PROLONGED DRUG TREATMENT OF HYPERTHYROIDISM BELTON A. BURROWS, M.D., AND (BY INVITATION) D. WARD SLINGERLAND, M. D. BOSTON
Two presently accepted modes of medical treatment for hyperthyroidism have major drawbacks: radioiodine therapy is often followed by hypothyroidism, antithyroid drug therapy by relapse. The incidence of hypothyroidism following radioiodine therapy is variously reported between twenty-five and fifty percent,1-5 and about three-fourths of patients who are euthyroid after treatment fail to respond normally to TSH stimulation4. The incidence of relapse following drug therapy is variously reported between fdrty-five and sixty percent.6-8 It has been recently suggested that therapy be stopped when a euthyroid state is reached (at about four months) and that failures and relapses be treated with alternative therapy.8 For the past twenty years we have been treating hyperthyroidism with continuous antithyroid drug therapy. The prognostic suppression test9 has been used to predict permanent remission. When the twentyfour hour radioiodine uptake is below 20% after three weeks of exogenous thyroid, therapy is stopped."' The use of thyrotropin releasing hormone (TRH) as a prognostic test" has also been evaluated. The present paper reports the long-term results of this therapeutic approach. METHOD Seventy-seven hyperthyroid patients have been treated with antithyroid drugs for one or more years except one who was treated for six months. They have been followed for at least one year after remission was achieved. These patients were veterans and there were only seven females. Twelve other patients were eliminated, six because they were given radioiodine treatment (usually elsewhere) and six because they died, from unrelated causes, before treatment was completed. None had prior surgical or radioiodine treatment. The usual treatment regimen was 100 mg of propylthiouracil (PTU) every 8 hours modified according to the functional result. Thyroid was From the Nuclear Medicine Service, Veterans Administration Hospital, Boston, Mass. 02130 and Department of Medicine, Boston University School of Medicine, Boston, MA 02118. Supported by the Medical Research Service of the Veterans Administration. 219
220
BURROWS AND SLINGERLAND
given on occasion but rarely on a continuing, long-term basis. The treatment and follow-up were always done by the authors. In 51 patients a prognostic suppression test was done after the antithyroid drug was stopped, usually at the end of about one year and after each subsequent year of treatment. Thyroid, 3 to 4 grains per day, was given for 3 weeks (or sometimes triiodothyronine, 75 to 100 micrograms per day, for one week) and a 24-hour thyroidal uptake of radioiodine determined. If this uptake was less than 20%, propylthiouracil treatment was not restarted unless clinical relapse occurred. If the uptake was over 20%, propylthiouracil was restarted. This has been and is continuing to be done for an unlimited time. The longest treatment is over 12 years, the shortest 6 months (the patient stopped treatment on his own at that time). In 46 patients 50 tests with TRH, 500 micrograms intravenously, were done and the responses in the blood levels of thyrotrophic stimulating hormone (TSH) and triiodothyronine (T3) 30, 60 and 120 minutes after injection determined. Twenty-two patients were so tested while receiving propylthiouracil to determine any prognostic value in the results. Twenty-four tests were done in patients in remission to determine the degree of reversion to normal of this test in a 'cured' hyperthyroid patient. RESULTS The overall remission rate for propylthiouracil treated patients is 68% (Table I) with an average follow-up of 7.1 years (range 1 to 19 years). Of the 52 patients in remission after therapy, 26 were taken off propylthiouracil therapy because of prognostic suppressions below 20%. Of 32 patients with suppression uptakes below 20%, 26 (81%) remain in remisTABLE I Remissions* in Hyperthyroid Patients Treated with Propylthiouracil for 0.5 to 12.3 Years Yrs. of Rx.
Remission
F.U. Yrs. Av. (Range)
Non-Supp.t
1 11 (1-19) 18 (1)§ 1.5-3 ..................... 10 3.4 (1-9) 10 >3-5 (Range 5-12.3) .......... 10 25 52 (68%) Total ..................... * Remission was determined by a 24 hour thyroidal uptake on suppression (after 3 weeks of exogenous thyroid) of less than 20% and continuing clinical and chemical .....................
euthyroidism. t The number of patients whose 24 hour uptakes on suppression were not less than 20% and who, therefore, resumed PTU therapy. t One patient was treated for less than a year. § Two patients who became hypothyroid 18 and 6 years respectively after PTU was
stopped.
221
PROLONGED DRUG TREATMENT OF HYPERTHYROIDISM
sion after therapy (average follow-up 4.8 years, range 1 to 14 years). Of the 25 patients continuing on propylthiouracil therapy because of suppressed uptakes above 20%, it is not known how many would remain in remission were they to be taken off therapy. Other studies,9, 12 suggest that 20-30% might remain euthyroid off therapy. Were 20% of this group of 25 to remain in remission off therapy the overall permanent remission rate would be about 75%. Of the 77 patients, two have become hypothyroid, one 18 and one 7 years after propylthiouracil was stopped. A total of 18 patients have had to be treated for 5 and more years. Of this group, 10 have been adequately suppressed (5 to 11 years after treatment was started) and remain in remission without treatment. One cannot say how long the remaining 8 will have to be treated. It should be noted that the patient treated the longest, 12 +years, recurred 13/4 years after treatment was stopped (suppressed uptake 14%) and is once more receiving propylthiouracil. In 14 patients (Table II) followed for 10 or more years (average 15, range 10.5 to 19 years) of remission after therapy, one patient (J.M.) became clinically and chemically hypothyroid after 18 years and one additional patient (P.F.) had an elevated TSH, other thyroid indices being normal, after 16 years. In 15 hyperthyroid patients treated for 5 or more consecutive years with propylthiouracil 4 or more yearly prognostic suppression tests were done. In 9 of the 15 there was a progressive diminution over a period of 3 to 6 years (Fig. 1). Seven of these 9 have been off propylthiouracil from 1 to 8 years and remain euthyroid. One (C.M.) of the 9 recurred 1 year TABLE II The Results of Long-Term Follow-up (>10 years) of Patients Treated with Propylthiouracil for Hyperthyroidism T4 (/±g/1OO ml)
T,R (%)
T, (ng/100 ml)
7.0 7.3
27 22
104
2.0 39.0
14
7.4
26
94
2.2
19
9.0
30
14 16 13 16
7.2 5.1 7.6 6.3
9. R.M. ........... 10. J.M.t ..........
101/2 18
6.0 2.3
29 18
11. J.N ............. 12. G.S ............. 13. C.S .............
15 18 11
9.8 10.3 7.3
30 25
Patient
F.U. (yrs.)*
1. D.C. ........... 2. P.F .............
19 16
3. R.F ............. 4. T.F
.............
J.G ............. S.G ............. S.Gr ............ L.G .............
5. 6. 7. 8.
14. G.Su. .......... 15 10.4 * After propylthiouracil treatment was stopped.
t Clinically hypothyroid.
TSH
(jiU/ml)
50.0 39.0 11.0 J.K ....... 34 4 (+5%)t 4.7 8.2 3.5 9.9 67 J.Ko .6 -10 (-6%)t 6.5 50.0 43.5 10.8 H.R ........ 50 34 (36%) 1.0 7.2 6.2 8.0 V.D ........ 23 2 (2%) 1.7 4.8 3.1 8.6 A.R ........ 22 51 (52%) 6.3 45.0 38.7 5.1 * The "suppression" test: a 24-hour 1311 uptake after 3 weeks off PTU and on thryoid (4 grains). t Last sample drawn at 60 minutes. .......
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
TABLE IV The T3 and TSH Responses to TRH in Patients "Adequately" and 'Inadequately Number of Patients
'3'I Uptake (%)* Av. (Range)
6
15 (9-20)
Suppressed"* AT3 (ng/100 ml)
TSH (MU/ml)
Basal
74 ± 15t
3.1
+
Peak
9.7 ± 1.9t
0.7
13 41 (23-67) 26 ± 8t 4.1 ± 0.8 17.8 ± 5.6t The "suppression test" is a 24-hour 131I uptake after 3 weeks off PTU and on thyroid (4 grains). "Adequate suppression" is 50.0 28.0 3.0 4.5 40.0
29.0 17.2 0.8 1.0 33.9
trolled by therapy. The later recrudescence of signs and symptoms, months to years after therapy has been stopped, is presumably a recurrence. With mounting evidence that there often remain abnormalities in the successfully treated patient, such as failure to respond to TRH"I and evidence of stimulatory immunoglobulins,'2 the difference between control and 'cure' is no longer clear. Approximately two decades ago we started to treat most of our hyperthyroid patients with antithyroid drugs for an indefinite time until remission without treatment was achieved. The overall 'cure' rate to date of 68% is better than most shorter-term treatment results. This will be no surprise to those who think the disease may run a limited,13 if often prolonged, course, and particularly not to some who think hyperthyroid patients will eventually become hypothyroid,'4-'6 We have little evidence to support the latter (2 instances in 77). The former belief may be true but there is recent evidence to suggest a possible long term effect of antithyroid drugs on the disease. 10,17 Recent emphasis has been on the attempts. to differentiate those patients who will stay in remission from those who will relapse after antithyroid drug therapy is stopped.8"' 17 The prognostic suppression test9 is of value and in our experience is about 80% accurate. The TRH test, despite early reports to the contrary,'8"9 appears to be of little prognostic use."'20 21 The present study indicates that a high proportion of patients (8/11) whose prognostic suppression tests were not below 20% had normal responses to TRH. In 2 of 6 patients with suppression tests below 20% the TRH response was low. In euthyroid patients in remission after antithyroid therapy a high proportion had subnormal TSH responses to TRH and some had hyper-responses. There is, then, a variety of combinations of TRH response in euthyroid patients who have been or are being treated with antithyroid drugs and there is no good correlation between TRH responsiveness and the prognostic suppression test. In contrast to an early assessment of antithyroid therapy and a move toward an alternative treatment8 we are persuaded by our results to
PROLONGED DRUG TREATMENT OF HYPERTHYROIDISM
225
continue antithyroid treatment indefinitely, as have others.13 The alternative therapy is usually radioiodine and 30-50% of such patients will require thyroid replacement. The odds of eventually coming off prolonged drug treatment with a functionally normal gland are excellent. 1. 2. 3. 4.
5.
6. 7.
8. 9. 10. 11.
12.
13. 14. 15. 16. 17. 18.
REFERENCES McGIRR, E. M., THOMSON, J. A., AND MURRAY, I. P. C.: Radioiodine therapy in thyrotoxicosis; a review of 908 cases. Scot. Med. J. 9: 505-513, 1964. DUNN, J. T., AND CHAPMAN, E. M.: Rising incidence of hypothyroidism after radioactive-iodine therapy in thyrotoxicosis. New Eng. J. Med. 271: 1037-1042, 1964. GREEN, M., AND WILSON, G. M.: Thyrotoxicosis treated by surgery or iodine-131 with special reference to development of hypothyroidism. Brit. J. Med. 1: 1005-1010, 1964. SLINGERLAND, D. W., DELL, E. S., AND BURROWS, B. A.: The spectrum of thyroid function after radioiodine treatment. In, Further Advances in Thyroid Research (K. Fellinger and R. Hofer, ed.) Vienna, G. Gistel and Cie, 1971, pp. 993-1003. EINHORN, J., AND WICKLUND, H.: Hypothyroidism following 131I treatment. J. Clin. Endocrinol. Metab. 26: 33-36, 1966. TROTTER, W. R.: Non surgical treatment of thyrotoxicosis. Proc. Roy. Soc. Med. 54: 869-871, 1961. HERSHMAN, J. M., GIVENS, J. R., CASSIDY, C. E. AND ASTWOOD, E. B.: Long-term outcome of hyperthyroidism treated with antithyroid drugs. J. Clin. Endocrin. Metab. 26: 803-807, 1966. GREER, M. A., KRAMMER, H., AND BOURNA, D. J.: A simplified short-term technique for treating Graves' disease with antithyroid drugs. Program American Thyroid Association, (Abst.), p. T-2, September 15-18, 1976. CASSIDY, C. E., AND VANDER LAAN, W. P.: Thyroid-suppression test in the prognosis of hyperthyroidism treated by antithyroid drugs. New Eng. J. Med. 262: 1228-1229, 1960. SLINGERLAND, D. W., SULLIVAN, J. J., DELL, E. S. AND BURROWS, B. A.: Thyroid suppression tests during drug treatment of hyperthyroidism. Clin. Endocrinology 5: 415-418, 1976. SLINGERLAND, D. W., SULLIVAN, J. J., DELL, E. S. AND BURROWS, B. A.: Effects of TRH in hyperthyroid patients treated with antithyroid drugs. Excerpta Medica, Seventh International Thyroid Conference, (Abst.), p. 78, 1975. McKENZIE, J. M.: Does LATS cause hyperthyroidism in Graves' disease? -Metabolism 21: 883-894, 1972. HOWARD, J. E.: Treatment of thyrotoxicosis. JAMA 202: 706-709, 1967. WOOD, L. C., PETERSON, M., AND INGBAR, S. H.: Delayed thyroid failure and decreased reserve following antithyroid therapy in Graves' disease. Program American Thyroid Association, (Abst.), p. 61, 1972. SATTLER, H.: Basedow's Disease. Grune and Stratton Co., New York, 1952. WOOD, L. C., AND MALOOF, F.: Thyroid failure after potassium iodide treatment of diffuse toxic goiter. Trans. of Assoc. of American Physicians, 88, 1975. ALEXANDER, W. D., McLARTY, D. G., HORTON, P. AND PHARMAKIOTIS, A. D.: Sequential assessment during drug treatment of thyrotoxicosis. Clin. Endocrinology 2: 4350, 1973. D'AMOUR, P., BANOVAC, K., SALISBURY MURPHY, S., FRIESEN, M. H. AND McKENZIE, J. M.: TRH-tests, T3-suppression tests and serum T4 concentrations in euthyroid Graves' disease. Program American Thyroid Association, (Abst.), p. T-9, Sept. 1215, 1973.
226
BURROWS AND SLINGERLAND
19. ORMSTON, B. J., ALEXANDER, L., EVERED, D. C., CLARK, F., BIRD, T., APPLETON, D. AND HALL, R.: Thyrotrophin response to thyrotrophin-releasing hormone in ophthalmic Graves' disease: correlation with other aspects of thyroid function, thyroid suppressibility and activity of eye signs. Clin. Endocrinology 2: 369-376, 1973. 20. CLIFrON-BLIGH, P., SILVERSTEIN, G. E., AND BURKE, G.: Unresponsiveness to thyrotropin-releasing hormone (TRH) in treated Graves' hyperthyroidism and in euthyroid Graves' disease. J. Clin Endocrinol. Metab. 38: 531-538, 1974. 21. MARTINO, E., PINCHERA, A., CAPIFERRI, R., MACCHIA, E., AMBRASINO, N. AND BASCHIERI, L.: Dissociation of responsiveness to thyrotropin-releasing hormone from thyroid suppressibility and outcome of hyperthyroidism following antithyroid drug therapy. Excepta Medica, Seventh International Thyroid Conference, (Abst.), p. 78, 1975.
DISCUSSION
DR. F. DENNETTE ADAMS (Boston): Were any patients treated with surgery? DR. BURROWS: We have had recorded results only on those patients who have been on propylthiouracil. DR. LEWIS DEXTER (Boston): Belton, you showed one patient where it took seven years to get him under control. Was he very symptomatic for those seven years while you were waiting for the response? DR. BURROWS: No. I should have defined that by 'remission' we mean a euthyroid state after the drug has been stopped. We certainly feel that we controlled the disease by giving adequate antithyroid compound. All that is required of these patients is that they continue to take the medication as prescribed until remission is achieved. Inderol was used in very few because the series was accumulated for the most part before this became popular.
Two presently accepted modes of medical treatment for hyperthyroidism have major drawbacks: radioiodine therapy is often followed by hypothyroidism, antithyroid drug therapy by relapse. The incidence of hypothyroidism following radioiodine therapy is variously reported between twenty-five and fifty percent,1-5 and about three-fourths of patients who are euthyroid after treatment fail to respond normally to TSH stimulation4. The incidence of relapse following drug therapy is variously reported between fdrty-five and sixty percent.6-8 It has been recently suggested that therapy be stopped when a euthyroid state is reached (at about four months) and that failures and relapses be treated with alternative therapy.8 For the past twenty years we have been treating hyperthyroidism with continuous antithyroid drug therapy. The prognostic suppression test9 has been used to predict permanent remission. When the twentyfour hour radioiodine uptake is below 20% after three weeks of exogenous thyroid, therapy is stopped."' The use of thyrotropin releasing hormone (TRH) as a prognostic test" has also been evaluated. The present paper reports the long-term results of this therapeutic approach. METHOD Seventy-seven hyperthyroid patients have been treated with antithyroid drugs for one or more years except one who was treated for six months. They have been followed for at least one year after remission was achieved. These patients were veterans and there were only seven females. Twelve other patients were eliminated, six because they were given radioiodine treatment (usually elsewhere) and six because they died, from unrelated causes, before treatment was completed. None had prior surgical or radioiodine treatment. The usual treatment regimen was 100 mg of propylthiouracil (PTU) every 8 hours modified according to the functional result. Thyroid was From the Nuclear Medicine Service, Veterans Administration Hospital, Boston, Mass. 02130 and Department of Medicine, Boston University School of Medicine, Boston, MA 02118. Supported by the Medical Research Service of the Veterans Administration. 219
220
BURROWS AND SLINGERLAND
given on occasion but rarely on a continuing, long-term basis. The treatment and follow-up were always done by the authors. In 51 patients a prognostic suppression test was done after the antithyroid drug was stopped, usually at the end of about one year and after each subsequent year of treatment. Thyroid, 3 to 4 grains per day, was given for 3 weeks (or sometimes triiodothyronine, 75 to 100 micrograms per day, for one week) and a 24-hour thyroidal uptake of radioiodine determined. If this uptake was less than 20%, propylthiouracil treatment was not restarted unless clinical relapse occurred. If the uptake was over 20%, propylthiouracil was restarted. This has been and is continuing to be done for an unlimited time. The longest treatment is over 12 years, the shortest 6 months (the patient stopped treatment on his own at that time). In 46 patients 50 tests with TRH, 500 micrograms intravenously, were done and the responses in the blood levels of thyrotrophic stimulating hormone (TSH) and triiodothyronine (T3) 30, 60 and 120 minutes after injection determined. Twenty-two patients were so tested while receiving propylthiouracil to determine any prognostic value in the results. Twenty-four tests were done in patients in remission to determine the degree of reversion to normal of this test in a 'cured' hyperthyroid patient. RESULTS The overall remission rate for propylthiouracil treated patients is 68% (Table I) with an average follow-up of 7.1 years (range 1 to 19 years). Of the 52 patients in remission after therapy, 26 were taken off propylthiouracil therapy because of prognostic suppressions below 20%. Of 32 patients with suppression uptakes below 20%, 26 (81%) remain in remisTABLE I Remissions* in Hyperthyroid Patients Treated with Propylthiouracil for 0.5 to 12.3 Years Yrs. of Rx.
Remission
F.U. Yrs. Av. (Range)
Non-Supp.t
1 11 (1-19) 18 (1)§ 1.5-3 ..................... 10 3.4 (1-9) 10 >3-5 (Range 5-12.3) .......... 10 25 52 (68%) Total ..................... * Remission was determined by a 24 hour thyroidal uptake on suppression (after 3 weeks of exogenous thyroid) of less than 20% and continuing clinical and chemical .....................
euthyroidism. t The number of patients whose 24 hour uptakes on suppression were not less than 20% and who, therefore, resumed PTU therapy. t One patient was treated for less than a year. § Two patients who became hypothyroid 18 and 6 years respectively after PTU was
stopped.
221
PROLONGED DRUG TREATMENT OF HYPERTHYROIDISM
sion after therapy (average follow-up 4.8 years, range 1 to 14 years). Of the 25 patients continuing on propylthiouracil therapy because of suppressed uptakes above 20%, it is not known how many would remain in remission were they to be taken off therapy. Other studies,9, 12 suggest that 20-30% might remain euthyroid off therapy. Were 20% of this group of 25 to remain in remission off therapy the overall permanent remission rate would be about 75%. Of the 77 patients, two have become hypothyroid, one 18 and one 7 years after propylthiouracil was stopped. A total of 18 patients have had to be treated for 5 and more years. Of this group, 10 have been adequately suppressed (5 to 11 years after treatment was started) and remain in remission without treatment. One cannot say how long the remaining 8 will have to be treated. It should be noted that the patient treated the longest, 12 +years, recurred 13/4 years after treatment was stopped (suppressed uptake 14%) and is once more receiving propylthiouracil. In 14 patients (Table II) followed for 10 or more years (average 15, range 10.5 to 19 years) of remission after therapy, one patient (J.M.) became clinically and chemically hypothyroid after 18 years and one additional patient (P.F.) had an elevated TSH, other thyroid indices being normal, after 16 years. In 15 hyperthyroid patients treated for 5 or more consecutive years with propylthiouracil 4 or more yearly prognostic suppression tests were done. In 9 of the 15 there was a progressive diminution over a period of 3 to 6 years (Fig. 1). Seven of these 9 have been off propylthiouracil from 1 to 8 years and remain euthyroid. One (C.M.) of the 9 recurred 1 year TABLE II The Results of Long-Term Follow-up (>10 years) of Patients Treated with Propylthiouracil for Hyperthyroidism T4 (/±g/1OO ml)
T,R (%)
T, (ng/100 ml)
7.0 7.3
27 22
104
2.0 39.0
14
7.4
26
94
2.2
19
9.0
30
14 16 13 16
7.2 5.1 7.6 6.3
9. R.M. ........... 10. J.M.t ..........
101/2 18
6.0 2.3
29 18
11. J.N ............. 12. G.S ............. 13. C.S .............
15 18 11
9.8 10.3 7.3
30 25
Patient
F.U. (yrs.)*
1. D.C. ........... 2. P.F .............
19 16
3. R.F ............. 4. T.F
.............
J.G ............. S.G ............. S.Gr ............ L.G .............
5. 6. 7. 8.
14. G.Su. .......... 15 10.4 * After propylthiouracil treatment was stopped.
t Clinically hypothyroid.
TSH
(jiU/ml)
50.0 39.0 11.0 J.K ....... 34 4 (+5%)t 4.7 8.2 3.5 9.9 67 J.Ko .6 -10 (-6%)t 6.5 50.0 43.5 10.8 H.R ........ 50 34 (36%) 1.0 7.2 6.2 8.0 V.D ........ 23 2 (2%) 1.7 4.8 3.1 8.6 A.R ........ 22 51 (52%) 6.3 45.0 38.7 5.1 * The "suppression" test: a 24-hour 1311 uptake after 3 weeks off PTU and on thryoid (4 grains). t Last sample drawn at 60 minutes. .......
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
TABLE IV The T3 and TSH Responses to TRH in Patients "Adequately" and 'Inadequately Number of Patients
'3'I Uptake (%)* Av. (Range)
6
15 (9-20)
Suppressed"* AT3 (ng/100 ml)
TSH (MU/ml)
Basal
74 ± 15t
3.1
+
Peak
9.7 ± 1.9t
0.7
13 41 (23-67) 26 ± 8t 4.1 ± 0.8 17.8 ± 5.6t The "suppression test" is a 24-hour 131I uptake after 3 weeks off PTU and on thyroid (4 grains). "Adequate suppression" is 50.0 28.0 3.0 4.5 40.0
29.0 17.2 0.8 1.0 33.9
trolled by therapy. The later recrudescence of signs and symptoms, months to years after therapy has been stopped, is presumably a recurrence. With mounting evidence that there often remain abnormalities in the successfully treated patient, such as failure to respond to TRH"I and evidence of stimulatory immunoglobulins,'2 the difference between control and 'cure' is no longer clear. Approximately two decades ago we started to treat most of our hyperthyroid patients with antithyroid drugs for an indefinite time until remission without treatment was achieved. The overall 'cure' rate to date of 68% is better than most shorter-term treatment results. This will be no surprise to those who think the disease may run a limited,13 if often prolonged, course, and particularly not to some who think hyperthyroid patients will eventually become hypothyroid,'4-'6 We have little evidence to support the latter (2 instances in 77). The former belief may be true but there is recent evidence to suggest a possible long term effect of antithyroid drugs on the disease. 10,17 Recent emphasis has been on the attempts. to differentiate those patients who will stay in remission from those who will relapse after antithyroid drug therapy is stopped.8"' 17 The prognostic suppression test9 is of value and in our experience is about 80% accurate. The TRH test, despite early reports to the contrary,'8"9 appears to be of little prognostic use."'20 21 The present study indicates that a high proportion of patients (8/11) whose prognostic suppression tests were not below 20% had normal responses to TRH. In 2 of 6 patients with suppression tests below 20% the TRH response was low. In euthyroid patients in remission after antithyroid therapy a high proportion had subnormal TSH responses to TRH and some had hyper-responses. There is, then, a variety of combinations of TRH response in euthyroid patients who have been or are being treated with antithyroid drugs and there is no good correlation between TRH responsiveness and the prognostic suppression test. In contrast to an early assessment of antithyroid therapy and a move toward an alternative treatment8 we are persuaded by our results to
PROLONGED DRUG TREATMENT OF HYPERTHYROIDISM
225
continue antithyroid treatment indefinitely, as have others.13 The alternative therapy is usually radioiodine and 30-50% of such patients will require thyroid replacement. The odds of eventually coming off prolonged drug treatment with a functionally normal gland are excellent. 1. 2. 3. 4.
5.
6. 7.
8. 9. 10. 11.
12.
13. 14. 15. 16. 17. 18.
REFERENCES McGIRR, E. M., THOMSON, J. A., AND MURRAY, I. P. C.: Radioiodine therapy in thyrotoxicosis; a review of 908 cases. Scot. Med. J. 9: 505-513, 1964. DUNN, J. T., AND CHAPMAN, E. M.: Rising incidence of hypothyroidism after radioactive-iodine therapy in thyrotoxicosis. New Eng. J. Med. 271: 1037-1042, 1964. GREEN, M., AND WILSON, G. M.: Thyrotoxicosis treated by surgery or iodine-131 with special reference to development of hypothyroidism. Brit. J. Med. 1: 1005-1010, 1964. SLINGERLAND, D. W., DELL, E. S., AND BURROWS, B. A.: The spectrum of thyroid function after radioiodine treatment. In, Further Advances in Thyroid Research (K. Fellinger and R. Hofer, ed.) Vienna, G. Gistel and Cie, 1971, pp. 993-1003. EINHORN, J., AND WICKLUND, H.: Hypothyroidism following 131I treatment. J. Clin. Endocrinol. Metab. 26: 33-36, 1966. TROTTER, W. R.: Non surgical treatment of thyrotoxicosis. Proc. Roy. Soc. Med. 54: 869-871, 1961. HERSHMAN, J. M., GIVENS, J. R., CASSIDY, C. E. AND ASTWOOD, E. B.: Long-term outcome of hyperthyroidism treated with antithyroid drugs. J. Clin. Endocrin. Metab. 26: 803-807, 1966. GREER, M. A., KRAMMER, H., AND BOURNA, D. J.: A simplified short-term technique for treating Graves' disease with antithyroid drugs. Program American Thyroid Association, (Abst.), p. T-2, September 15-18, 1976. CASSIDY, C. E., AND VANDER LAAN, W. P.: Thyroid-suppression test in the prognosis of hyperthyroidism treated by antithyroid drugs. New Eng. J. Med. 262: 1228-1229, 1960. SLINGERLAND, D. W., SULLIVAN, J. J., DELL, E. S. AND BURROWS, B. A.: Thyroid suppression tests during drug treatment of hyperthyroidism. Clin. Endocrinology 5: 415-418, 1976. SLINGERLAND, D. W., SULLIVAN, J. J., DELL, E. S. AND BURROWS, B. A.: Effects of TRH in hyperthyroid patients treated with antithyroid drugs. Excerpta Medica, Seventh International Thyroid Conference, (Abst.), p. 78, 1975. McKENZIE, J. M.: Does LATS cause hyperthyroidism in Graves' disease? -Metabolism 21: 883-894, 1972. HOWARD, J. E.: Treatment of thyrotoxicosis. JAMA 202: 706-709, 1967. WOOD, L. C., PETERSON, M., AND INGBAR, S. H.: Delayed thyroid failure and decreased reserve following antithyroid therapy in Graves' disease. Program American Thyroid Association, (Abst.), p. 61, 1972. SATTLER, H.: Basedow's Disease. Grune and Stratton Co., New York, 1952. WOOD, L. C., AND MALOOF, F.: Thyroid failure after potassium iodide treatment of diffuse toxic goiter. Trans. of Assoc. of American Physicians, 88, 1975. ALEXANDER, W. D., McLARTY, D. G., HORTON, P. AND PHARMAKIOTIS, A. D.: Sequential assessment during drug treatment of thyrotoxicosis. Clin. Endocrinology 2: 4350, 1973. D'AMOUR, P., BANOVAC, K., SALISBURY MURPHY, S., FRIESEN, M. H. AND McKENZIE, J. M.: TRH-tests, T3-suppression tests and serum T4 concentrations in euthyroid Graves' disease. Program American Thyroid Association, (Abst.), p. T-9, Sept. 1215, 1973.
226
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19. ORMSTON, B. J., ALEXANDER, L., EVERED, D. C., CLARK, F., BIRD, T., APPLETON, D. AND HALL, R.: Thyrotrophin response to thyrotrophin-releasing hormone in ophthalmic Graves' disease: correlation with other aspects of thyroid function, thyroid suppressibility and activity of eye signs. Clin. Endocrinology 2: 369-376, 1973. 20. CLIFrON-BLIGH, P., SILVERSTEIN, G. E., AND BURKE, G.: Unresponsiveness to thyrotropin-releasing hormone (TRH) in treated Graves' hyperthyroidism and in euthyroid Graves' disease. J. Clin Endocrinol. Metab. 38: 531-538, 1974. 21. MARTINO, E., PINCHERA, A., CAPIFERRI, R., MACCHIA, E., AMBRASINO, N. AND BASCHIERI, L.: Dissociation of responsiveness to thyrotropin-releasing hormone from thyroid suppressibility and outcome of hyperthyroidism following antithyroid drug therapy. Excepta Medica, Seventh International Thyroid Conference, (Abst.), p. 78, 1975.
DISCUSSION
DR. F. DENNETTE ADAMS (Boston): Were any patients treated with surgery? DR. BURROWS: We have had recorded results only on those patients who have been on propylthiouracil. DR. LEWIS DEXTER (Boston): Belton, you showed one patient where it took seven years to get him under control. Was he very symptomatic for those seven years while you were waiting for the response? DR. BURROWS: No. I should have defined that by 'remission' we mean a euthyroid state after the drug has been stopped. We certainly feel that we controlled the disease by giving adequate antithyroid compound. All that is required of these patients is that they continue to take the medication as prescribed until remission is achieved. Inderol was used in very few because the series was accumulated for the most part before this became popular.
