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Valerie Thurston and E. D. Williams

Abstract.

To study the effects of radiation from 131I on thyroid C cells, newborn rats were given 0, 5 or 10 μCi 131I and studied at 3 monthly intervals over 2 years. Routine stains, calcitonin immunolocalization and quantitation were used to study follicular and C cells.

Both radiation doses led to almost complete disappearance of C cells, with only scattered morphological abnormal surviving cells. After a year, some animals showed focal reappearance of C cells; these isolated clusters were interpreted as clones of cells, derived after a considerable lag period, from the very few surviving C cells which had not been sterilized. This focal regeneration was dosedependent. It is concluded that C cells are much more radiosensitive to radiation from 131I than follicular cells. These observations support the use of 131I therapy in the treatment of post-operative thyroid residues in patients with C cell hyperplasia, or microscopic intrathyroid deposits of medullary carcinoma.

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Valerie Thurston and E. D. Williams

Abstract.

Neonatal Wistar rats were given either 0, 5 or 10 μCi 131I within 24 h of birth. Following weaning, they were fed a diet high, normal or deficient in vitamin D, for up to 2 years. Animals were sacrificed at approximately 3 monthly intervals, and serial sections of thyroid scanned for C cell tumours following calcitonin localization. Plasma calcium levels were also measured, and all results statistically analyzed.

As expected, those animals given the high vitamin D had significantly raised calcium levels over those on a normal D diet, whilst those given a low D diet had lower calcium levels than normal.

Analysis of the incidence of C cell tumours showed that those given a high D diet had significantly more C cell tumours, whilst those on a low D diet had significantly fewer than normal. Radiation dose also influenced C cell tumour incidence.

There was a significant relationship between the vitamin D content of the diet and the incidence of C cell tumours, with those animals on a high D diet having the largest number of tumours. It is suggested that vitamin D or its metabolites may directly promote C cell growth, and that the high incidence of C cell tumours in the normal laboratory rat reflects the artificially high vitamin D content of the laboratory rat diet. The dietary vitamin D content may also be relevant to the variation in geographical incidence of medullary carcinoma in man. We consider it likely that vitamin D metabolites may play a significant role in the control of C cell function, hyperplasia and tumour formation in the rat, and that this may be more important in tumour formation than the role of serum calcium variation.

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Stella M. Triggs and E. D. Williams

ABSTRACT

It is known that tumours of several endocrine glands can be induced by a combination of a physiological stress and radiation. It was decided to assess the effect of radiation and of changes in dietary calcium on the development of thyroid tumours in the rat. Three hundred rats were given either 0, 5 or 10 μCi of 131I in their first day of life. Each of these groups was subdivided after weaning, and maintained on a diet that was either high, normal or low in calcium. The animals were killed at intervals up to 27 months of age, and the numbers of thyroid tumours recorded.

Follicular tumours were first noted at 9 months of age, and their frequency increased steadily with age. The effect of radiation was highly significant, only one tumour occurred in a non-irradiated animal. There was a small increase in frequency in follicular tumours in the high calcium diet group as compared to the low calcium diet group.

C cell tumours were first noted at 9 months of age, and their incidence again increased with age. Significantly more tumours occurred in the radiated than in the non-irradiated animals. No significant variation occurred in relation to dietary calcium.

It is concluded that an increase in dietary calcium, known to be mildly goitrogenic, may also be important in the carcinogenesis of follicular but not C cell tumours, and that radiation, known to be carcinogenic for thyroid follicular cells is also carcinogenic for C cells.

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D. Wynford-Thomas, B. M. J. Stringer, and E. D. Williams

Abstract.

This study was designed to provide a reliable quantitative assessment of the circadian rhythm of mitotic activity in the follicular cell population of the rat thyroid, and the effect on this rhythm of prolonged stimulation by a raised level of circulating TSH, induced by goitrogen administration.

Mitotic activity in groups of control and goitrogen-treated rats was assessed by a stathmokinetic technique during four 4-h periods spaced equally through one 24-h cycle. Particular attention was paid to the method of sampling to eliminate systematic and minimise random errors, and to the assesment of rhythmicity which was carried out by an appropriate statistical method.

A highly significant circadian rhythm was found in control animals with a daytime peak (12.00 to 16.00 h). Goitrogen treatment led to a 5- to 6-fold increase in the mean but a loss of detectable rhythmicity.

The results show that the presence and timing of this circadian rhythm must be taken into account in future studies of thyroid growth, and they throw some light on the possible mechanisms of its control. Comparison of the rhythm with that of serum TSH reported previously raises the possibility of a dominant control by this hormone even in euthyroid animals and suggests that it may act on cells in the G2 and/or G1/G0 phases of the cell cycle.

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B. Stringer, D. Wynford-Thomas, B. Jasani, and E. D. Williams

Abstract.

Adult male rats were fed a goitrogen, aminotriazole, for 74 days at a dose known to suppress thyroid function completely. At the end of this period, these animals along with matched controls were killed in groups of seven at 3 hourly intervals throughout a 24 hour period, and serum TSH, T3, T4 and albumin assayed.

No significant circadian rhythms of T3, T4 or albumin were found in either, but a highly significant rhythm of TSH was demonstrated both in controls and goitrogen treated groups, with a diminished relative amplitude in the latter.

The results indicate that a significant diurnal rhythm of serum TSH persists in the rat despite long-term blockade of thyroid hormone synthesis and that the existence of this rhythm is therefore independent of the presence of circulating T3 or T4.

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D. Wynford-Thomas, B. M. J. Stringer, and E. D. Williams

Abstract.

We have previously shown that administration of goitrogen to the rat leads to a sustained elevation of serum TSH but to only a short-lived burst of mitotic activity in the thyroid, growth eventually ceasing after a few months. This work investigates the possibility that this progressive desensitisation may result simply from continued exposure to high levels of TSH and examines the effect of a period of interruption of goitrogen treatment on the sensitivity of the gland to subsequent TSH stimulation.

Rats were treated with the goitrogen aminotriazole (ATA) for an initial period of 80 days to reach the plateau of thyroid growth. ATA was then withdrawn for 25 days and subsequently re-introduced for a further 35 days. Animals were killed in groups of 8 at frequent intervals and the following measurements carried out: — Serum TSH, T3 and T4, thyroid weight, follicular cell number and mitotic activity.

The initial period of ATA treatment led to a 5-fold increase in serum TSH, a 10-fold increase in thyroid weight and a 9-fold increase in follicular cell number. Mitotic activity stabilised at a few times control levels. Following withdrawal of ATA, TSH and mitotic activity fell to below normal. Thyroid weight fell by 66% but there was no significant fall in follicular cell number. Re-introduction of ATA simply led to a return of all variables to their previous 'stimulated' levels. There was no second burst of mitotic activity and no renewed thyroid growth.

The results show that the desensitisation of follicular cells to the growth-stimulating action of TSH following prolonged stimulation is not reversed by withdrawal of the stimulus, and is therefore unlikely to be mediated by a 'downregulation' at receptor or post-receptor level of the type observed for functional responses in vitro.

Other possible mechanisms are discussed.

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D. Wynford-Thomas, B. M. J. Stringer, and E. D. Williams

Abstract.

This study was designed to investigate the changes in growth and function which occur in the rat thyroid during prolonged TSH stimulation.

Animals maintained on the goitrogen aminotriazole were sacrificed together with controls at frequent intervals over a period of 5 months. The levels of serum T3 and T4 and TSH were measured by radioimmunoassay. Functional activity was assessed by measurement of the thyroid/serum iodide ratio (T/S) and growth by measurement of thyroid weight, follicular cell number and follicular cell mitotic activity.

Serum T3 and T4 rapidly fell to undetectable levels within 2 weeks. The level of serum TSH rose to a stable 5-fold maximum after 4 weeks. The T/S ratio followed a closely similar pattern rising to a sustained 7-fold maximum. Thyroid weight and follicular cell number increased rapidly for the first few weeks but the growth rate declined progressively, falling almost to zero after 80 days. Mitotic activity rose dramatically to a 30-fold peak after 7 days but then declined almost to normal after 80 days, consistent with the observed change in cell number. The results thus demonstrate a clear dissociation between the functional and proliferative activity of the thyroid follicular cells during prolonged stimulation by a sustained elevation of serum TSH and point to the existence of specific growth regulating mechanisms which limit the mitotic response.

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H. R. Harach, D. A. Escalante, A. Oňativia, J. Lederer Outes, E. Saravia Day, and E. D. Williams

Abstract. Iodine prophylaxis was introduced to the moderately severe goitre endemic area in Salta, Argentina, in 1963. All thyroidectomies from a 20 year period were reviewed, and 148 thyroid malignancies carefully studied. The period from 5 to 15 years after iodization was associated with a lower frequency of follicular carcinomas and a higher frequency of papillary carcinomas than the period before and up to 5 years after prophylaxis. Lymphoid infiltration in the non-tumorous thyroid was relatively infrequent before iodine prophylaxis: it was much higher in each of the post-prophylaxis periods. These results, in agreement with other studies, support the view that an increased iodine intake is associated with an increased incidence of papillary carcinoma of the thyroid and thyroiditis.

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J. Reeve, M. Tellez, J. R. Green, R. Hesp, U. Elsasser, R. Wootton, P. Hulme, D. Williams, J. A. Kanis, R. G. G. Russell, E. B. Mawer, and P. J. Meunier

Abstract.

Five patients with involutional osteoporosis were treated with 24,25 dihydroxycholecalciferol (24,25-(OH)2D3) for 6 months, in doses sufficient to double plasma levels at that time. Dietary calcium absorption transiently improved by nearly 2 mmol Ca per day at 2 weeks, but this effect was lost by 6 months. The calcium and phosphate balances followed the trends in calcium absorption. Only twenty-five dihydroxyvitamin D levels changed little. Histomorphometric and kinetic indices of new bone formation and bone blood flow remained stable but there was an increase in urine hydroxyproline at 6 months, which was of borderline statistical significance. Treatment at this dosage of 24,25(OH)2D3, which increased plasma levels within the physiological range, conferred no measurable long-term benefit on our patients. Larger doses, or combination therapy, may warrant further clinical evaluation in osteoporosis.