quire a knowledge of the time-response relations following stimulation with (Einhorn 1958).

Transcription

1 Radiumhemmet (Professor Sven Hultberg), Karolinska sjukhuset, Stockholm EFFECT OF REPEATED THYROTROPHIN DOSES ON THE UPTAKE OF RADIOACTIVE IODINE BY THE HUMAN THYROID: TIME-RESPONSE RELATIONS By J. Einhorn and Gunnel Wikholm ABSTRACT Three injections of thyrotrophin were administered in euthyroid patients at intervals of 24 hours. Their effects on the iodine accumulation rate in the thyroid were determined at various intervals after the final injection. The iodine accumulation rate increased with repeated TSH injections. The effect reached its maximum 15\p=n-\18hours after the final injection. It is suggested that to ensure the maximal uptake of radioiodine following repeated injections of TSH, the radioiodine dose should be administered approximately 15 hours after the last injection. Thyrotrophin (thyrotrophic hormone, TSH) is used clinically mainly in con nection with investigations and treatment with radioactive iodine. It is useful for tests during the course of thyroid medication and for differential diagnosis between primary hypothyreosis and hypothyreosis due to pituitary insufficiency. It can also be administered during radioiodine therapy of normal, hyperfunctioning, or neoplastic thyroid tissue to increase the uptake of radioiodine by the treated tissue. Both the diagnostic and the therapeutic use of TSH re quire a knowledge of the time-response relations following stimulation with thyrotrophin. These relations have previously been studied in humans after a single dose of thyrotrophic hormone. The iodine accumulation in the thyroid begins to increase after a latent period of 8 hours following the intramuscular injection of thyrotrophin (Stanley 8c Astwood 1949); it reaches a maximum between 18 and 24 hours after the injection and then gradually decreases (Einhorn 1958). Repeated injections of thyrotrophin are often indicated in clinical practice. When this is the case, the iodine-accumulating function of the thyroid is under

2 the influence of repeated stimuli which have a complex mechanism of action and effects that probably overlap. The present investigation was designed to - elucidate the time-response relations after the last of a series of TSH injections which had been given at intervals of 24 hours. MATERIAL The series consisted of 46 patients with no known thyroid disease, selected from the wards of Radiumhemmet. Patients in poor general condition or with known cardiac or renal disease were excluded, as were those who had received drugs known to influence the thyroid function. METHODS Thyrotrophin (»Actyron«, Ferring, Malmö) was administered by intramuscular in jection. Each patient received a total of three injections of 5 USP units at intervals of 24 hours. The 24-hour interval is, for practical reasons, the one most commonly used in clinical work. The iodine accumulation in the thyroid was determined prior to administration of thyrotrophin and subsequently 18 hours after the first and also after the second injection. In patients determinations were made 12, 15, 18, 24 and 36 hours as well as five days after the third injection. The results reported do not include cases in which any of the projected tests were impracticable. The examinations were made by means of the radioactive isotope 132I (half-life 2.3 hours), which allowed of repeated tests in the same patient at short intervals. A method reported by Larsson 8c Jonsson (1955) was employed for determining the accumulation rate of radioiodine in the thyroid. The tracer dose of 132I was injected intravenously and the counting rates measured over the neck were continuously recorded. The difference between the counting rates 1 minute and 11 minutes after the injection was, after corrections for the physical decay of I32I and for changes in the residual radioactivity in the thyroid during the test period (Einhorn 1958), expressed in per cent of the counting rates ob tained from a solution of 132I with the same activity as that of the administered tracer dose. This value (termed H or initial accumulation rate) is also influenced by changes in extrathyroidal radioiodine within the volume of tissue scanned by the counter; it can be used, however, as an arbitrary index for the accumulation rates of radioiodine in the thyroid (Larsson 1955; Einhorn 1958). The results of the tests in each patient were calculated as the difference between the H value before and after initiation of thyrotrophin treatment (the H difference). A positive difference points to an increase in the iodine accumulation function of the thyroid following administration of thyro trophin. RESULTS There were major individual variations in the magnitude of the effect of thyrotrophin on the accumulation rate, expressed as the H difference. The time curve nevertheless showed a characteristic course which was seen to occur with great regularity in the patients studied. The results are detailed in Fig. 1 and Table 1.

3 H-diff. percent H-diff per cent Hours after second q~ TSH injection V^ Hours after third TSH injection A. The effect on the thyroidal radioiodine accumulation rate reaches its maximum after hours, then abates. The tests were made in patients. The broken line re presents the time curve that might be ex pected after the third TSH injection as suming that the effect of repeated injections were purely summative Exam, of patients -Exam, of 16 patients TSH ] 5 USP units Hours after third TSH injection B, Effect on the thyroidal radioiodine ac cumulation rate 3-12 hours after the third injection of TSH in a group of 16 patients. Fig. 1. Time-response relations following repeated intramuscular injections of TSH.

4 Table 1. Time-response relations after the third injection of thyrotrophin (see Fig. 1). The difference calculated between H values at two consecutive tests in the same patient. Differences greater than zero signify an increase, and those smaller than zero a de crease in the thyroidal radioactive iodine accumulation rate during the relevant interval. Time after TSH, hours Number of patients Mean of the differences, per cent Standard error of the mean , < 0.01 > 0.05 < < The iodine accumulation rate increased with repeated (three) injections of TSH. No rise or fall of the H value was demonstrable during the 12 hours immediately following the final injection of TSH. Later the H values rose, reaching, in most patients, a maximum 15 or 18 hours after the final injection. Thereafter they tended to return to the original level. Five days after the third injection, however, the values were still significantly higher than they had been prior to administration of TSH (P <C 0.001). For statistical analysis of the results obtained between 12 and 36 hours after the final injection of TSH, individual differences between the H values re corded at two consecutive tests on the same patients, were made up into series, i. e. one for each interval between tests. The mean and standard error were calculated for each series. The t test was used to ascertain whether the means differed significantly from zero (Table 1). Of the intervals studied, that between 12 and 15 hours after the third injection showed a significant increase of the initial accumulation rate. Between 18 and 36 hours there was a continuous fall. The decrease was already significant (P <i 0.001) during the interval from 18 to 24 hours after the final injection. The thyrotrophin dose of 5 USP units daily for three days caused no appre ciable distress in these euthyroid patients. DISCUSSION When three injections of TSH were given at 24-hour intervals, the iodine accumulation rate increased after each dose, though following the final dose, the rise was not demonstrable until hours after the injection. Following - a single TSH injection the effect on the iodine accumulating function of the

5 thyroid can be demonstrated, however, after a latent period of only 8 hours (Stanley 8c Astwood 1949). It reaches its maximum after hours and abates rapidly during the second day following the TSH injection (Einhorn 1958). This decrease may overlap any incipient effect of a subsequent injection; hence the apparently longer latent period after the last of the three TSH injections. Similar overlapping may be responsible in part for the fact that the maximum effect after the last series of thyrotrophin injections occurs earlier than that after a single injection. It has been suggested that the optimum time for ad ministering the dose of radioiodine is 18 hours after a single thyrotrophin in jection (Einhorn 8c Larsson 1959). When injections of TSH are repeated at 24-hour intervals, the corresponding optimum time is about 15 hours after the final TSH injection, if the aim is to attain the maximal uptake of radioiodine by the thyroid. In most of the cases reported here, the effect on the thyroidal uptake of radioiodine already decreased during the interval from hours after the final dose of TSH. The mechanism of thyrotrophin action on the thyroid gland is not known, but an increased thyroidal uptake of iodine is probably one of the final links in a chain of reactions initiated by the administration of thyrotrophin (Keating et al. 1945; Rawson et al. 1955; cf. Halmi et al. 1953, 1960; Taurog et al. 1958). Overlapping of the effects of repeated thyrotrophin doses would presumably result in initiation of a further chain of reactions before the termination of the preceding one. Since many factors in the thyroid gland are affected by each dose of thyrotrophin, the effect of repeated doses on the thyroidal uptake of radioiodine can scarcely be expected to be merely cumulative. Yet it may be worth while ascertaining whether and in what way the observed time-response relations differ from those which might result from pure summation. Fig. 1 shows the time curve as it might be expected to appear after the third injection of thyrotrophin if the effect of the latter had been added to the effects of the two preceding injections as pure summation. This curve was plotted on the basis of those time-response relations following a single thyrotrophin injection described previously and studied by the same method (Einhorn 1958). The observed time curve does not differ greatly from the summation curve, though the maximum effect on the thyroidal uptake of radioiodine does occur earlier and, moreover, the effect begins to subside earlier than hight have been anticipated. Halmi (1957) and Halmi et al. (1960) observed in a rats a decrease of the thyroid/serum 131I concentration ratio during the first few hours following in jection of TSH. With our technique and TSH doses, however, we have not detected, after the final thyrotrophin injection, any depression of the thyroidal accumulation rate of radioiodine as increased by previous TSH doses (Fig. 1 B). This work was supported by a grant from Swedish Cancer Society.

6 REFERENCES Baker S. P., Gaffney G. W., Shock N. W. Sc Landowne M.: J. Geront. 14 (1959) 37. Einkorn J.: Studies on the Effect of Thyrotrophic Hormone on the Thyroid Function in Man. Acta radiol. (Stockh.) Suppl. 160 (1958). Einhorn J. Sc Larsson L. G.: J. clin. Endocr. 19 (1959) 28. Halmi N. S., Spirtos.., Bogdanove E. M. Se Lipner H. J.: Endocrinology 52 (1953) 19. Halmi N. S. In: Wolstenholme C. E. W. & Millar E. C. P., Eds. Ciba Found. Colloq. on Endocrinology, vol. 10. Regulation and Mode of Action of Thyroid Hormones. London (1957) 79. Halmi N. S., Granner D. K., Doughman D. J., Peters B. H. Sc Midler G.: Endocrino logy 67 (1960) 70. Keating F. R. Jr., Rawson R. W'., Peacock W. Se Evans R. D.: Endocrinology 36 (1945) 137. Larsson L. G.: Studies on Radioiodine Treatment of Thyrotoxicosis. Acta radiol. (Stockh.) Suppl. 126 (1955). Larsson L. G. Sc Jonsson L.- Acta Radiol. (Stockh.) 43 (1955) 81. Rawson R. W'.. Rail J. E. Sc Sonenberg M. In: Pincus G. & Thimann K. V., Eds. The Hormones, vol. 3. New York (1955) 455. Stanley M. M. Se Astwood..: Endocrinology 44 (1949) 49. Taurog., Tong W. S- Chaikoff I. L.: Endocrinology 62 (1958) 664. Received on January 20th, 1961.