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C. Menegay, C. Juge and A. G. Burger

Abstract.

3,5,3'-triiodothyroacetic acid is an effective inhibitor of TSH secretion in central hyperthyroidism. Serum 3,5,3'-triiodothyroacetic acid was measured with an RIA preceded by immunoprecipitation. An anti-3,5,3'-triiodothyroacetic acid antibody was obtained in rabbits, using 3,5,3'-triiodothyroacetic acid coupled to hemocyanin and diazotized benzidine as antigen (crossreactivity with T4, T3, tetraiodothyroacetic acid was 0.2, 1.1, and 5%, respectively). Endogenous 3,5,3'-triiodothyroacetic acid levels could not be detected in 14 euthyroid, 10 hypothyroid and 10 hyperthyroid sera (detection limit 0.055 nmol/l). Kinetic studies were performed in 6 healthy male subjects who received an oral and an iv dose of 1050 μg of 3,5,3'-triiodothyroacetic acid. The serum measurements were analysed according to a non-compartmental method. The half-life of 3,5,3'-triiodothyroacetic acid was 6 h 22 min ± 29 min, the volume of distribution was 114 ± 9 1/70 kg, and the plasma clearance rate was 298 ± 14 1 · (70 kg)−1 · day−1. Highest 3,5,3'-triiodothyroacetic acid levels were measured after 40 min (for T3 2–3 h) and its absorption was 67±6%. The nadir of the mean TSH levels was 0.72 ± 0.09 mU/l 6 h after 3,5,3'-triiodothyroacetic acid administration. However, the time course of serum TSH response did not differ from that obtained after administration of 37.5 μg T3. The dose-response effect for TSH was studied using oral doses of 350, 700, 1400 and 2800 μg 3,5,3'-triiodothyroacetic acid. TSH was measured 9 h after 3,5,3'-triiodothyroacetic acid administration at 17.00 h, and compared with control serum TSH levels obtained at 08.00 h (1.53 ± 0.11) and at 17.00 h the day before the test (1.87 ± 0.11). They were 1.05 ± 0.15 (N = 9, mean ± sem), 0.83 ± 0.08 (N = 24), 0.66 ± 0.06 (N = 24), and 0.43 ± 0.02 mU/l (N = 6), respectively. In conclusion, TSH inhibition by 3,5,3'-triiodothyroacetic acid is similar to T3, with a potency ratio of 1 to 18.

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T. Lemarchand-Béraud, A.-C. Holm, G. Bornand and A. Burger

ABSTRACT

In a previous study, human lymphocyte nuclei were found to possess high affinity, low capacity binding sites for triiodothyronine (T3) and thyroxine (T4). The number of receptors per cell was similar for T3 and T4 (115±20), but the equilibrium affinity constant (Ka) for T3 (2.20±0.23 1010 m −1) was twice that for T4 (1.05 ± 0.25 1010 m −1). The present study shows that human lymphocyte nuclei also bind highly purified [125I]tetrac and [125I]rT3. The number of specific binding sites was 60 for tetrac and 40 for rT3. The Ka for tetrac (2.12 ± 0.29 1010 m −1) was similar to that of T3, whereas that of rT3 (1.31 ± 0.2110 m −1) was similar to that of T4. The Ka was the same when measured in intact cells and in nuclei isolated after incubation. Despite the similar Ka for tetrac, rT3 and T3, as obtained by direct measurements, tetrac had only 2 % and rT3 0.1 % of the T3 potency in T3 displacement studies. [125I] tetrac was displaced 50% by 20 fmol of T3 and [125I]rT3 by 8 fmol.

These results show that tetrac and rT3 do bind as strongly to nuclear receptors as T3 and T4, but that when competing with T3 the apparent affinities decrease considerably for tetrac and rT3. Thus, the nuclear binding of these two analogues probably has no significance under physiological conditions, but may play some role under pathological conditions when the formation of T3 is decreased and that of rT3 and tetrac is increased. This may represent an adaptive mechanism in T4 inactivation.

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A. G. Burger, M. Berger, K. Wimpfheimer and E. Danforth

Abstract.

Thyroid hormone metabolism and plasma concentrations of TSH were studied after short-term hypocaloric refeeding of rats starved for 2–6 days. Carbohydrate and protein (10 kcal) refeeding after 4 days of starvation resulted in a rapid increase in serum T3 (P<0.01) and, less consistently of T4. Plasma TSH did not change. These findings were not due to changes in the metabolic clearance rates or in thyroid hormone binding proteins, as the disappearance of injected labelled T3 and T4, and the free fractions of T3 and T4, were unchanged. Increased thyroidal secretion, and for T3, increased peripheral conversion from T4 were therefore responsible for these changes. Fat refeeding had no immediate effect on plasma T4, T3 or TSH. After 6 days of starvation, refeeding of any nutrient was ineffective in altering the plasma concentrations of T3 and T4.

The intraperitoneal administration of nicotinamide (100 mg/100 g body weight) to starving animals caused an increase in blood glucose and a decrease in blood betahydroxybutyrate similar to that which followed carbohydrate refeeding; T3, however, did not increase. In spite of producing a profile of substrates in the serum similar to that found following carbohydrate refeeding, nicotinamide administration had no effect on the blood lactate/ pyruvate ratio which was increased following carbohydrate refeeding. Therefore, the cytoplasmic redox state, as reflected by the lactate/pyruvate ratio, may be closely related to the control of peripheral thyroid hormone metabolism.

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A. G. Burger, D. Engler, C. Sakoloff and V. Staeheli

ABSTRACT

The effects of tetraiodothyroacetic (Tetrac) and triiodothyroacetic acids (Triac) on thyroid function have been investigated in euthyroid and hyperthyroid subjects. 50, 100, 200, 400 or 800 μg of Triac were administered to 8 euthyroid volunteers three times (tds) over a 24 hour period. 3 × 800 μg Triac/24 h was sufficient to cause a significant reduction in serum T3. Tetrac, given as an iv bolus of 3600 μg, produced a sustained reduction in serum T3 for up to 4 days after the injection. Intermediate doses of Tetrac (1200 μg) or Triac (400 μg tds) significantly reduced the TSH response to TRH (66 % and 43 % respectively).

Seven hyperthyroid patients received Triac 200 μg tds for 2 days, and in 2, a rapid decrease in serum T3 was seen. Similar changes in serum T3 were also produced with iodide administration.

The results suggest that 1) in euthyroidism, Tetrac and Triac act directly at the pituitary level to inhibit the TSH response to TRH; 2) in some cases of hyperthyroidism, Triac produces a block in T3 secretion by virtue of the iodide produced by its metabolism.

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M. Lambert, A. G. Burger, P. De Nayer and C. Beckers

Abstract. In order to test the reactivity of TSH to TRH during amiodarone treatment we investigated 7 hypothyroid subjects treated with 50 μg T3/day. A TRH test (200 μg iv) was performed before and after 6 weeks of treatment with 400 mg amiodarone/day. Amiodarone treatment induced a significant increase in serum total and free T3 (from 2.17 ± 0.13 to 3.55 ± 0.58 nmol/l and from 5.6 ± 0.61 to 9.46 ± 1.41 pmol/l). Basal TSH levels were significantly decreased and the maximal stimulation of TSH 20 min after TRH injection was only 20.0 ± 3.3 mU/l during amiodarone treatment compared with 61.4 ± 10.4 mU/l before treatment. These results indicate that in hypothyroid patients treated with amiodarone, the TSH response to TRH is blunted and that this is likely to be related to the higher total and free T3 levels or to a direct effect of amiodarone at the pituitary level.

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A. C. J. Burgers and G. J. van Oordt

Amongst the Vertebrates, excitement colour reactions have been described in fishes, amphibians and reptiles. Most Amphibia show an excitement pallor if exposed to noxious stimuli. In a previous paper, however, one of us has shown (Burgers, Boschman & van de Kamer, 1953) that amongst the Amphibia, the South African clawed toad Xenopus, like Polypedates reinwardtii (Siedlecki, 1909) is an exception with regard to its melanophore reactions. Both these species react to excitement stimuli with a distinct darkening. This reaction was named »excitement darkening« (Burgers et al., 1953, p. 72). Our findings concerning Xenopus were confirmed by Ketterer & Remilton (1954) who observed a noticeable darkening in Xenopus following rough handling.

Moreover, adrenaline to which the melanophores of the lower Vertebrates generally react with pigment concentration1, has a pigment dispersing effect on the melanophores of pale Xenopus.

Our first assumption that the excitement darkening was due to a sudden excretion

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J. N. Hugues, A. Reinberg, D. Jordan, J. Sebaoun, E. Modigliani and A. G. Burger

Abstract.

Diurnal fluctuations of plasma TSH were investigated in ad libitum fed rats as well as after a 3 day starvation period in order to study the relationship between the circadian pattern of TSH secretion and nutritional status. Our study showed the persistence of a circadian TSH rhythm after a 3 day starvation without any change in the amplitude of plasma TSH variations. However, the 24 h average plasma TSH levels were significantly lower. A suggestive acrophase occurred at the same period of the day in starved and fed rats. Our results suggest that the control of plasma TSH concentrations and nycthemeral rhythm are not closely related and may even possibly be independent of one another.

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M.J. MÜLLER, K.J. ACHESON, A. G. BURGER, E. JEQUIER and A. VON ZUR MÜHLEN

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Cristiana Juge-Aubry, Pierre Dôme, Catherine A. Siegrist-Kaiser, Alessandro M. Capponi and Albert G. Burger

Abstract.

In glial cell cultures, iodothyronine 5'-deiodinase type II is stimulated by dibutyryl cAMP. Serum-free medium increases enzyme activity and prolongs the half-life of the enzyme. T4 and rT3 specifically inhibit this activity. We tested whether enzyme inactivation by T4 was mediated by changes in cytosolic free calcium concentration and/or phospholipid turnover. Intracellular calcium concentration was decreased either by chelation of extracellular calcium or by chelation of extracellular and intracellular calcium. Neither basal hypothyroid 5'-deiodinase activity nor its inactivation by T4 were modified in such experimental conditions, compared with control cells incubated in normal calcium-containing medium. T4 by itself had no effect on the cytosolic free calcium concentration for up to 20 min. Studies on phospholipid turnover included norepinephrine in parallel to T4 as positive stimulation control. While norepinephrine clearly accelerated phosphoinositide turnover, there was no effect of T4 on any phospholipid turnover. These results suggest that neither cytosolic free calcium nor phospholipid turnover is involved in T4-dependent modulation of 5'-deiodinase type II activity in astrocytes in culture.

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M. J. MÜLLER, A. G. BURGER, E. JEQUIER and K.J. ACHESON