was further elucidated by calculating the T3/T4 and rT3/T4 ratios. T3/T4 ratio declined fourfold from 43.3.10(-3) in the severe hypothyroid to 11.7.10(-3) in the hyperthyroid range. The results support the hypothesis of a peripheral autoregulation of T4 to T3 conversion which appears to be operative at both ends of the T4 spectrum and which serves to maintain or defend serum T3 levels.     

Effects of the infusion of glucagon on the blood levels of thyroid hormones

We have attempted to determine if mild hyperglucagonemia induced by exogenous glucagon infusion induces changes of serum thyroid hormone levels. Eleven healthy subjects, overnight fasting, received glucagon infusion (2 mg/90 min i.v.), whereas 5 healthy subjects (control group) received normal saline infusion. In the subjects infused with exogenous glucagon plasma glucagon concentrations increased from 130 +/- 24 pg/ml to 550 +/- 68 pg/ml at the end of infusion. At the same time no significant changes in serum T3, rT3 and T4 levels were found. A significant increase in serum rT3 levels was found 270 min after glucagon infusion withdrawal, whereas serum T4 levels remained unaltered during the whole period. Normal saline infusion failed to induce any variation in control group, however a late (at 6th hour) mild increase of serum rT3 in these subjects resulted comparable to the same increase of glucagon infused subjects. The results from this study suggest that mild increase in plasma glucagonemia, as found in patients with severe illness, does not induce a short-time significant lowering of serum T3 and a simultaneous rise of serum rT3 in normal subjects.     

Thyroid function tests in children with congenital hypothyroidism on L-thyroxine treatment

The plasma levels of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3) and immunoradiometrically assayed thyrotropin (IRMA TSH) have been measured in 28 L-T4-treated children with congenital hypothyroidism as well as in a control group (group C). The patients were subdivided into 2 groups according to the nonsuppressed (group A) or suppressed (group B) TSH response to TSH-releasing hormone (TRH). Basal IRMA TSH correlated with the TSH increment after TRH and it was significantly lower in group B vs. groups A and C, while no difference was present between groups A and B in regard to T4, FT4 and rT3, all higher than in group C. FT3 levels were similar in the 3 groups. In children, as in adults, basal IRMA TSH seems to be a reliable index in monitoring overtreatment.     

Effect of ethanol and linoleic acid on changes in biliary excretion of iodothyronines possibly related to thyroxine deiodination in rat liver

Groups of male rats weighing about 350 g were inserted polyethylene tubings into bile duct and femoral vein under pentobarbital anesthesia. Several iodothyronines (i.e. T4, T3, rT3, 3,5-T2, 3,3'-T2 and 3',5'-T2) were estimated in 2-hr portions of bile with the aid of specific radioimmunoassay. After the infusion of ethanol (0.3 ml/hr/rat for 4 hr) an increase of biliary excretion of rT3 and a decrease of 3,5-T2 was found as compared to controls. When 5 mg linoleic acid was added to 1.2 ml ethanol, the increase of rT3 was significantly higher than that after ethanol only and, in addition, significant increase of 3',5'-T2 excretion was found. It was concluded that both ethanol and unsaturated fatty acids may inhibit 5'-monodeiodination in the liver and that unsaturated nonesterified fatty acids may exert such effect even when administered intravenously without underlying metabolic disorders.     

Decreased ratio of serum T3:rT3 in patients with hyperthyroidism

In 14 hyperthyroid patient serum T4:rT3 ratio was significantly lower (399 +/- 20) than in the control subjects (572 +/- 20; p less than 0.001). A similar pattern was found for serum T3:rT3 ratio. In the hyperthyroid group the ratio was significantly lower (10.5 +/- 0.5) than in the control group (12.5 +/- 0.6; p less than 0.05). The data suggest that in hyperthyroidism the organism might shift conversion of T4 from biologically active T3 to poorly calorigenic rT3. It seems possible that the proportionately increased generation of rT3 than that of T3 may be a defence mechanism of the body, as it was found in systemic illnesses and starvation.     

Central stimulatory effect of leptin on T3 production is mediated by brown adipose tissue type II deiodinase

To assess whether intracerebroventricular leptin administration affects monodeiodinase type II (D2) activity in the tissues where it is expressed [cerebral cortex, hypothalamus, pituitary, and brown adipose tissue (BAT)], hepatic monodeiodinase type I (D1) activity was inhibited with propylthiouracil (PTU), and small doses of thyroxine (T4; 0.6 nmol. 100 g body wt(-1). day(-1)) were supplemented to compensate for the PTU-induced hypothyroidism. Two groups of rats were infused with leptin for 6 days, one of them being additionally treated with reverse triiodothyronine (rT3), an inhibitor of D2. Control rats were infused with vehicle and pair-fed the amount of food consumed by leptin-infused animals. Central leptin administration produced marked increases in D2 mRNA expression and activity in BAT, changes that were likely responsible for increased plasma T3 and decreased plasma T4 levels. Indeed, plasma T3 and T4 concentrations were unaltered by central leptin administration in the presence of rT3. The additional observation of a leptin-induced increased mRNA expression of BAT uncoupling protein-1 suggested that the effect on BAT D2 may be mediated by the sympathetic nervous system.     

TRH test in patients with diabetes mellitus type 1 and/or autoimmune thyroiditis. Changes in the pituitary-thyroid axis, reverse T3, prolactin and growth hormone levels

The response of the pituitary- thyroid axis, reverse triiodothyronine (rT3), prolactin, and growth hormone (GH) levels following TRH stimulus (Relefact TRH 200 microg 2 amp. i.v.) was examined in patients with autoimmune diabetes type 1 (DM1, n=30), with autoimmune thyroiditis (AT, n=25), and with concurrent DM1 and AT (n=22) to evaluate the influence of DM1 and AT of autoimmune pathogenesis on the above-mentioned hormonal parameters. Statistical analysis (ANOVA) showed that: a) the response of TSH did not differ from control groups (C); b) free triiodothyronine (fT3), free thyroxine (fT4) and their ratio in DM1, DM1+AT and C rose in 120 and 180 min, while a similar increase was not seen in AT (p<0.000001); c) rT3 was not present in any group, with rT3 levels higher in AT (p<0.00002) and lower in DM1 (p<0.02); d) the response of GH had a paradoxical character in some patients in all groups, most often in DM1 (52 %, DM1 vs C, p <0.01). The characteristic response difference was not in the peak GH level, but the delayed return to basal levels in DM1 (p<0.0001) and an abrupt one in AT (p<0.0001). The major findings in DM1 were the differences in GH response, while significant impairment of pituitary-thyroid axis and PRL response to TRH was absent. AT was associated with impairment of TRH stimulated fT3, fT4, fT3/fT4 response and changes in rT3 levels, in spite of preserved TRH-stimulated TSH secretion. GH response in AT patients was also altered.     

Bile secretory characteristics of beta-muricholate and its taurine conjugate are similar to those of ursodeoxycholate in the rat

Ursodeoxycholate (UDC) has very high biliary transport maxima values (Tm) for its conjugates as well as the capability of inducing choleresis rich in bicarbonate concentration in the bile in rats. We examined in the present study whether these properties are shared by beta-muricholate (beta-MC), using beta-MC, alpha-muricholate (alpha-MC) and tauro-beta-MC (T beta-MC) in the rat. Bile samples were collected every 20 min for 2 hr in male rats under the infusion of alpha- or beta-MC (1.2 mumol/min/100g). The choleretic response was quicker in beta-MC infused rats than in rats infused with alpha-MC. Bile salt excretion rates increased radically in both experiments. However, in beta-MC infused rats, the bile salt excretion rate began to decrease after 40 min, whereas in alpha-MC infused rats, it continued to increase after 1 hr. Bile bicarbonate concentration significantly increased in beta-MC infused rats but not in alpha-MC infused rats. The Tm of T beta-MC was 2 times higher than the Tm value for taurocholate and was comparable to that of tauroursodeoxycholate (TUDC) which was previously found by the authors. The bile flow (Y, microliter/min/100 g) was significantly correlated with the bile salt excretion rate (X, mumol/min/100 g) [Y = (6.90 +/- 0.24) X + (5.5 + 1.06), n = 41, -0.98, P less than 0.01)], the slope value being higher than that found for TUDC. The results suggest that UDC and beta-MC (and their conjugates) have very similar bile secretory characteristics and may probably share the same transport system in the rat.     

A study of hepatic metabolism of thyroxine in BB/W rats treated with L-thyroxine

The effect of thyroxine (T4) on T4 conversion to triiodothyronine (T3) and reverse T3 (rT3) was studied in BB/W rats. A colony of 38 BB/W rats was obtained and half were treated with thyroxine (T4), 1 mg per liter of drinking water. At 106 days of age the following groups were identified: nondiabetic, no T4 treatment, 8 rats; nondiabetic, T4 treated, 8 rats; diabetic, no T4 treatment, 10 rats; diabetic, T4 treated, 7 rats. All animals with diabetes were treated with insulin. T4 conversion to T3 and rT3 was assessed in liver homogenates in 0.1 M Tris-HCl buffer, pH 7.4, with or without 5 mM dithiothreitol (DDT). Serum T4 and rT3 were significantly elevated in both T4-treated groups (P less than 0.001), while serum T3 was not affected in either. Basal T4 deiodination to T3 by the liver homogenate did not change on treatment with T4; the addition of DTT increased T3 production in the homogenate from T4 treated nondiabetic animals (P less than 0.05). In both nondiabetic and insulin-treated diabetic rats there was no effect of T4 on the rate of rT3 production. Since, in the rat, 30-40% of circulating T3 is a direct contribution of thyroid gland secretion, and that would be absent in our T4-suppressed animals, the normal serum T3 may reflect increased absolute peripheral T3 production from the greater concentration of circulating T4.     

Apparent increase in type I 5'-deiodinase activity induced by antiepileptic medication in mentally retarded subjects

BACKGROUND/OBJECTIVES: Thyroid function measurements in 3 mentally retarded patients treated with antiepileptic drugs (phenytoin or carbamazepine) showed normal thyroid-stimulating hormone (TSH) responses in spite of markedly low levels of total thyroxine (T(4)), triiodothyronine (T(3)), and free thyroxine (FT(4)) concentrations; free triiodothyronine (FT(3)), as well as mean thyroxine-binding globulin (TBG) concentrations were normal. The objective of the present investigations was to determine if antiepileptic medication in these patients contributed to the disparate TSH and thyroid hormone (TH) levels. METHODS: Thyroid tests and other laboratory parameters were measured by conventional techniques. RESULTS: Circulating TH changes noted in retarded patients were similar to those observed in control subjects receiving carbamazepine alone. Reverse T(3) (rT(3)) levels in all patients were either undetectable or below the normal range. CONCLUSIONS: As type I 5'-deiodinase has a higher affinity for rT(3) than T(4), an increased activity of this enzyme would enhance rT(3) deiodination and reduce serum rT(3) concentration whereas enhanced T(4) deiodination would aid in normalizing intracellular FT(3) concentration. The finding of normal serum FT(3) concentration was consistent with normal TSH response and clinical euthyroidism in both retarded and control subjects. While phenytoin-induced increase in type I 5'-deiodinase has been previously noted, the present studies demonstrate a similar effect of carbamazepine on 5'-deiodinase.     

Thyroid hormone concentrations in rats after chronic nicotine metabolite administration

In an attempt to evaluate the observed relationship of chronic cigarette smoking and reduced thyroid hormone activity, the major urinary metabolites of nicotine were administered to rats for 78 weeks. The animals were divided equally into one control (n = 33) and three treatment groups. Treatment group 1 received 0.1% (w/v continine, group 2 received 0.02% pure trans-nicotine-N'-oxide, and group 3 received 0.02% of a trans/cis mixture (64/36%) of nicotine-N'-oxide. Plasma and urinary nicotine and cotinine concentrations were determined as well as a variety of thyroid hormone parameters. Pure trans-nicotine-N'-oxide was more extensively metabolized to its cotinine end product, relative to the diasteromeric N'-oxides, mixture. Serum triiodothyronine (T3) was markedly reduced in animals receiving nicotine-N'-oxides, but was not different in the cotinine treatment group when compared to control values. A reduction in serum thyroxine (T4) values was noted only among those rats receiving the pure trans-nicotine-N'-oxide. The T3/T4 ratio, free T3 index, T3 uptake, and rT3 were altered in animals receiving nicotine-N'-oxides. These findings indicate that specific nicotine metabolites alter thyroid hormone concentrations after chronic low-dose administration and possibly do so through back conversion to the parent compound, nicotine.     

Serum TSH, T4, T3, FT4, FT3, rT3, and TBG in youngsters with non-ketotic insulin-dependent diabetes mellitus

Several parameters of thyroid function were studied in 112 non-ketoacidotic youngsters with insulin-dependent diabetes mellitus (IDDM). Levels of thyroxine (T4), reverse triiodothyronine (rT3), thyroxine-binding globulin (TBG) and T3 were lower than in controls, whereas FT4, and FT3 were normal. T4 levels in IDDM patients were positively related to T3, rT3 and TBG, and inversely related to haemoglobin A1 (HbA1). However, only 4 patients showed biochemical hypothyroidism (T4 less than 5 micrograms/100 ml), whereas their FT4, FT3 and thyroid-stimulating hormone (TSH) levels were normal. Concurrent variations of T3 and rT3 levels were found in IDDM patients; thus, their T3/rT3 ratios were stable or higher than in controls, indicating that peripheral deiodination of T4 is preferentially oriented to production of rT3 only during ketoacidosis. Although changes in thyroid function may reflect the degree of metabolic control of diabetes in a large population, the clinical usefulness of serum thyroid hormone measurements in an individual case still appears to be limited.     

Plasma iodothyronines in the domestic fowl: newly hatched to early adult stages, with special reference to reverse triiodothyronine (rT3)

Circulating concentrations of thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine (rT3) were measured in chicks before, during, and after hatching, up to 9 weeks of age. T4 decreased prior to hatching, rose after emergence, and was variable in the immature domestic fowl. T3 increased prior to emergence, decreased until 5 days after hatching, and increased again by 1 week of age, after which the levels declined. Plasma rT3 declined prior to hatching, remained low until 5 days after emergence, and then increased, again, to 0.14-0.19 ng/ml between 1-9 weeks of age.     

Thyroid hormone response to thyrotrophin releasing hormone (TRH) in the sex-linked dwarf chicken

The effect of an injection of thyrotrophin releasing hormone (TRH) on plasma levels of thyroid hormones was studied in dwarf and normal Rhode Island Red chickens with similar genotypes other than for the sex-linked dwarf gene dw. The sex-linked dwarf chickens had different plasma iodothyronine levels from control normal chickens: high thyroxine (T4), low triiodothyronine (T3) and similar reverse T3 (rT3) levels. The injection of TRH (10 micrograms/kg) in 5-day- and 5-week-old normal chickens increased the plasma T4 within 30 min without a significant increase in T3, whereas the injection of TRH in 11-and 26-week-old normal chickens increased plasma T3 60 min later. In dwarfs the response of T4 to TRH was the same as that in normals but no increased T3 response was observed. The plasma level of rT3 was not influenced by the TRH injection in either strain. These results suggest that although in the sex-linked dwarfs thyroidal response to exogenous TRH is similar to that of normals, the dwarf gene dw inhibits the conversion of T4 to T3 in peripheral tissues without any inhibitory effect on rT3 production.     

Low-T3 syndrome and signal-averaged ECG in haemodialysed patients

The study was designed to evaluate the potential link between low-T3 syndrome and signal-averaged ECG parameters (SAECG) in a group of hemodialyzed patients (HD-pts). 52 selected HD-pts (without relevant thyroid and cardiac diseases) were included. SAECGs were performed postdialysis together with evaluating free triiodothyronine (fT3), free thyroxine (fT4), reverse triiodothyronine (rT3), thyroid stimulating hormone levels and echocardiography. For each SAECG, QRS duration (QRSd), root-mean-square voltage of the terminal 40 ms of the QRS (RMS40), and low-amplitude signal duration (LAS40) were measured. Abnormal SAECGs were found in 30.8 % of HD-pt. HD-pts with decreased fT3 and increased rT3 values (low-T3 positive) revealed higher QRSd and LAS40 values in comparison with low-T3 negative HD-pts (p = 0.019, p < 0.001 respectively). Low-T3 positive HD-pts had lower RMS40 values than low-T3 negative patients (p < 0.001). The Pearson test showed significant correlations between QRSd and fT3 (r = -0.592, p < 0.001); QRSd and rT3 (r = 0.562, p < 0.001); RMS40 and fT3 (r = 0.432, p = 0.009); RMS40 and rT3 (r = -0.325, p = 0.025). On multivariate analysis, both fT3 and rT3 levels were found to be independent predictors of QRSd and RMS40 values. Our study showed that decreased fT3 and increased rT3 concentrations due to low-T3 syndrome influence SAECG parameters in HD-pt.     

Potentiation of thyroxine 5-deiodination by aminotriazole

Aminotriazole, a goitrogen, in addition to its known inhibitory effects on the thyroid, demonstrated a unique effect on peripheral deiodination of thyroxine (T4). In contrast to the well-known peripheral effects of goitrogens such as propylthiouracil in inhibiting 5'-deiodinase activity, i.e., to effect a decrease in T4 to triiodothyronine (T3) conversion, aminotriazole had no effect on the 5'-deiodinative pathway. Rather, this goitrogen appeared to stimulate the alternative pathway, viz. T4 5-deiodination, resulting in an increased reverse triiodothyronine (rT3) serum concentration. This was shown in comparisons of serum T4, T3 and rT3 concentrations and serum T3/T4 and rT3/T4 ratios between rats treated with aminotriazole and T4, and rats treated with T4 alone. The finding that aminotriazole may specifically enhance T4 5-deiodination, independently of T4 5'-deiodination, is novel, as this has not been observed in the case of other goitrogens. It is of interest that this goitrogen is devoid of sulphur, which is a prominent constituent of thiourylene compounds which have been noted to affect 5'-deiodination. The potentiating effect of aminotriazole on 5-deiodination of T4 was not attributable to dietary factors.     

Synergistic effect of cortisol and thyrotrophin releasing hormone on lung maturation in the fetal sheep entails connective tissue maturation.

Pressure-volume relationships and collagen and elastin contents were measured in the lungs of fetal sheep infused either with saline (n = 4), thyrotrophin-releasing hormone (TRH; n = 6), cortisol (n = 9) or TRH plus cortisol (n = 10) at 128 days of gestation (term = 149 days) for 7 days. Lung distensibility (V40 = 1.8 +/- 0.1 ml/g wet wt; mean +/- SD) and stability (V5 = 0.6 +/- 0.1) increased along with collagen (C) (10.1 +/- 2.7 micrograms/mg) and elastin (E) contents (128 +/- 35 ng/mg) in the animals infused with TRH plus cortisol and were significantly higher (p < 0.05) than those observed in TRH (V40 0.62 +/- 0.07; V5 0.32 +/- 0.04; C 3.53 +/- 1.3; E 38.2 +/- 8.3), cortisol (V4 0.66 +/- 0.6; V5 0.27 +/- 0.03; C 4.27 +/- 0.8; E 41.02 +/- 12.7) or saline infused fetuses (V40 0.40 +/- 0.1; V5 0.20 +/- 0.06; C 3.28 +/- 0.9; E 31.5 +/- 9.2). Plasma concentrations of prolactin (PRL), triiodothyronine (T3) and cortisol (F) were also higher in the group of fetuses infused with both hormones in comparison with the other groups. In fetuses treated with TRH plus cortisol, PRL (32 +/- 8.3 ng/ml) and T3 (308.3 +/- 36 micrograms/dl) were significantly higher than in those infused with cortisol alone (PRL 3.7 +/- 2.3; T3 128 +/- 30) or with saline (PRL 4.2 +/- 1.6; T3 < 5 micrograms/dl). In the group treated with TRH alone, PRL also increased significantly (37 +/- 6.4), but T3 increased only slightly (18 +/- 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiopulmonary bypass: a low T4 and T3 syndrome with blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH)

Thyroid hormone serum concentrations, the thyrotropin (TSH) and prolactin (PRL) response to thyrotropin-releasing hormone (TRH) were evaluated in patients undergoing cardiopulmonary bypass (CPB) conducted in hypothermia. During CPB a marked decrease of thyroxine (T4) and triiodothyronine (T3) concentration with a concomitant increase of reverse T3 (rT3) were observed similarly to other clinical states associated with the 'low T3 syndrome'. Furthermore, in the present study elevated FT4 and FT3 concentrations were observed. In a group of patients, TRH administered during CPB at 26 degrees C elicited a markedly blunted TSH response. In these patients, PRL concentration was elevated but did not significantly increase after TRH. The increased concentrations of FT4 and FT3 were probably due to the large doses of heparin administered to these patients. Thus, the blunted response of TSH to TRH might be the consequence of the elevation of FT4 and FT3 in serum, however, other factors might play a role since also the PRL response to TRH was blocked.     

Iodothyronine content in the pig thyroid gland

An analysis has been carried out on the contents and reciprocal proportions of three principal iodothyronines (T4, T3 and rT3) in the thyroids of fed and fasted piglets of 8-10 wk and in adult pigs. The mean T4 concentration averaged 62.0 +/- nmol/100 mg wet tissue (in adults: 18.5 +/- 4.3 nmol/100 mg tissue); T3, 9.5 +/- 0.9 nmol/100 mg tissue (in adults: 1.58 +/- 0.2 nmol/100 mg tissue); rT3, 3.0 +/- 0.3 nmol/100 mg tissue. The reciprocal ratios of the hormones in the piglets' thyroids were: for T3:T4, 0.150 (in adults, 0.114) and for rT3:T4, 0.050 (in adults, 0.023). Mean T4:T3:rT3 ratio in piglets and adult pigs was 20.5:3.1:1 and 66.1:5.6:1, respectively. The results from all examined iodothyronines, show the higher absolute concentration in piglets' than in adult pigs' thyroid tissue, while the reciprocal proportions of the hormones reveal smaller T4 thyroid contents (comparing with T3 and rT3) in piglets than in adults. No changes of absolute thyroidal contents or reciprocal ratios of the iodothyronines were observed in fed and fasted piglets. In a comparison, the pig thyroid contains more triiodothyronine and a higher ratio T3:T4 than that in some other species.