Augmentation of Thyrotropin Responses to ThyrotropinReleasing Hormone Following Small Decreases in Serum Thyroid Hormone Concentrations MANSOUR SABERI AND ROBERT D. UTIGER Endocrine Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19174 ABSTRACT. To determine whether slight decreases in serum thyroid hormone concentrations resulted in augmentation of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), TSH responses to TRH were determined before and after 13 days of iodide treatment in 20 normal subjects. Slight reductions in serum thyroxine (T4) and/or triiodothyronine (T3) concentrations and slight increases in basal serum TSH concentrations occurred in normal subjects treated with 50 or 250 mg iodide daily, though serum T4> T3 and TSH concentrations remained within their respective normal range. In contrast, TSH responses to TRH were significantly greater at the end of the iodide treatment period. In the subjects who received 50 mg iodide daily, mean basal serum TSH concentra-

M

ANY studies in recent years have demonstrated that secretion of thyrotropin (TSH) from the pituitary is inversely related to the circulating thyroxine (T4) and triiodothyronine (T3) concentrations. The availability of synthetic thyrotropin releasing hormone (TRH) has allowed further exploration of the physiology of TSH secretion. Studies reported from this laboratory have shown that very small increases in serum T4 and T3 concentrations, whether of exogenous or endogenous origin, markedly attentuate or abolish the TSH response to TRH (1,2). Impaired or absent TSH responses to TRH have been observed in patients with autonomous thyroid adenomas or euthyroid Graves' disease who had no clinical or laboratory manifestations of hyperthyroidism whatever (3-8). The present study was undertaken to deReceived September 10, 1974. Supported by USPHS Grants 5 RO 1 AM 14039, 5 TO 1 AM 05649 and RR 00040 (Clinical Research Center).

tions were 3.1 and 3.2 /i,U/ml before and 4.9 and 4.6 ^tU/ml after iodide. Post-TRH mean peak serum TSH concentrations were 14.2 /iU/ml before and 27.4 fj.U/ml after iodide (P < 0.01). A very similar augmentation of peak serum TSH was found in the subjects who received 250 mg iodide daily (before iodide, peak TSH 17.2 /xU/ml; after iodide, peak TSH 28.7 fji\J/ml). No changes in serum T4, T3 or TSH concentrations or TSH responses to TRH followed iodide administration in 4 thyroxinetreated hypothyroid patients. These results indicate that slight reductions in serum T4 and T3 concentrations result in increased pituitary sensitivity to TRH, just as small increases in serum T4 and T3 concentrations decrease sensitivity to TRH. (J Clin Endocrinol Metab 40: 435, 1975)

termine whether slight reductions in serum T4 and T3 concentrations might result in augmentation of the TSH response to TRH, as slight serum T4 and T3 increases have been shown to inhibit it. To reduce serum T4 and T3 concentrations, normal subjects were treated with inorganic iodide, recently shown by Vagenakis and coworkers (9) to have an anti-thyroid effect in such subjects, and their TSH responses to TRH were determined before and at the end of the iodide treatment period. The results confirm that iodide administration causes slight decreases in serum T4 and T3 concentrations and slight increases in serum TSH concentrations in normal subjects and demonstrate that these changes are associated with a marked enhancement of the TSH response to TRH. Thus, the pituitary thyrotroph appears to be as sensitive to slight reductions as it is to slight increases in serum thyroid hormone concentrations. Similar results have recently been presented by Vagenakis et al. (10).

435

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

JCE & M • 1975 Vol 40 • No 3

SABERI AND UTIGER

436

Materials and Methods Study Subjects. Twenty normal men, aged 18 to 30, and 3 women and 1 man with thyroidal hypothyroidism receiving thyroxine therapy were studied. Each subject was informed of the nature of the study and gave written consent. Study Protocol. Ten normal men were given 50 mg iodide (KI) daily. Another ten normal men were given 250 mg iodide daily. The four hypothyroid patients were given 50 mg iodide daily. These patients had been receiving 0.1 to 0.2 mg thyroxine daily for at least 1 month prior to study. Each subject initially received 400 fig TRH (Abbott) intravenously. Blood was collected at - 5 , 0, 5, 10, 15, 20, 30, 45, 60, 90, 120 and 180 min after TRH administration. After a 1-week interval, blood samples for T4, T3 and TSH determinations were collected daily for 5 days. Iodide was then administered once daily for 13 days, blood being collected at the time of each daily iodide dose. At the time of the last iodide dose, a second TRH test was performed. Subsequently, blood was collected every 2 days for 14 days. In the hypothyroid patients, only the two TRH tests before and after iodide administration were performed.

Hormone and statistical analyses. Serum T4 was measured by competitive protein binding analysis (11). Serum T3 and TSH were measured by radioimmunoassay (12,13). Normal ranges for these hormones in this laboratory are: T4, 5 to 11 /Ltg/100 ml; T3, 70 to 150 ng/100 ml; and TSH < 1.5 to 8 //.U/ml. Intraassay coefficients of variation for the three hormones were: T4, 5.3%; T3, 4.4%; and TSH, 12.4%. All samples from an individual subject were analyzed at the same time. Results are presented as the mean of determinations on any individual study day (±SEM) and were analyzed by the paired t test, using the mean of the 5 pretreatment days as control (14).

Results

Effect of iodide in normal subjects. Serum TSH, T 3 , and T 4 concentrations before, during and after iodide administration in the two groups of normal subjects are shown in Figs. 1 and 2. In the subjects receiving 50 mg iodide daily (Figure 1), there was no change in serum T 4 concentrations. Pretreatment serum T 3 concentrations varied from 127 to 134 ng/100 ml. D u r i n g iodide administration, the serum T 3 concentration decreased slightly but was

I I I I I I I I I'V I I I

I 1 1 I I I I I I// I

7

9

DAYS

13

15

17

20

I

FIG. 1. Mean serum T4) T3 and TSH concentrations in 10 normal subjects before, during and after administration of iodide, 50 mg/day. The vertical bars indicate ±1 SEM. The asterisks indicate values significantly different than control.

I

24

28

32

DAYS

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

r

437

INCREASED TSH RESPONSES TO TRH AFTER IODIDE

FIG. 2. Mean serum T4) T3 and TSH concentrations in 10 normal subjects before, during and after administration of iodide, 250 mg/day. The vertical bars indicate ±1 SEM. The asterisks indicate values significantly different from control.

7 9 DAYS

\

significantly lower than before treatment, 120 ng/100 ml (P < 0.01), only on the last day of iodide treatment (day 18). Pretreatment serum TSH concentrations varied from 2.9 to 3.8 fxU/ml, and though remaining within the normal range, were significantly higher than before treatment on the 4th, 6th through 11th and 13th days of iodide treatment (days 9, 11 to 16 and 18) (P < 0.05-0.01). The highest serum TSH concentration was 5.8 fiU/ml Serum T3 and TSH concentrations returned to control levels shortly after iodide withdrawal. The results in the normal subjects receiving 250 mg iodide daily (Fig. 2) were similar to those already described, although significant reductions in serum T4 and T3 concentrations were somewhat more frequent. Pretreatment serum T4 concentrations varied from 7.1 to 7.4 /Ag/100 ml. Serum T4 concentrations were significantly lower on 5 of the last 8 days of iodide administration (days 11, 12, 14, 16 and 18) (P < 0.05-0.01). The lowest serum T4 concentration was 6.7 /xg/100 ml. Pretreatment serum T3 concentrations varied from 118 to 127 ng/100 ml. Serum T3

13

15

17

20

24

28

DAYS

concentrations were significantly lower on 4 of the last 6 days of iodide administration (days 13 to 15 and 18) (P < 0.05-0.001). The lowest serum T3 concentration was 102 ng/100 ml. Pretreatment serum TSH concentrations varied from 3.4 to 3.9 /xU/ml. Serum TSH concentrations were significantly increased on 4 of the last 7 days of iodide administration (days 12 and 15 to 17) (P < 0.05-0.02). The highest mean serum TSH concentration was 5.4 fiU/ml. Serum T4, T3 and TSH concentrations returned to control levels within several days following iodide withdrawal. TSH and thyroidal responses to TRH. The TSH responses to TRH in the normal subjects before and after iodide are shown in Fig. 3. In the subjects who received 50 mg iodide daily, the basal ( - 5 and 0 min) serum TSH concentrations were 3.1 and 3.2 /uU/ml and the peak after TRH was 14.2 /xU/ml before iodide administration. At the end of the iodide treatment period, the serum TSH concentrations at all times after TRH were significantly higher following iodide administration (P < 0.05-0.001).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

JCE & M • 1975 Vol 40 • No 3

SABERI AND UTIGER

438

Iodide-50 mg/day

TRH

•—•

30

Before After

FIG. 3. Serum TSH responses to TRH before and after iodide administration. Top, 50 mg iodide. Bottom, 250 mg iodide. The vertical bars indicate ±1

lodide-25Omg/day

TRH

•—•

Before

SEM.

After

-5 0 10 20 30

60

90

180

TIME-minutes

In the subjects who received 250 mg iodide daily, the basal (—5 and 0 min) serum concentrations were 3.7 and 3.5 fiU/ml and peak after TRH was 17.2 /xU/ml before iodide administration. At the end of the iodide treatment period, the basal TSH concentrations were 4.8 and 4.5 /xU/ml and the peak after TRH was 28.7 /uU/ml. Serum TSH concentrations at all times after TRH were again significantly higher following iodide administration (P < 0.02-0.01). Basal and peak serum T4 and T3 concentrations after the two doses of TRH in both iodide treatment groups are shown in Table 1. Peak serum T4 and T3 concentrations most frequently occurred 180 min after TRH administration, both before and after iodide administration. The increment in serum T4 concentration, but not that in serum T3 concentration, was significantly lower after iodide administration in both groups.

Iodide studies in hypothyroid patients. The basal and peak serum TSH concentrations after TRH in the T4-treated hypothyroid patients are shown in Table 2. Both basal and peak serum TSH concentrations varied widely in the different patients studied, no doubt a consequence of varying doses of T4 therapy. Iodide administration had no effect on either basal serum T4, T3 or TSH concentrations or the peak serum TSH concentrations after TRH in any of the patients. These results demonstrate that the alterations in TSH responses to TRH observed in the normal subjects were not due to an effect of iodide on the pituitary gland. Discussion The results of this study confirm the report of Vagenakis and coworkers (9) that administration of inorganic iodide results

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

1

439

INCREASED TSH RESPONSES TO TRH AFTER I O D I D E TABLE 1. Basal and peak serum T4 and T3 concentrations after TRH before and after iodide administration to normal subjects After iodide

Pretreatment

Basal

Peak

Basal

Peak

(Mg/100ml)

Oxg/100 ml) 50 mg iodide

7.2 ± 0.2*

9.3 ± 0.5**

7.4 ± 0.4

8.0 ± 0.4**

250 mg iodide

6.6 ± 0.3

8.4 ± 0.5***

6.8 ± 0.4

7.5 ± 0.4***

T,

T,

Basal

Basal1

Peak

(ng/100 ml)

(ng/100 ml) 50 mg iodide 250 mg iodide

Peak

126 i 7*

169 ± 9

121 ± 4

168 ± 9

108 ± 3

159 ± 8

102 ± 3

140 + 6

* Mean ± SEM. •* Difference between increments, P < 0.01. *** Difference between increment.*i, P < 0.02.

in small but significant decreases in serum T3 and T4 concentrations and small but significant increases in serum TSH concentrations in normal subjects. Nevertheless, all hormone concentrations remained within their respective normal ranges. The changes observed were somewhat variable and significant changes occurred more frequently in the subjects receiving the larger dose of iodide. However, the magnitude of the changes were similar in the two groups, except in the case of serum T4 concentra-

tions which did not change significantly in the subjects receiving 50 mg iodide daily. Because of differences in experimental design and analysis, these results cannot be directly compared to those of Vagenakis et al. (9), but the magnitude of the changes in serum T4, T3 and TSH concentrations was similar in the two studies. The decrease in serum T3 and T4 concentrations during iodide administration is probably a consequence of decreased thyroidal secretion (15,16), plus, in the case of T3, decreased availability of T4 for peripheral conversion to T3. Iodide inhibition of thyroid hormone synthesis in normal subjects is transient (17) and therefore not likely to result in alterations in secretion in subjects with adequate preformed stores of T4 and T3, as was presumably the case in these normal subjects. Iodide has not been shown to alter peripheral degradation of T4 (18). The lack of change in serum T4 and T3 concentrations during iodide administration in the T4-treated hypothyroid patients is further evidence against a peripheral iodide effect. In the normal subjects basal serum TSH concentrations increased no more than 2 to 3 /w,U/ml, whereas peak serum TSH concentrations after TRH were 10 to 15 ;u,U/ml greater following iodide administration. Thus, slight increases in basal serum TSH concentrations but markedly augmented TSH responses to TRH followed slight

TABLE 2. Basal and peak serum TSH concentrations after TRH after administration in hypothyroid patients before and after iodide treatment After iodide

Pretreatment TSH Patient* F.B. A.O. C.P. W.D.

T< (Mg/100 ml)

T3 (ng/100 ml)

6.4 5.6 7.9 6.4

68 68 113 72

TSH

Basal Peak (^U/ml) 12.7 48.6 3.0 6.2

71.5 305.0 5.5 22.7

T4 (/xg/100 ml)

T3 (ng/100 ml)

6.6 5.3 10.2 6.2

68 67 101 71

Basal Peak (MU/ml) 8.6 42.0 1.5 5.8

66.0 320.0 2.5 25.0

* Thyroxine dose in these patients as follows: F.B. and A.O. 0.1 mg/day, C.P. 0.15 mg/day, W.D. 0.2 mg/day.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

440

JCE & M • 1975 Vol 40 • No 3

SABERI AND UTIGER

reductions in serum T4 and T3 concentrations that were of short duration. Similar results have been found in normal subjects given lithium carbonate for three weeks (19). These findings, taken in conjunction with the observations reported elsewhere that blunting or abolition of TSH responses to TRH followed slight elevations in serum T4 and/or T3 concentrations (1,2), indicate how sensitively the thyrotrophs can recognize minor alterations in the intensity of negative feedback control. Thus, the thyrotrophs can effect increases in serum TSH and thus thyroid secretion, when serum thyroid hormone concentrations have fallen, or reduce TSH and thus thyroid secretion, when thyroid hormone concentrations have increased, as a result of very minor changes in serum thyroid hormone concentrations. The protective effect of operation in either direction, before thyroid hormone concentrations have varied widely, is evident. These results also indicate that the magnitude of the TSH response to TRH is an indicator of basal TSH secretion. since alterations in TSH responses to TRH occur in situations in which basal TSH concentrations would be expected to be altered, though this may not be demonstrable with the presently available TSH radioimmunoassays. Thus, clinically euthyroid patients with very minor degrees of thyroid insufficiency, whose basal serum TSH concentrations are within the normal range, should have augmented TSH responses to TRH. Such augmented responses have been found in some patients with Hashimoto's disease and subclinical hypothyroidism (5,20,21). Conversely, clinically euthyroid patients whose thyroidal secretion is partially autonomous, and in whom basal serum TSH concentrations are probably subnormal, should have diminished or absent TSH responses to TRH. Such diminished or absent responses have been found in patients with thyroid adenomas and euthyroid Graves' disease,

as well as in normal subjects receiving small doses of exogenous thyroid hormones (1-8). The increased serum TSH concentrations after TRH following iodide administration were not followed by greater increments in serum T4 or T3 concentrations. In fact, the serum T4 increment after TRH was decreased. Peak serum T4 concentrations might, in some instances, have been missed since in some studies peak serum T4 concentrations occurred 4 to 6 hours after TRH (22,23). However, there is no reason to believe peak T4 concentrations would have occurred later only following iodide treatment. Since the TJT3 ratio of thyroglobulin should be higher following iodide administration (24), greater impairment in serum T3 than T4 responses might have been expected. Reduced increases in serum T3 responses to TRH were found by Vagenakis et al; the T4 responses were not described (10). Acknowledgments We thank Miss Cordelia Shute and her staff of the Clinical Research Center for help with the clinical studies, Mrs. Maryanne O'Neil and Miss Leona Scott for technical assistance and Mrs. Beth Fischer and Mrs. Olivia Phillips for secretarial help.

References 1. Synder, P. J., and R. D. Utiger, J Clin Invest 51: 2077, 1972. 2. , and J Clin Invest 52: 2305, 1973. 3. Ridgway, E. C , B. D. Weintraub, J. L. Cevallos, M. C. Rack, and F. MaloofJ Clin Invest 52: 2783, 1973. 4. Sanchez-Franco, F., M. D. Garcia, L. Cacicedo, A. Martin-Zurro, F. Escobar del Rey, and G. Morreale de Escobar, J Clin Endocrinol Metab 38: 1098, 1974. 5. Franco, P. S., J. M. Hershman, E. D. Haigler, Jr., and J. A. Pittman, Jr., Metabolism 22: 1357, 1973. 6. Chopra, I. J., U. Chopra, and J. Orgiazzi, / Clin Endocrinol Metab 37: 955, 1973. 7. Ormston, B. L., L. Alexander, D. C. Evered, F. Clark, T. Bird, D. Appleton, and R. Hall, Clin Endocrinol 2: 369, 1973. 8. Clifton-Bligh, P., G. E. Silverstein, and G. Burke, 7 Clin Endocrinol Metab 38: 531, 1974.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

INCREASED TSH RESPONSES TO TRH AFTER IODIDE 9. Vagenakis, A. G., P. Downs, L. E. Braverman, A. Burger, and S. H. Ingbar, / Clin Invest 52: 528, 1973. 10. Vagenakis, A., F. Azizi, G. Portnay, L. Braverman, B. Rapoport, and S. Ingbar, J Clin Invest 54: 913, 1974. 11. Murphy, B. P. J Clin Lab Med 66: 161, 1965. 12. Lieblich, J., and R. D. Utiger, J Clin Invest 51: 157, 1972. 13. Odell, W. D., J. F. Wilber, and R. D. Utiger, Recent Progr Harm Res 23: 47, 1967. 14. Snedecor, G. W., and W. G. Cochran, Statistical Methods, Iowa State Univ Press, 6th edition, 1967, p. 91. 15. Mercer, C. J., J. M. Westerink, and D. D. Adams, Lancet 2: 19, 1960. 16. Wartofsky, L., B. J. Ransil, and S. H. Ingbar,y Clin Invest 49: 78, 1970.

441

17. Stanley, M. M., J Clin Endocrinol Metab 9: 941, 1949. 18. De Groot, L. ].,] Clin Endocrinol Metab 26: 778, 1966. 19. Lauridsen, U. B., C. Kirkegaard, and J. Nerup, J Clin Endocrinol Metab 39: 383, 1974. 20. Evered, D. D., B. J. Ormston, P. A. Smith, R. Hall, and T. Bird, Br Med] 1: 657, 1973. 21. Gordin, A., P. Saarinen, R. Pelkonen, and B. A. Lamberg, Ada Endocrinol 75: 274, 1974. 22. Kalberg, A., S. Almquist, and S. Werner, Ada Endocrinol 67: 288, 1971. 23. Uller, R. F., A. J. Van Herle, and I. J. Chopra, y Clin Endocrinol Metab 37: 741, 1973. 24. Nagataki, S., H. Uchimura, Y. Masuyama, K. Nakao, and K. Ito, y Clin Endocrinol Metab 35: 18, 1972.

Erratum In the article "The Effects of Growth Hormone Therapy on Collagen Metabolism in Children," by G. P. August, W. Hung, and J. C. Houck, which appeared in J Clin Endocrinol Metab 39: 1103, 1974, there is a typographical error. On page 1106, line 5: 6.3 /u.g/100 ml should read 6.3

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 12:40 For personal use only. No other uses without permission. . All rights reserved.

Augmentation of thyrotropin responses to thyrotropin-releasing hormone following small decreases in serum thyroid hormone concentrations.

Augmentation of Thyrotropin Responses to ThyrotropinReleasing Hormone Following Small Decreases in Serum Thyroid Hormone Concentrations MANSOUR SABERI...
550KB Sizes 0 Downloads 0 Views

Recommend Documents