Original Article
Lack of Effect of Thyroxine in Patients with Graves' Hyperthyroidism Who Are Treated with an Antithyroid Drug
N Engl J Med 1996; 334:220-224January 25, 1996
- Abstract
Background
Antithyroid drugs are effective in patients with hyperthyroidism due to Graves' disease, but the rate of recurrence after treatment is high. In a recent Japanese study, adjunctive treatment with thyroxine (T4) was associated with a recurrence rate 20 times lower than that among patients who received only an antithyroid drug. If these results are confirmed, combined therapy with an antithyroid drug and T4 might become the treatment of choice for all patients with Graves' hyperthyroidism.
Methods
We treated 111 patients (89 women and 22 men) who had Graves' hyperthyroidism. All patients initially received 40 mg of carbimazole daily for one month. Then one group received carbimazole alone for 17 months (52 patients), and the other group received carbimazole plus T4 for 17 months and T4 alone for 18 months (59 patients). In the carbimazole group, the dose was adjusted after one month to maintain a normal serum thyrotropin concentration. In the carbimazole–T4 group, the dose of carbimazole was not changed, but 100 μg of T4 per day was added to the regimen and the dose was adjusted to maintain an undetectable serum thyrotropin concentration (<0.04 μU per milliliter).
Results
At the time of our analysis, 53 of the 111 patients had completed at least 3 months of follow-up (median, 12 months) after carbimazole was withdrawn. Hyperthyroidism recurred in eight patients in each group after a mean (±SD) of 6±4 months in the carbimazole group and 7±4 months in the carbimazole–T4 group. There was no difference between the recurrence rates in the two groups, despite the fact that serum thyrotropin concentrations were undetectable in 73 percent of patients in the carbimazole–T4 group on at least 75 percent of their visits.
Conclusions
The administration of T4 to patients with Graves' disease during carbimazole treatment and after its withdrawal neither delays nor prevents the recurrence of hyperthyroidism.
Media in This Article
Figure 2
Mean (±SE) Serum Concentrations of Thyrotropin-Receptor Antibodies in the Carbimazole Group and the Carbimazole–T4 Group, According to the Length of Time from the Start of the Study.Figure 3
Proportion of Patients Remaining Euthyroid, According to the Length of Time since the End of Carbimazole Treatment.Article Activity
- Article
Antithyroid drugs are effective in controlling hyperthyroidism because they inhibit thyroid hormone production. In patients with hyperthyroidism caused by Graves' disease, these drugs may also have an immunosuppressive effect, causing a decrease in the serum concentrations of thyrotropin-receptor antibodies.1 The main disadvantage of antithyroid drug therapy is that the rate of recurrence after treatment is stopped varies widely, from 25 percent to 90 percent.2,3 Factors that affect the recurrence rate include the dosage and the duration of treatment.4 One reason for using high doses of antithyroid drugs, which must be combined with thyroid hormone if hypothyroidism is to be averted, is the belief that the postulated immunosuppressive effect may be related to the dose. For example, in one study the recurrence rate was 55 percent among patients treated with an antithyroid drug alone and 25 percent among those given combined therapy.5 In a large, prospective, multicenter European trial,6 however, combination therapy was no more effective than antithyroid treatment alone.
The high rates of recurrence have led many physicians to favor subtotal thyroidectomy or therapy with radioactive iodine for patients with Graves' hyperthyroidism. When Hashizume et al.7 reported in 1991 that the rate of recurrence of hyperthyroidism in Japanese patients could be reduced from 35 percent to less than 2 percent by 18 months of treatment with methimazole, with thyroxine (T4) added after the first six months and continued for three years after the methimazole was discontinued, this finding was considered by many the most important development in the management of Graves' hyperthyroidism in many years. If the results of Hashizume et al. were confirmed in different ethnic groups, this combined regimen might well become the treatment of choice for patients with Graves' hyperthyroidism. We undertook this study to determine the efficacy of the combination of an antithyroid drug and T4 in another group of patients.
Methods
We studied 111 consecutive, previously untreated patients with hyperthyroidism due to Graves' disease. The diagnosis of hyperthyroidism was made on clinical grounds and on the basis of elevated concentrations of free T4 and total triiodothyronine (T3) and undetectable serum thyrotropin concentrations (<0.04 μU per milliliter). The determination that Graves' disease was the cause of the hyperthyroidism was based on the presence of diffuse goiter, ophthalmopathy or pretibial myxedema, or detectable serum concentrations of thyrotropin-receptor antibodies (detected in 88 percent of the patients). All the patients had a normal or high thyroidal uptake of iodine 131, and technetium 99m pertechnetate imaging showed a diffuse pattern of uptake. All patients gave informed consent for their participation in the study.
All the patients were treated initially with 20 mg of carbimazole twice daily (40 mg per day) for one month. They were then randomly assigned to receive carbimazole alone (52 patients) or carbimazole plus T4 (59 patients). In the carbimazole group, the dose of carbimazole was adjusted as necessary to achieve normal serum concentrations of thyrotropin, free T4, and T3; the patients did not receive a placebo in place of T4. The patients in the carbimazole–T4 group continued to receive 20 mg of carbimazole twice daily, but T4 was added at an initial dose of 100 μg daily. The dose of T4 was adjusted as necessary to achieve an undetectable serum thyrotropin concentration (<0.04 μU per milliliter). When this degree of suppression of serum thyrotropin was achieved, serum free T4 concentrations were in the upper part of the normal reference range or slightly high and serum T3 concentrations were normal. All patients in both groups received carbimazole for 18 months. T4 was given to patients in the carbimazole–T4 group for 35 months — with carbimazole for 17 months and then for 18 months after carbimazole was discontinued. The dose of T4 was not changed when carbimazole was discontinued.
The patients were examined clinically, and blood was collected for estimation of the serum concentrations of thyrotropin, free T4, T3, and thyrotropin-receptor antibodies at the initial visit, at one month, at three months, and at three-month intervals thereafter for up to three years. All three physicians participating in the study were aware of the group assignment of the patients; to ensure consistency, adjustments to therapy were determined by a single physician.
Treatment was deemed to have failed in the patients in the carbimazole group if hyperthyroidism recurred after carbimazole was withdrawn. In those in the carbimazole–T4 group, treatment was considered to have failed if there was clinical and biochemical evidence of hyperthyroidism while the patient was taking T4 alone.
Measurement of Serum Thyrotropin, T4, T3, and Thyrotropin-Receptor Antibodies
Serum thyrotropin was measured by an immunochemiluminometric assay (Amerlite TSH-30, Kodak Clinical Diagnostics, Amersham, United Kingdom), with a functional limit of detection of 0.04 μU per milliliter8 and a coefficient of variation of less than 10 percent over the range of 0.04 to 100 μU per milliliter (normal range, 0.15 to 3.5). The serum thyrotropin concentration was defined as suppressed if the value was below 0.04 μU per milliliter; undetectable values were assigned a value of 0.04 μU per milliliter for purposes of analysis.
Free T4 and T3 were measured in serum with commercial kits (Amerlite-MAB and Amerlite Total T3, Kodak Clinical Diagnostics). The interassay coefficients of variation were less than 10 percent over the ranges measured.
Serum thyrotropin-receptor antibodies were measured by an assay in which the capacity of the patient's serum to inhibit the binding of 125I-labeled thyrotropin to its receptors was tested (RSR, Cardiff, United Kingdom); in this assay, biologically active thyrotropin standardized against Medical Research Council Long-Acting Thyroid Stimulator Standard B was used. A value of 7 U per liter for serum thyrotropin-receptor antibodies was defined as the upper limit of normal. Values greater than this had a sensitivity of 81 percent and a specificity of 96 percent for the diagnosis of Graves' hyperthyroidism in our laboratory.
Statistical Analysis
Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS, Chicago). All statistical tests were two-tailed. The results are given as means ±SD unless otherwise stated. The Mann–Whitney U test was used to assess differences between groups, and the Wilcoxon paired signed-rank test to assess differences within groups. The rates of decrease in the serum levels of thyrotropin-receptor antibodies in the two groups were compared with the Hollander test for parallelism after logarithmic transformation of the results. Rates of recurrence were determined by life-table analysis, and the differences between the groups were assessed with the Gehan statistic.
Results
The characteristics of the two groups before treatment were similar (Table 1Table 1
Characteristics of the Patients with Graves' Hyperthyroidism before Treatment.). Ten patients in each group were withdrawn from the study: five because of the side effects of the drug (urticaria, arthralgia, or nausea), six because of noncompliance, and nine because of a change in residence. At the time of the analysis, 53 patients had completed carbimazole treatment and at least three months of follow-up thereafter. Forty-five of the 53 patients had been followed for six months (of the remainder, 6 had recurrences and 2 had less than six months of follow-up). Of the 45, 30 had been followed for 12 months (5 of the remainder had recurrences and 10 had less than 12 months of follow-up); 23 had been followed for 18 months (5 of the remainder had recurrences and 2 had follow-up of less than 18 months). The median follow-up period was 12 months.Doses of Carbimazole and T4
The dose of carbimazole required to maintain normal serum thyrotropin, free T4, and T3 concentrations in the patients in the carbimazole group fell during the first six months and then reached a plateau at 10±5 mg daily. By design, the dose was 40 mg daily throughout the study period in the carbimazole–T4 group; in this group the daily dose of T4 required to maintain an undetectable serum thyrotropin concentration was 167±41 μg.
Effects of Treatment on Serum Thyroid Hormone and Thyrotropin Concentrations
During the first month of treatment with 40 mg of carbimazole per day, the mean serum free T4 concentration fell from 5.0±3.0 to 1.4±1.3 ng per deciliter (from 64±39 to 18±17 pmol per liter) (Figure 1Figure 1
Mean (±SE) Serum Free T4 and Thyrotropin Concentrations in the Carbimazole Group and the Carbimazole–T4 Group, According to the Length of Time from the Start of the Study.), and the serum T3 concentration fell from 409±195 to 150±65 ng per deciliter (from 6.3±3.0 to 2.3±1.0 nmol per liter). There was no difference in the rate of decrease in the concentration of either hormone between patients in the carbimazole group and those in the carbimazole–T4 group. Thereafter, the mean serum free T4 concentrations were consistently higher in the carbimazole–T4 group (Figure 1). There was no difference in serum T3 concentrations between the groups at any time.The mean serum thyrotropin concentration in the carbimazole group after one month was 0.31 μU per milliliter (thyrotropin was undetectable in 87 percent of the patients). The value increased to a peak of 3.0 μU per milliliter at three months, after which it ranged from 1.2 to 1.9 μU per milliliter until carbimazole was discontinued. The proportion of patients with an undetectable serum thyrotropin concentration at these times varied from 7 to 10 percent. Overt biochemical (but asymptomatic) hypothyroidism (indicated by a low serum free T4 concentration and an increased serum thyrotropin concentration) occurred in 13 patients at three months but was corrected by a reduction in the dose of carbimazole.
In the carbimazole–T4 group, overt biochemical hypothyroidism (also asymptomatic) occurred in only two patients at three months and was corrected by increasing the dose of T4. Serum thyrotropin concentrations were undetectable in 73 percent of the patients on at least 75 percent of their visits during carbimazole–T4 therapy. In half the remaining patients, it was not possible to maintain an undetectable serum thyrotropin concentration because of symptoms of hyperthyroidism; these patients continued to receive the maximal tolerated dose of T4 and are included in the subsequent analysis.
At the first follow-up evaluation, three months after the withdrawal of carbimazole, the mean serum thyrotropin concentrations in the carbimazole group had fallen from 1.9±3.3 to 0.35±0.30 μU per milliliter (P<0.001), but the mean serum free T4 concentration was virtually unchanged (from 1.2±0.3 to 1.4±0.5 ng per deciliter [16±4 to 18±6 pmol per liter]). In the carbimazole–T4 group, the mean serum thyrotropin concentration fell from 0.3±0.1 to 0.1±0.04 μU per milliliter (P = 0.02), and the mean serum free T4 concentration rose from 2.0±0.2 to 2.5±0.3 ng per deciliter (25.7±2.6 to 32.2±3.9 pmol per liter; P = 0.03).
Effect of Treatment on Serum Concentrations of Thyrotropin-Receptor Antibodies
Serum thyrotropin-receptor antibody concentrations fell progressively during the 18 months of carbimazole therapy, from 23.4±28.4 to 3.4±7.3 U per liter in the carbimazole group and from 30.6±35.0 to 5.3±12.1 U per liter in the carbimazole–T4 group (Figure 2Figure 2
Mean (±SE) Serum Concentrations of Thyrotropin-Receptor Antibodies in the Carbimazole Group and the Carbimazole–T4 Group, According to the Length of Time from the Start of the Study.). There was no difference in mean serum concentrations of thyrotropin-receptor antibodies or in the proportion of patients in whom thyrotropin-receptor antibodies were present between the two groups at the start of carbimazole treatment. Similarly, there was no difference in the rate of decrease in the antibody concentrations during or at the end of carbimazole treatment. After the withdrawal of carbimazole, serum concentrations of thyrotropin-receptor antibodies remained similarly low in both groups.Recurrence of Hyperthyroidism
Patients at risk for a recurrence of hyperthyroidism were those still being followed up who had not already had relapses. There were 45 such patients at 3 months, 41 at 6 months, 37 at 9 months, 30 at 12 months, 26 at 15 months, and 23 at 18 months.
Eight patients in the carbimazole group had recurrent hyperthyroidism a mean of 6±4 months after the discontinuation of carbimazole, at which time their serum free T4 concentrations ranged from 2.7 to 7.0 ng per deciliter (34 to 90 pmol per liter), and their serum T3 concentrations ranged from 195 to 474 ng per deciliter (3.0 to 7.3 nmol per liter). Recurrent hyperthyroidism developed in eight patients in the carbimazole–T4 group a mean of 7±4 months after the discontinuation of carbimazole and while they were taking thyroxine in a dose that, when given in combination with carbimazole, was associated with a euthyroid state. At the time of recurrence, the serum free T4 concentrations in these patients ranged from 3.0 to 7.0 ng per deciliter (39 to 90 pmol per liter), and their serum T3 concentrations ranged from 188 to 630 ng per deciliter (2.9 to 9.7 nmol per liter). All but one of the eight patients with recurrent hyperthyroidism in the carbimazole–T4 group remained overtly hyperthyroid after the withdrawal of T4; the remaining patient had subclinical hyperthyroidism.
At the time of recurrence, thyrotropin-receptor antibodies could not be detected in serum from four of the eight patients in the carbimazole group and three of the eight patients in the carbimazole–T4 group. In all those with detectable thyrotropin-receptor antibodies in serum, the concentration at the time of recurrence was less than that at the time of diagnosis. Life-table analysis showed no difference between the rates of relapse in the two groups (P = 0.41) (Figure 3Figure 3
Proportion of Patients Remaining Euthyroid, According to the Length of Time since the End of Carbimazole Treatment.).Discussion
In contrast to Hashizume et al.,7 we found that the addition of T4 to carbimazole in the treatment of patients with Graves' hyperthyroidism and the continued administration of T4 after carbimazole therapy was stopped did not decrease the rate of recurrence. Although only 53 patients had completed carbimazole therapy at the time of this report, the rates of relapse in the two groups were similar. Even if a small difference between the groups were to become apparent with greater numbers of patients and longer follow-up, the potential benefit of T4 would be outweighed by the development of symptoms of hyperthyroidism in some of the patients in the carbimazole–T4 group. In addition, the prolonged suppression of thyrotropin secretion entails the risk of such undesirable effects as atrial fibrillation9 and possibly osteoporosis.10
The rationale for attempting to suppress endogenous thyrotropin secretion was that the release of antigens by the thyroid gland would be inhibited and the immune response modified in such a way as to make the long-term remission of Graves' disease more likely. Serum thyrotropin concentrations were more effectively suppressed in the T4-treated group in our study than in the Japanese study, yet unlike Hashizume et al., we were unable to demonstrate any additional decrease in serum concentrations of thyrotropin-receptor antibodies in the group treated with carbimazole and T4, as compared with the group treated with carbimazole alone. Although their study is not directly comparable to ours, Tamai et al. were unable to demonstrate a T4-induced decrease in persistently elevated serum thyrotropin-receptor antibody concentrations in Japanese patients who had previously been treated with methimazole for 12 months.11
What are the possible explanations for the apparent discrepancy between the results of our study and that reported by Hashizume et al.?7 One is differences in the details of treatment and in the choice of drug. For example, Hashizume et al. used methimazole, whereas we used carbimazole. The latter is rapidly converted to methimazole, and there is no evidence that carbimazole is anything other than a precursor of methimazole. Another possible explanation is differences in iodine intake. The average daily intake of iodine in Japan is 470 μg,12 about three times that in the United Kingdom,13 but — if anything — higher iodine intake is associated with a higher rate of recurrence of hyperthyroidism.14-16 Given the higher iodine intake in Japan, the rates of recurrence there are relatively low,7,17 raising the possibility that in Japanese patients the thyroid gland has in some way become adapted to their higher dietary iodine intake. The initial depletion of thyroidal iodine during antithyroid drug therapy, followed by the suppression of iodine uptake by T4 in the presence of reduced serum concentrations of thyrotropin-receptor antibodies, might be sufficient to prevent recurrences in the short term in Japanese patients who are inherently resistant to the effects of iodine.
One would expect the organic iodine content of the thyroid glands of Japanese patients with Graves' hyperthyroidism to be greater and their response to antithyroid drugs correspondingly slower than those of the patients in our study. Indeed, this was the case, since doses of 30 mg of methimazole daily were given for six months without inducing hypothyroidism in the Japanese study, before thyroxine or placebo was added. In our patients, carbimazole was given at a dose of 40 mg daily for only one month before it was reduced or T4 was added to prevent the possible development of hypothyroidism. The patients in the carbimazole–T4 group received greater doses of antithyroid drug during the 18-month study and received the combination of an antithyroid drug and T4 for a longer period than their Japanese counterparts (17 vs. 12 months); these variations in dose and timing might have been expected to result in a greater chance of remission among the patients in our study.
There are obviously genetic differences between patients in Japan and the United Kingdom, and it is perhaps naive to assume that the pathogenesis of disease and its response to treatment will be similar in all ethnic groups. Major histocompatibility complex class II antigens (HLA antigens) are an important factor in the development of organ-specific autoimmune disease, of which Graves' disease is an example. Although HLA-B8 and HLA-DR3 are overrepresented among patients with Graves' disease in the United Kingdom, HLA-B35 is overexpressed in Japanese patients.18 Whether these differences account for variations in the natural history of the hyperthyroidism of Graves' disease is not known.
Whatever the reasons for the differences between the two studies, our inability to confirm the finding of Hashizume et al. that the administration of T4 reduces the risk of recurrent hyperthyroidism caused by Graves' disease after the discontinuation of antithyroid drug therapy argues against a dose-related immunosuppressive action of carbimazole (and presumably methimazole). Our findings also argue against a role for thyrotropin in maintaining thyroid-antigen expression as an important factor in sustaining Graves' hyperthyroidism. At a practical level, our results provide no evidence that thyroxine increases the efficacy of antithyroid drug therapy for the treatment of patients with hyperthyroidism due to Graves' disease.
- References
References
1
Weetman AP , McGregor Am,Hall R . Evidence for an effect of antithyroid drugs on the natural history of Graves' disease. Clin Endocrinol (Oxf) 1984;21:163-172
CrossRef | Web of Science | Medline2
Sugrue D ,McEvoy M ,Feely J , Drury Mi. Hyperthyroidism in the land of Graves: results of treatment by surgery, radio-iodine and carbimazole in 837 cases. Q J Med 1980;49:51-61
Web of Science | Medline3
Franklyn JA . The management of hyperthyroidism. N Engl J Med 1994;330:1731-1738
Full Text | Web of Science | Medline4
Allannic H ,Fauchet R ,Orgiazzi J , et al. Antithyroid drugs and Graves' disease: a prospective randomized evaluation of the efficacy of treatment duration. J Clin Endocrinol Metab 1990;70:675-679
CrossRef | Web of Science | Medline5
Romaldini JH ,Bromberg N ,Werner RS , et al. Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves' hyperthyroidism. J Clin Endocrinol Metab 1983;57:563-570
CrossRef | Web of Science | Medline6
Reinwein D ,Benker G ,Lazarus JH ,Alexander WD . A prospective randomized trial of antithyroid drug dose in Graves' disease therapy. J Clin Endocrinol Metab 1993;76:1516-1521
CrossRef | Web of Science | Medline7
Hashizume K ,Ichikawa K ,Sakurai A , et al. Administration of thyroxine in treated Graves' disease: effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. N Engl J Med 1991;324:947-953
Full Text | Web of Science | Medline8
Spencer CA ,Takeuchi M ,Kazarosyan M ,McKenzie F ,Beckett GJ ,Wilkinson E . Interlaboratory/intermethod differences in functional sensitivity of immunometric assays of thyrotropin (TSH) and impact on reliability of measurement of subnormal concentration of TSh. Clin Chem 1995;41:367-374
Web of Science | Medline9
Sawin CT ,Geller A ,Wolf PA , et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249-1252
Full Text | Web of Science | Medline10
Toft AD . Thyroxine therapy. N Engl J Med 1994;331:174-180
Full Text | Web of Science | Medline11
Tamai H ,Hayaki I ,Kawai K , et al. Lack of effect of thyroxine administration on elevated thyroid stimulating hormone receptor antibody levels in treated Graves' disease patients. J Clin Endocrinol Metab 1995;80:1481-1484
CrossRef | Web of Science | Medline12
Ishizuki Y ,Hirooka Y ,Murata Y . Urinary iodide excretion in Japanese people and thyroid dysfunction. Nippon Naibunpi Gakkai Zasshi 1992;68:550-556
Medline13
Lee SM ,Lewis J ,Buss DH ,Holcombe GD ,Lawrance PR . Iodine in British foods and diets. Br J Nutr 1994;72:435-446
CrossRef | Web of Science | Medline14
Alexander WD ,Harden RM ,Koutras DA ,Wayne E . Influence of iodine intake after treatment with antithyroid drugs. Lancet 1965;2:866-868
CrossRef | Web of Science | Medline15
Wartofsky L . Low remission after therapy for Graves disease: possible relation of dietary iodine with antithyroid therapy results. JAMA 1973;226:1083-1088
CrossRef | Web of Science | Medline16
Solomon BL ,Evaul JE ,Burman KD ,Wartofsky L . Remission rates with antithyroid drug therapy: continuing influence of iodine intake? Ann Intern Med 1987;107:510-512
Web of Science | Medline17
Tamai H ,Nakagawa T ,Fukino O , et al. Thionamide therapy in Graves' disease: relation of relapse rate to duration of therapy. Ann Intern Med 1980;92:488-490
Web of Science | Medline18
Volpe R. Graves' disease: pathogenesis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid: a fundamental and clinical text. 6th ed. Philadelphia: J.B. Lippincott, 1991:648-57.
- Citing Articles (31)
Citing Articles
1
Prakash Abraham, Alison Avenell, Susan C McGeoch, Louise F Clark, John S Bevan, Prakash Abraham. 2010. Antithyroid drug regimen for treating Graves' hyperthyroidism. .
CrossRef2
Laszlo Hegedüs. (2009) Treatment of Graves' Hyperthyroidism: Evidence-Based and Emerging Modalities. Endocrinology & Metabolism Clinics of North America 38:2, 355-371
CrossRef3
Su He Wang, James R. Baker. 2008. Autoimmune thyroid diseases. , 1023-1033.
CrossRef4
Bindu Nayak, Steven P. Hodak. (2007) Hyperthyroidism. Endocrinology & Metabolism Clinics of North America 36:3, 617-656
CrossRef5
Hirokazu Sato, Shohei Harada, Susumu Yokoya, Toshiaki Tanaka, Kohtaro Asayama, Masatomo Mori, Nozomu Sasaki. (2007) Treatment for Childhood-Onset Graves' Disease in Japan: Results of a Nationwide Questionnaire Survey of Pediatric Endocrinologists and Thyroidologists. Thyroid 17:1, 67-72
CrossRef6
Jonathan Sherman, Geoffrey B. Thompson, Aida Lteif, W. Frederick Schwenk, Jon van Heerden, David R. Farley, Seema Kumar, Donald Zimmerman, Marilyn Churchward, Clive S. Grant. (2006) Surgical management of Graves disease in childhood and adolescence: an institutional experience. Surgery 140:6, 1056-1062
CrossRef7
Fereidoun Azizi. (2006) The safety and efficacy of antithyroid drugs. Expert Opinion on Drug Safety 5:1, 107-116
CrossRef8
Beate Quadbeck, Rudolf Hoermann, Ulla Roggenbuck, Susanne Hahn, Klaus Mann, Onno E. Janssen. (2005) Sensitive Thyrotropin and Thyrotropin-Receptor Antibody Determinations One Month After Discontinuation of Antithyroid Drug Treatment as Predictors of Relapse in Graves' Disease. Thyroid 15:9, 1047-1054
CrossRef9
Luigi Bartalena, Maria Laura Tanda, Fausto Bogazzi, Eliana Piantanida, Adriana Lai, Enio Martino. (2005) An update on the pharmacological management of hyperthyroidism due to Graves’ disease. Expert Opinion on Pharmacotherapy 6:6, 851-861
CrossRef10
Prakash Abraham, Alison Avenell, Wendy A Watson, Christine M Park, John S Bevan, Prakash Abraham. 2005. Antithyroid drug regimen for treating Graves' hyperthyroidism. .
CrossRef11
Cooper, David S., . (2005) Antithyroid Drugs. New England Journal of Medicine 352:9, 905-917
Full Text12
Elizabeth N Pearce, Lewis E Braverman. (2004) Hyperthyroidism: advantages and disadvantages of medical therapy. Surgical Clinics of North America 84:3, 833-847
CrossRef13
David S Cooper. (2003) Hyperthyroidism. The Lancet 362:9382, 459-468
CrossRef14
R. Hörmann. 2002. , 168-179.
CrossRef15
Rudolf Hoermann, Beate Quadbeck, Ulla Roggenbuck, István Szabolcs, Johannes Pfeilschifter, Wieland Meng, Kirsten Reschke, Klaus Hackenberg, Juergen Dettmann, Brigitte Prehn, Herbert Hirche, Klaus Mann. (2002) Relapse of Graves' Disease After Successful Outcome of Antithyroid Drug Therapy: Results of a Prospective Randomized Study on the Use of Levothyroxine. Thyroid 12:12, 1119-1128
CrossRef16
Jacques Orgiazzi, Anne-Marie Madec. (2002) Reduction of the Risk of Relapse After Withdrawal of Medical Therapy for Graves' Disease. Thyroid 12:10, 849-853
CrossRef17
Yoshinori Nakagawa, Kouki Mori, Saeko Hoshikawa, Makiko Yamamoto, Sadayoshi Ito, Katsumi Yoshida. (2002) Postpartum recurrence of Graves' hyperthyroidism can be prevented by the continuation of antithyroid drugs during pregnancy. Clinical Endocrinology 57:4, 467-471
CrossRef18
D. Maugendre, C. Massart. (2001) Clinical value of a new TSH binding inihibitory activity assay using human TSH receptors in the follow-up of antithyroid drug treated Graves' disease. Comparison with thyroid stimulating antibody bioassay. Clinical Endocrinology 54:1, 89-96
CrossRef19
Weetman, Anthony P., . (2000) Graves' Disease. New England Journal of Medicine 343:17, 1236-1248
Full Text20
Jacques Orgiazzi. (2000) ANTI–TSH RECEPTOR ANTIBODIES IN CLINICAL PRACTICE. Endocrinology & Metabolism Clinics of North America 29:2, 339-355
CrossRef21
Paul Atkins, S. Bernard Cohen, Brenda Joyce Phillips. (2000) Drug Therapy for Hyperthyroidism in Pregnancy. Drug Safety 23:3, 229-244
CrossRef22
J Raza, PC Hindmarsh, CGD Brook. (1999) Thyrotoxicosis in children: thirty years’experience. Acta Paediatrica 88:9, 937-941
CrossRef23
Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Mathilde Brandt, Marie-Louise Hartoft-Nielsen, Pierre Carayon, Karsten Buschard. (1999) Thyrotropin Stimulates Specifically the Expression of the Autoantibody Binding Domains of the Thyroperoxidase Molecule. Autoimmunity 29:4, 323-331
CrossRef24
D. Maugendre, A. Gatel, L. Campion, C. Massart, I. Guilhem, Y. Lorcy, J. Lescouarch, J. Y. Herry, H. Allannic. (1999) Antithyroid drugs and Graves' disease - prospective randomized assessment of long-term treatment. Clinical Endocrinology 50:1, 127-132
CrossRef25
Michael Hermann, Rudolf Roka, Birgit Richter, Michael Freissmuth. (1998) Early relapse after operation for Graves' disease: Postoperative hormone kinetics and outcome after subtotal, near-total, and total thyroidectomy. Surgery 124:5, 894-900
CrossRef26
Georg Benker, Dankwart Reinwein, Georg Kahaly, Lennart Tegler, W. Donald Alexander, Johanes Fassbinder, Herbert Hirche, . (1998) Is there a methimazole dose effect on remission rate in Graves' disease? Results from a long-term prospective study. Clinical Endocrinology 49:4, 451-457
CrossRef27
Nicky J. Leech, Colin M. Dayan. (1998) Controversies in the management of Graves' disease. Clinical Endocrinology 49:3, 273-280
CrossRef28
Stefan K. G. Grebe, Colin M. Feek, Henry C. Ford, Jocelyn N. Fagerstrom, Diane P. Cordwell, John W. Delahunt, Robyn J. Toomath. (1998) A randomized trial of short-term treatment of Graves' disease with high-dose carbimazole plus thyroxine versus low-dose carbimazole. Clinical Endocrinology 48:5, 585-592
CrossRef29
Pascal Pujol, Abdul Osman, Sophie Grabar, Jean-Pierre Daures, Florence Galtier-Dereure, Catherine Boegner, Line Baldet, Regine Raye, Jacques Bringer, Claude Jaffiol. (1998) TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates. Clinical Endocrinology 48:5, 635-640
CrossRef30
John H Lazarus. (1997) Hyperthyroidism. The Lancet 349:9048, 339-343
CrossRef31
Wiersinga, Wilmar M., . (1996) Immunosuppression of Graves' Hyperthyroidism — Still an Elusive Goal. New England Journal of Medicine 334:4, 265-267
Full Text
