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Enhanced release of T3 and rT3 compared to T4 from thyroglobulin during autolysis of dog thyroid homogenate

Peter Laurberg

Abstract.

Previous studies on the secretion of thyroxine (T4), 3,5,3'-triiodothyronine (T3), and 3,3',5'-triiodothyronine (rT3) from perfused dog thyroids have indicated that a differential rate of secretion of various iodothyronines may take place.

The aim of the present study was to evaluate whether the proteolysis of thyroglobulin taking place during secretion could be involved in this phenomenon. Homogenate from the same dog thyroid was incubated either at pH 3.6 for 18 h without added protease or with pronase at pH 8.4 for 18 h. Iodothyronines were measured radioimmunologically in ethanol extracts of the hydrolysates. No significant deiodination of T4 to T3 and rT3 took place during incubation. During acid autolysis 17.5 ± 3.5% (mean ± SE, n = 5) of the T4 found after pronase hydrolysis was liberated, while 31.6 ± 4.8% of the T3 and 21.2 ± 4.2% of the rT3 were liberated (both values were significantly higher than that found for T4). Since iodothyronines in thyroglobulin are released nearly quantitatively during pronase hydrolysis, the results indicate that thyroid proteases acting at acid pH, liberates T3 and rT3 more easily than T4 from thyroglobulin.

This could be the mechanism behind the relatively high secretion of T3 and rT3 observed during acceleration of secretion from perfused thyroid lobes, and the relatively high secretion of T4 observed during deceleration of secretion.

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THE RELATIVE DISTRIBUTION OF THYROXINE, TRIIODOTHYRONINE AND 3,3′,5′-(REVERSE)-TRIIODOTHYRONINE IN VARIOUS FRACTIONS OF THYROGLOBULIN

Peter Laurberg

ABSTRACT

Thyroglobulin fractions rich and poor in new thyroglobulin were separated by means of DEAE-cellulose chromatography of dog thyroid extracts and by zonal ultracentrifugation in a sucrose gradient of guinea pig thyroid extract incubated at low temperature. The distribution of thyroxine, triiodothyronine and 3,3′,5′-(reverse)-triiodothyronine in hydrolysates of the different fractions was estimated by radioimmunoassays. Following DEAE-cellulose chromatography there was a small but statistically significant increase in the T4/T3 ratio in thyroglobulin fractions eluted at high ionic strength - that is fractions relatively rich in stable iodine but poor in fresh thyroglobulin. There were no differences in the T4/rT3 ratios between the different fractions. The ratios between iodothyronines were almost identical in the various thyroglobulin fractions following zonal ultracentrifugation in a sucrose gradient of cold treated guinea pig thyroid extract.

These findings lend no support to the possibility that a relatively high content of triiodothyronines in freshly synthesized thyroglobulin modulates the thyroid secretion towards a preferential secretion of triiodothyronine and 3,3′,5′-(reverse)-triiodothyronine at the expense of the secretion of thyroxine.

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lodothyronine Release from the Perfused Canine Thyroid

Peter Laurberg

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T4 AND T3 RELEASE FROM THE PERFUSED CANINE THYROID ISOLATED IN SITU

Peter Laurberg

ABSTRACT

A method for once-through perfusion of the canine thyroid isolated in situ is described. The perfusion medium was a modified Krebs Ringer buffer with 4 % dextran added. In 4 control experiments the T4 and T3 concentrations in effluent were stable or slightly falling during 3 h perfusion. There were no significant alterations in the T4/T3 ratio in the effluent during these experiments.

A 10-min infusion of bovine TSH (1 mU/ml) caused an increase in the release of T4 and T3 after 15–25 min. The T4/T3 ratio in the effluent was significantly reduced after TSH stimulation. However, the ratio returned to pre-stimulation values while the hormone release was still very high. T4 and T3 content of the contralateral thyroid was determined after homogenation and hydrolysis with pronase. The T4/T3 ratio in the homogenate was twice as high as the T4/T3 ratio in the effluent during control perfusion. Thus there was a preferential secretion of T3 from the perfused canine thyroid and this was increased after TSH stimulation.

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Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism?

Peter Laurberg

Therapy of Graves’ hyperthyroidism with thionamide anti-thyroid drugs is accompanied by a gradual remission of the autoimmune aberration in the majority of patients. The most likely mechanism behind this remission has been considered to be a direct immunosuppressive effect of thionamide drugs. However, a number of findings in clinical studies of patients with Graves’ disease indicate that remission is probably not caused by a special effect of thionamide drugs. Many studies have shown that remission is linked to restoration of the euthyroid state, and that it is independent of drug dose and type. Moreover, similar remission is observed when patients become euthyroid after thyroid surgery. In an explanatory model described, it is assumed that the autoimmune aberration of Graves’ disease is often basically quit mild and self-limiting. Patients may become ill by the running of a vicious cycle of hyperthyroidism worsening the autoimmunity, and autoimmunity worsening the hyperthyroidism. Once patients are made euthyroid by one or the other drug or by thyroid surgery, the majority of patients will gradually enter remission of the disease. The conclusion that remission is associated with restoration of the euthyroid state, and that it is not a special drug effect, highlights the importance of making and keeping patients with Graves’ disease euthyroid.

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OPPOSITE VARIATIONS IN SERUM T3 AND REVERSE T3 DURING PROPYLTHIOURACIL TREATMENT OF THYROTOXICOSIS

Peter Laurberg and Jørgen Weeke

ABSTRACT

Blood samples for determination of serum total and free reverse triiodothyronine (rT3), triiodothyronine (T3) and thyroxine (T4) were obtained daily in 6 previously untreated thyrotoxic patients during periods of propylthiourazil (PTU) (600 mg per day) or methimazol (MMI) (45 mg per day) administration.

PTU induced about 60 per cent increase in both total and free serum rT3. This was accompanied by a rapid decrease in serum T3 and a more gradual decline in serum T4. MMI administration to untreated patients was followed by a gradual parallel decrease in rT3, T3 and T4. Turn from PTU to MMI produced a rapid decrease in serum rT3 and increase in serum T3 in all 6 patients. The relative variations in the free and total concentrations of iodothyronines were practically identical.

The increase in serum rT3 after PTU is most likely explained either by enhanced deiodination of T4 to rT3 or by an inhibitory effect of PTU on rT3 degradation.

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24-h profile of serum rT3 and serum 3,3'-T2 in normal man

Jørgen Weeke and Peter Laurberg

Abstract.

In a previous study we found a night surge in serum free T3 varying in parallel with that of serum TSH. In order to evaluate whether diurnal alterations in peripheral iodothyronine monodeiodination may be involved we have measured two products of peripheral deiodination, 3,3',5'-T3 (rT3) and 3,3'-T2 in serum samples obtained at short intervals during a 24-h period in 5 normal male subjects. Serum rT3 was rather stable during the period albeit with a trend towards lower levels during the night when the subjects were in bed. In order to obtain a measure of free rT3 a free rT3 index was calculated using the combined variations in per cent free T4 and free T3. Night and day levels of this rT3 index were found identical, suggesting a lack of diurnal variation in serum free rT3. Likewise serum 3,3'-T2 levels were identical during the day and night periods.

The results suggest that variations in peripheral iodothyronine deiodinations are not involved in the night increase in serum free T3.

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Serum TSH and serum thyroid peroxidase antibody fluctuate in parallel and high urinary iodine excretion predicts subsequent thyroid failure in a 1-year study of patients with untreated subclinical hypothyroidism

Jesper Karmisholt and Peter Laurberg

Objective

To explore the possibility of predicting decline or improvement in thyroid function over 1 year, and to investigate the correlations of serum TSH (s-TSH) with hypothyroidism-related symptoms and signs, serum thyroid peroxidase antibody (s-TPO-Ab) and urinary iodine excretion in individual patients with untreated subclinical hypothyroidism (SH).

Design

Monthly repeated measurement study without intervention.

Methods

Twenty-one patients without former thyroid disease who had been identified with s-TSH between 5 and 12 mU/l and normal serum thyroxine (s-T4) at two occasions were enrolled. Subsequently, 13 monthly measurements of s-TSH, hypothyroidism-related symptoms and signs, serum free T4, s-TPO-Ab and urinary iodine excretion were performed.

Results

Over the study year, s-TSH increased significantly in 5 patients, 16 had unchanged s-TSH, whereas none improved. From clinical and biochemical inclusion data, it was not possible to predict who would later increase in s-TSH. In individual patients, a highly significant correlation between s-TSH and s-TPO-Ab was found (r=0.37, P<0.0001) and also between s-TSH and urinary iodine excretion (r=0.14, P=0.034). No correlation between s-TSH and clinical symptoms and signs was observed. Time shift showed best correlation between s-TSH and s-TPO-Ab measured at the same time point, whereas urinary iodine excretion correlated best to s-TSH and s-TPO-Ab obtained 1 month later.

Conclusion

At the time of inclusion, it was not possible to identify the 24% of SH patients who would show deterioration in thyroid function over the following year. Impairment in thyroid function varied in parallel with thyroid autoimmunity, whereas high urinary iodine excretion predicted high s-TSH and s-TPO-Ab 1 month later.

Free access

THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

Peter Laurberg and Stine Linding Andersen

Background

Antithyroid drugs (ATDs) may have teratogenic effects when used in early pregnancy.

Objective

To review the association between the time period of ATD exposure in early pregnancy and the development of birth defects.

Methods

We identified publications on birth defects after early pregnancy exposure to the ATDs methimazole (MMI; and its prodrug carbimazole (CMZ)) and propylthiouracil (PTU). Cases of birth defects after ATD treatment had been initiated or terminated within the first 10 weeks of pregnancy were identified and studied in detail.

Results

A total of 92 publications were read in detail. Two recent large controlled studies showed ATD-associated birth defects in 2–3% of exposed children, and MMI/CMZ-associated defects were often severe. Out of the total number of publications, 17 included cases of birth defects with early pregnancy stop/start of ATD treatment, and these cases suggested that the high risk was confined to gestational weeks 6–10, which is the major period of organogenesis. Thus, the cases reported suggest that the risk of birth defects could be minimized if pregnant women terminate ATD intake before gestational week 6.

Conclusion

Both MMI and PTU use in early pregnancy may lead to birth defects in 2–3% of the exposed children. MMI-associated defects are often severe. Proposals are given on how to minimize the risk of birth defects in fertile women treated for hyperthyroidism with ATDs.

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ENDOCRINOLOGY IN PREGNANCY: Pregnancy and the incidence, diagnosing and therapy of Graves’ disease

Peter Laurberg and Stine Linding Andersen

Thyroid hormones are essential developmental factors, and Graves’ disease (GD) may severely complicate a pregnancy. This review describes how pregnancy changes the risk of developing GD, how early pregnancy by several mechanisms leads to considerable changes in the results of the thyroid function tests used to diagnose hyperthyroidism, and how these changes may complicate the diagnosing of GD. Standard therapy of GD in pregnancy is anti-thyroid drugs. However, new studies have shown considerable risk of birth defects if these drugs are used in specific weeks of early pregnancy, and this should be taken into consideration when planning therapy and control of women who may in the future become pregnant. Early pregnancy is a period of major focus in GD, where pregnancy should be diagnosed as soon as possible, and where important and instant change in therapy may be warranted. Such change may be an immediate stop of anti-thyroid drug therapy in patients with a low risk of rapid relapse of hyperthyroidism, or it may be an immediate shift from methimazole/carbimazole (with risk of severe birth defects) to propylthiouracil (with less risk), or maybe to other types of therapy where no risk of birth defects have been observed. In the second half of pregnancy, an important concern is that not only the mother with GD but also her foetus should have normal thyroid function.