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Angel A. Zaninovich

ABSTRACT

The peripheral metabolism of thyroxine (T4) was studied before and after the administration of oestrogens in 21 patients with Graves' disease and in 5 subjects with thyrotoxicosis factitia. In addition, 6 patients with Graves' disease while receiving oestrogen treatment were given 600 mg of diphenylhydantoin (DPH) orally daily; the study on the peripheral metabolism of T4 was similarly performed. Oestrogens induced the following changes in T4 metabolism: a decrease in the concentration of free T4 in the serum, an increase in serum total T4, slowing of the fractional turnover, and contraction of the distribution space. The extrathyroidal T4 pool remained unchanged. These changes led to a decrease in daily T4 degradation rate from 469 μg in the control period to 348 μg during oestrogen therapy (P < 0.001). Fifteen of these patients showed apparent clinical improvement. The 2 subjects with T4-thyrotoxicosis factitia had decreased T4 degradation and remission of symptomatology following oestrogen administration; on the other hand, 3 subjects with T3-thyrotoxicosis factitia had no appreciable amelioration of their symptoms. The administration of DPH to oestrogen-treated patients with Graves' disease induced a slight acceleration of the absolute T4 turnover. It is concluded that the decreased T4 degradation induced by oestrogens in spontaneous and iatrogenic hyperthyroidism was mediated by an increase in T4-binding globulin capacity in the serum.

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Angel A. Zaninovich

ABSTRACT

The reciprocal effects of loading doses of thyroxine (T4) or triiodothyronine (T3) on the deiodination of their 125iodine-labelled isotopes by rat muscle and liver homogenates were studied. In 21 experiments muscle homogenates deiodinated a mean 45.0 % of a tracer dose of [125I]T4 and 18.0% of [125I]T3. On addition of graded amounts of non-radioactive T4 or T3 the percentual deiodination of both labelled hormones progressively declined. This effect was significantly greater in homogenates incubated with non-radioactive T4, thus reflecting a stronger affinity of this hormone for muscle deiodinating sites. This correlate with the greater displacement of [125I]T3 as revealed by the percentage of recovered labelled hormone. In 18 experiments liver homogenates deiodinated a mean 14.6% of a tracer amount of [125I]T4 and 8.5% of [125I]T3. The addition of a T4- or a T3-load was followed by a smaller decrease in percentual deiodination of both labelled hormones as compared to muscle homogenates. Unlike the effects observed in muscle, the breakdown of [125I]T4 and [125I]T3 by liver homogenates was equally affected by similar amounts of stable T4 or T3. It is concluded that in the present in vitro system T4 and T3 share cellular sites of deiodination in rat muscle and liver and that, at least in muscle, which constitutes over one-half of the rat body weight T4 appears to be preferentially deiodinated.

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Angel A. Zaninovich, Osvaldo Degrossi, and Hector Gotta

ABSTRACT

The effects of oestrogens on serum thyroxine-binding globulin (TBG) capacity and on the peripheral metabolism of thyroxine were studied in patients with hepatic cirrhosis as well as in a group of normal subjects. Oestrogens increased TBG capacity in cirrhosis from 24.7 to 38.4 μg/100 ml whereas in normal subjects TBG capacity was raised from 22.8 to 48.6 μg. While the fractional turnover of thyroxine in cirrhosis did not change with the administration of oestrogens, the space of distribution was reduced. As a result of these changes, the extra-thyroidal thyroxine pool was similar to the pre-treatment values and hence the daily degradation rate of thyroxine remained unchanged.

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Rubén Boado, Edgardo Ulloa, and Angel A. Zaninovich

Abstract.

In the present work the effects of oestradiol benzoate (EB) on pituitary and plasma concentrations of TSH, plasma T4 and T3, and thyroidal activity of male and female rats have been studied. Wistar rats weighing between 150 to 200 g were injected sc with varying doses of EB in corn oil for 9 or 30 days. The animals were exsanguinated by cardiac puncture and the hypophyses removed and individually homogenized at 4°C in 200 μl PBS buffer. Pituitary and plasma TSH were measured by radioimmunoassay. Thyroidal activity was evaluated by a 4 h 131I uptake and by 48 h thyroidal release plasma slopes derived form the ratio PB[125I] (from thyroidal secretion) to PB[131I] (from exogenous [131I]T4). In both male and female rats the 10 and 25 μg doses of EB produced a significant decrease in pituitary TSH content; this effect was more pronounced when the 25 μg dose was given over 30 days. Plasma T4 decreased significantly; plasma T3 was moderately elevated in all groups (NS) and significantly increased in female rats treated with 25 μg EB (P < 0.01). It is concluded that EB induced a marked depression of intrapituitary TSH, probably due to a decrease in synthesis, without affecting the release of TSH into the circulation. Moreover, EB accelerated peripheral T4 kinetics and thyroid gland activity, albeit to a moderate degree.

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Rubén Boado, Susana Deza, and Angel A. Zaninovich

Abstract. Previous works from this laboratory have demonstrated that oestradiol benzoate (EB) in euthyroid male and female rats induced a significant decrease in the pituitary content of TSH while serum levels of this hormone remained normal. The present work studied the effects of EB (25 μg/100 g body weight, during 9 days) on the peripheral metabolism of [125I]rTSH and on the pituitary and plasma concentration of TSH in euthyroid and hypothyroid rats. No significant variations were observed in [125I]rTSH kinetics of EB-treated euthyroid rats vs untreated controls: fractional turnover rate 2.8 ± 0.2 vs 3.0 ± 0.3%/min, distribution space 6.5 ± 0.4 vs 6.8 ± 0.5 ml/100 g body weight, disposal rate 18.4 ± 2.4 vs 18.1 ± 1.9 μU/100 g/min and extrapituitary pool 645 ± 42 vs 614 ± 43 μU/100 g body weight. Similarly, in hypothyroid rats oestrogens induced no changes in TSH kinetics except for an increase in distribution space (P < 0.025). However, oestrogens decreased the pituitary pool of TSH (P < 0.001) in both euthyroid and hypothyroid rats and increased the plasma TSH in hypothyroid animals (P<0.01), all vs their respective controls. Neither hypothyroid group had detectable plasma levels of T4 and T3. In summary: 1) the marked decrease of pituitary TSH with normal plasma TSH induced by EB appears unrelated to the peripheral metabolism of TSH, 2) the results from hypothyroid rats suggest that EB stimulates the release of TSH from the pituitary gland.

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Angel A. Zaninovich, Osvaldo Degrossi, and Victorio Pecorini

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Rubén Boado, Edgardo Ulloa, and Angel A. Zaninovich

Abstract.

The present work studied the TSH response to TRH in T4- and T3-treated normal rats and in rats with depressed intrapituitary conversion of T4 to T3. Euthyroid normal rats were injected iv with a single dose of 6 μG T4/100 g body weight, 1 μg T3/100 g or normal saline. Another group treated with iopanoic acid (IOP) received 1 or 10 μg T4/100 g, 0.21 or 2.5 μg T3/100 g, or saline as control. Twenty min later 1 μg TRH/100 g was injected iv. Blood samples were drawn at times 0, 20 min (immediately preceding the injection of TRH) and 30 min (10 min post-TRH) for measurement of plasma T4, T3 and TSH. Other groups of IOP-treated rats were injected iv with 150 μCi of [3',5'-125I]T4; the hypophyses were removed at 30 min and homogenized in PBS buffer, extracted and chromatographed in tertiary amyl alcohol:hexane:ammonia. The control group of rats had a 13-fold increase in plasma TSH 10 min after the TRH injection, while rats treated with 6 μg T4/100 g had a 7.6-fold increase (P < 0.01 vs control increment) and rats treated with 1 μg T3/100 g had no change in TSH response as compared to controls. In IOP-treated rats injected with 10 μg T4/100 g there was a smaller increase in the TSH response to TRH as compared to control (P < 0.01), and a similar smaller response was seen in rats treated with 2.5 μg T3/100 g (P < 0.01 vs control). IOP-treated animals given 1 μg T4 or 0.21 μg T3/100 g had no significant changes in TSH response to TRH. It seems probable that T4 possesses an intrinsic hormonal capacity to regulate the secretion of TSH before it monodeiodinates to T3.

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Angel A. Zaninovich, R. Boado, O. Degrossi, and A. J. Matty

ABSTRACT

The reciprocal effects of loading amounts of thyroxine (T4) or triiodothyronine (T3) on the in vivo deiodination of their 125I-labelled isotopes by the rat were studied. It was found that the deiodination of a tracer amount of [125I]T3 as measured by the 24-h urinary 125iodide was significantly decreased after administration of a loading dose of non-radioactive T4. A similar decrease in deiodination of [125I]T3 was observed following the injection of a T3 load. In experiments in which the deiodination of [125I]T4 was assessed, the effects on this of loading doses of non-radioactive T4 or T3 differed; while stable T4 induced a significant decrease in deiodination of [125I]T4, stable T3 was without effect. The data is in agreement with the view that T4 and T3 share tissue deiodinating sites and that in such a system T4 appears to have a stronger avidity for those sites.

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Angel A. Zaninovich, Robert Volpé, Roberto J. Soto, and Calvin Ezrin

ABSTRACT

In patients with liver cirrhosis the rate of disappearance of radioactivity from the blood during the 20 to 50 minute interval following the intravenous injection of 131I labelled L-T4 has been found to be markedly delayed compared to normal subjects. That this delay is due mainly to decreased hepatic uptake, was shown by a reduced 10 minute hepatic uptake of this labelled hormone. The principle binding proteins for T4 were not affected in a manner that would increase serum binding of the hormone. The 10 minute hepatic uptake of 131I labelled L-T3 was also reduced in the cirrhosis group, suggesting that the normal liver also contains binding sites for T3, and these are diminished in cirrhosis.