Eur J Endocrinol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1530/eje.1.01904
European Journal of Endocrinology, Vol 152, Issue 5, 695-701
Copyright © 2005 by European Society of Endocrinology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Azizi, F
Right arrow Articles by Sheikholeslami, F
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Azizi, F
Right arrow Articles by Sheikholeslami, F
CLINICAL STUDY

Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine

F Azizi, L Ataie, M Hedayati, Y Mehrabi and F Sheikholeslami

Endocrine Research Center and the Division of Cardiology, Taleghani Medical Center, Shaheed Beheshti University of Medical Sciences, PO Box 19395-4763, Tehran, I.R. Iran

(Correspondence should be addressed to F Azizi; Email: Azizi{at}erc.ac.ir)


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective: To investigate the long-term effects of continuous methimazole (MMI) therapy.

Design and methods: Five hundred and four patients over 40 years of age with diffuse toxic goiter were treated with MMI for 18 months. Within one year after discontinuation of MMI, hyperthyroidism recurred in 104 patients. They were randomized into 2 groups for continuous antithyroid and radioiodine treatment. Numbers of occurrences of thyroid dysfunction and total costs of management were assessed during 10 years of follow-up. At the end of the study, 26 patients were still on continuous MMI (group 1), and of 41 radioiodine-treated patients (group 2), 16 were euthyroid and 25 became hypothyroid. Serum thyroid and lipid profiles, bone mineral density, and echocardiography data were obtained.

Results: There was no significant difference in age, sex, duration of symptoms and thyroid function between the two groups. No serious complications occurred in any of the patients. The cost of treatment was lower in group 1 than in group 2. At the end of 10 years, goiter rate was greater and antithyroperoxidase antibody concentration was higher in group 1 than in group 2. Serum cholesterol and low density lipoprotein-cholesterol concentrations were increased in group 2 as compared with group 1; relative risks were 1.8 (1.12–2.95, P < 0.02) and 1.6 (1.09–2.34, P < 0.02) respectively. Bone mineral density and echocardiographic measurements were not different between the two groups.

Conclusion: Long-term continuous treatment of hyperthyroidism with MMI is safe. The complications and the expense of the treatment do not exceed those of radioactive iodine therapy.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The major clinical problem of antithyroid therapy is the 20–70% relapse of hyperthyroidism following discontinuation of treatment (1–5). Reports of low remission rate therapy (6, 7) and ease, effectiveness and low expense of radioiodine therapy (8, 9), has led to increasing reliance on radioiodine treatment for hyperthyroidism. In fact, more than two thirds of the members of the American Thyroid Association choose radioiodine as the treatment of choice for virtually all patients with Graves’ disease (10). This practice is not common in members of the European Thyroid Association, since two thirds of these prefer antithyroid drugs as the first approach to the treatment of hyperthyroidism (11). However, almost all thyroidologists agree that the treatment of choice in cases of recurrence after original therapy is that of radioiodine.

Hypothyroidism occurs in 50–70% of patients after low dose and in 90–100% following high dose radioiodine treatment (12, 13). Over replacement of thyroxine may cause alterations in heart (14, 15) and bones (16, 17) and the potency, uniformity and reproducibility of thyroxine preparations may be variable (18, 19). Adding these to the lack of patients’ compliance (20, 21) may make the long-term precise management of hypothyroidism somewhat problematic.

The aim of this study was to investigate the effectiveness of continuous antithyroid drug treatment and to compare the benefits and side effects of the said therapy with those of radioiodine treatment.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
This randomized controlled clinical trial was performed between March 1989 and June 2002 in Tehran, Iran.

Selection of patients

Patients older than 40 years of age, diagnosed with hyperthyroidism due to diffuse toxic goiter were treated with methimazole (MMI); five hundred and four patients were enrolled for the study. Patients were kept euthyroid by MMI therapy, and at the end of 18 months of treatment, MMI was discontinued. Twelve patients had a relapse of disease while on treatment, 21 were lost at follow-up and eight chose ablation therapy. These 41 patients (8%) were excluded from the study.

Within one year after discontinuation of MMI therapy, 104 of 463 patients (22%) experienced overt symptoms and signs of hyperthyroidism. They were assigned by randomization into two groups for treatment with either MMI or radioactive iodine, adopting random sampling numbers. Nineteen patients wanted treatment options other than those offered by random allocation and were excluded from the study. Eventually, 34 patients in the MMI group and 51 patients in the radioiodine group remained for additional study.

Study protocol

Thirty-four patients received 10 mg MMI twice daily during the first month and 10 mg daily during the second month of therapy. All patients received maintenance doses of 2.5–10 mg daily from the third month on; MMI administration continued and 26 patients (78%) completed 10.2±0.5 years of follow-up (range 9.2–11.1 years).

Radioiodine was delivered to 51 patients in doses calculated using the following formula:


The mean dose of radioiodine was 7.9±5.1 mCi with a range of 5 to 13 mCi. Forty-one patients (80%) returned for follow-up visits for 10.1±0.4 years (range 9.3–10.9 years).

After monthly visits for the first 3 months of therapy, all patients in both groups were visited every 3 months for the first year and, if stable, every 6 months thereafter. At each visit, a complete history was taken, a physical examination was performed and the side effects of treatment were ascertained. A blood sample for cell blood count (CBC) and the measurement of serum alanine aminotransferase (ALT), asparate aminotransferase (AST), thyroxine (T4), tri-iodothyronine (T3), free (f) T4, free (f) T3 and thyrotropin (TSH) concentrations were obtained from each patient. Numbers of occurrences of thyroid dysfunction during the years of follow-up were recorded. Diagnoses of hyper- or hypothyroidism both overt and subclinical were made according to the following criteria: euthyroid (TSH level within the normal range, 0.1–5.0 mU/l inclusive); hypothyroid (TSH >5.0 mU/l and T4 <4.5 µg/dl); subclinical hypothyroid (TSH >5.0 mU/l, T4 ≥4.5 µg/dl, fT4 ≥0.7 ng/dl); hyperthyroid (TSH <0.1 mU/l, T4 >12.5 µg/dl and/or T3 >200 ng/dl) and subclinical hyperthyroid (TSH <0.1 mU/l, T4 ≤12.5 µg/dl, fT4 ≤2.0 ng/dl and T3 ≤200 ng/dl). In all patients the dosage of MMI or L-thyroxine was adjusted to maintain patients in a euthyroid state and to keep serum T4 and T3 concentrations within the middle range of normal values.

Final visit  At the end of the study, weight and height were measured and body mass index (BMI) was calculated. A questionnaire was completed to assess the status of cigarette smoking and the history of age at menarche and menopause in women. A research dietitian using dietary recall estimated the level of calcium intake. Physical activity was assessed by the Lipid Research Clinic questionnaire (22) and the quality of life was evaluated by a specific questionnaire SF-36 (23). A thorough physical examination was performed and goiter was graded according to the World Health Organisation (WHO) classification (24). The same doctor (L A) carried out all assessments of goiter by palpation. Every patient had a lipid profile, and measurements of calcium, phosphorus, parathyroid hormone (PTH), thyroid function tests and thyroid antibodies, 24-h urine-free deoxypyridinoline, bone mineral density, electrocardiography (EKG) and echocardiography were performed.

The Human Research Review Committee of the Shaheed Beheshti University of Medical Sciences approved the study, and informed consent was obtained from all patients.

Measurement and procedures

Serum ALT, AST, bilirubin, alkaline phosphatase, creatinine, calcium, phosphorus cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-C) measurements were carried out using routine methods and low-density lipoprotein cholesterol (LDL-C) was calculated. Excretion of free deoxypyridinoline in 24-h urine samples was measured by radioimmunoassay using a Gamma BCT DPD kit from Immunodiagnostic Systems Limited, Boldon, UK.

Hormone and antibody measurements  Serum T4 and T3 were measured by radioimmunoassay, and serum TSH by immunoradiometric assay using kits from Orion Diagnostica (Espoo, Finland). We measured fT4 and fT3 by saturation analysis using kits from Diagnostic Products Co. (Los Angeles, CA, USA) intact PTH by the ELISA method using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX, USA), antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibodiy (TgAb) by immunoenzymometric assay (Radim, Pomezia, Rome, Italy) and urinary iodine levels by a digestion method (24).

Reference ranges of serum parameters for euthyroid adult subjects are: T4, 4.5–12.5 µg/dl; T3, 80–200 ng/dl; TSH, 0.1–5.0 mU/l (µU/ml); fT4, 0.7–2.0 ng/dl; fT3, 2.2–5.0 pg/ml; PTH, 8.8–76.6 pg/ml; TPOAb, <100 IU/ml; TgAb, <100 IU/ml. To convert values to SI units, for T4, T3 and PTH multiply by 12.87, 0.01 536 and 0.80 respectively. Interassay and intra-assay coefficent of variations for all tests were less than 8 and 10% respectively.

Bone mineral density  Bone mineral density (BMD) was measured by dual-energy-X-ray absorptiometry (DEXA) with a Lunar DPX device (Madison, Wisconsin, USA). Densitometry was performed on L1–L4 vertebral regions, femur (neck, trochanter, ward and total) and forearm (mid shaft, upper distal part and total radius). BMD was expressed in units as gram per square centimeter and as Z scores. The Z score was calculated as the number of standard deviations between the patients’ BMD and the age- and sex-matched reference mean value. Precision errors, established with a local normal population, were less than 1.46% for all locations (spine, hip and radius).

Echocardiographic and Doppler measurements  Complete M-mode and two-dimensional Doppler echocardiographic analysis was performed with an ultrasound mechanical system equipped with a 3.5 MHZ transducer (Kontron Instruments Sigma 44 hvcd). M-mode and two-dimensional recordings were obtained with the patients in the lateral recumbent position.

Costs

Costs were calculated from the actual expenses incurred during nearly 10 years of follow-up in each of the two groups. Hospital and ambulatory costs for thyroid-related events and illnesses were calculated and added to the total costs for each patient in the three groups. All costs were actual and when obscure (less than 15%), were estimated from the perspectives of the health care system. They are expressed both in Iranian rials and US dollars.

Statistical analysis

We planned to enroll 102 patients for the study before randomization. This sample estimate was based on data from the literature that up to 50% of hypothyroid patients on levothyroxine are non compliant and may have increased serum TSH (20, 21), and that nearly 5–20% of hyperthyroid patients treated with MMI for 1–2 years may eventually develop thyroid failure (2, 7). To detect an absolute difference in number of events with increased TSH in group 1 and those patients in group 2 who developed hypothyroidism, with two sided alpha level <0.05 and a power of 0.90, the number in each group was estimated to be 25. Since nearly 40–50% of radioiodine-treated patients may not develop thyroid failure (6–9) and considering the 35% attrition rate, we planned to have 51 patients in each of the radioiodine- and MMI-treated groups. Base-line and outcome variables were compared with the use of Student’s t-test, Mann-Whitney, chi-square and Fisher’s exact tests. To determine relative risk, the percent of goiter, the number of patients with reduced bone mineral density below 1.5 S.D. of Z scores and the number of patients with serum cholesterol above 200 mg/dl and LDL-C over 130 mg/dl in both groups of MMI-treated and radioiodine-treated hypothyroid patients were considered. A value of P < 0.05 was considered significant. Statistical analysis was performed using SPSS 9.05 software (SPSS Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
No statistical differences in age, sex, duration of symptoms, size of goiter and thyroid function tests were seen in the patients in the MMI-treated or radioiodine-treated groups at the time of randomization, before treatment or in those patients who were excluded from the study (Table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1 Baseline characteristics of 104 patients with recurrent hyperthyroidism before treatment with MMI or radioiodine. Results are means±S.D.
 
Final thyroid status

Final thyroid status in 84 patients who completed 9.3–11.1 years of follow-up is shown in Fig. 1Go. Of 34 patients who were treated with MMI, 26 patients (78%) completed a mean of 10.2 years of follow-up (group 1). Mean±S.D. daily dosage of MMI was 4.9±1.3 mg in this group.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 1 The occurence of eu-, hyper- and hypothyroidism in 104 patients with recurrent hyperthyroidism who were randomly assigned to MMI or radioiodine therapy. Numbers in parantheses indicate number of patients in each group.

 
Forty-one patients in the radioiodine group completed a mean of 10.1 years of follow-up (group 2) and 10 patients were lost at follow-up. Nine patients required 1 to 3 additional doses of radioiodine and 6 out of 9 became hypothyroid. Ultimately, 16 patients (39%) remained euthyroid and 25 patients (61%) became hypothyroid 3 months to 8 years after receiving radioiodine treatment.

Events and costs during follow-up

During 10 years of successive MMI treatment in the 26 patients of group 1, except for minor allergic symptoms, no serious complications, including agranulocytosis, occurred. Patients in group 1 had 627 measurements of thyroid function tests with 37 of these (5.9%) showing a TSH level of more than 5.0 mU/l and 48 (7.6%) showing a TSH level below 0.3 mU/l. In patients of group 2, 989 measurements of thyroid function tests were carried out. On 127 occasions (12.8%), TSH was over 5.0 mU/l and on 90 occasions (9.1%) it was below 0.3 mU/l. Corresponding figures were 21.1% and 14.9% in 25 patients who became hypothyroid after radioiodine therapy (P < 0.001 and <0.01, as compared with group 1 respectively).

The overall costs of management of hyperthyroidism and related complications was 5070000±26000 rials ($631±32), and 5530000±29000 ($691±36) in groups 1 and 2 respectively (P < 0.001).

Variables at the final visit

The clinical and biochemical data in 67 patients at the end of the study are summarized in Table 2Go. At the final visit, 2 patients in group 1 and 3 patients in group 2 were still menstruating, and the rest of the female patients were in menopause. In addition, there were no significant differences in age of menarche and start and duration of menopause in women, physical activity, CBC, blood indices, and serum concentrations of alkaline phosphatase, ALT, AST and bilirubin between the two groups.


View this table:
[in this window]
[in a new window]
  		Table 2 Clinical and biochemical variables at the end of the study in the two groups of patients with hyperthyroidism. Values are means±S.D.
 
Before randomization, goiter was present in 79.2% of the cases. At the end of the study, the total goiter rate was 50% in group 1 and 25% in group 2 (P < 0.05). Mean serum concentrations of T4, T3, fT4, fT3, and TSH concentrations were not significantly different between the two groups (Table 2Go). Mean TPOAb titer was significantly higher in group 1 as compared with group 2. The frequency of TPOAb above 100 IU/ml was 52% and 16% in groups 1 and 2 respectively (P < 0.01).

Serum cholesterol and LDL-cholesterol concentrations were significantly increased in group 2 as compared with group 1 (P < 0.01). The frequency of cholesterol above 200 mg/dl (5.17 mmol/l) was 35% and 74% and that of LDL-cholesterol above 130 mg/dl (3.36 mmol/l) was 22% and 52.6% in groups 1 and 2 respectively.

At the end of the study, the mean Z scores for BMD were lower, but not significantly so, in group 2 in all locations, as compared with group 1 (Table 3Go). Urinary concentration of free deoxypyridinoline was 21.2±14.1 and 30.1±27.3 mmol/mmol creatinine in groups 1 and 2 respectively (not statistically significant, NS).


View this table:
[in this window]
[in a new window]
  		Table 3 Bone mineral density at the end of the study. Results are means±S.D. of Z scores.
 
There were no significant changes in echocardiographic data between the two groups. Mean scores of the questionnaires for quality of life were 41±9.5 and 40±10 (NS) for mental and 48±9 and 46±7 (NS) for physical components in groups 1 and 2 respectively.

When relative risks of variables were compared between the two groups, a significant reduction in numbers of patients with suppressed serum TSH levels during follow-up and in the percentage of patients with hypercholesterolemia and elevated LDL-cholesterol were found in group 1 (Fig. 2Go). Meanwhile, the relative risk for total goiter rate and elevated antithyroperoxidase favored radioiodine treatment.



View larger version (15K):
[in this window]
[in a new window]
  		Figure 2 The relative risk and confidence interval (CI) of the derangements in TSH secretion during follow-up and the rates of occurrence of goiter, serum antithyroperoxidase antibody above 100 IU/l, hypercholesterolemia above 200 mg/dl, hyper LDL-cholesterolemia over 130 mg/dl and osteoporosis defined as bone mineral density (BMD) below 1.5 standard deviation of Z score at the final visit in the continuous MMI-treated patients (group 1), as compared with the radioiodine-treated patients (group 2).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In the present study, we focused on the potential benefit of long-term continuous methimazole therapy for diffuse toxic goiter. Nearly 10 years of follow-up of such patients showed that this mode of treatment is safe and its cost does not exceed that of radioiodine treatment.

The most obvious objective in the treatment of hyperthyroidism is to render the patient euthyroid and off drug therapy. However, all of the three forms of treatment of hyperthyroidism i.e. antithyroid drugs, surgery and radioiodine therapy, fail to achieve this objective.

Radioiodine is increasingly considered the treatment of choice because of its safety and ease of administration (25). The major event of radioiodine therapy is thyroid failure; hypothyroidism may develop many years after the patient has been rendered euthyroid by radioiodine (26), so that long-term follow-up of thyroid function is essential.

In the present study, we observed that the numbers of abnormal serum TSH concentrations occurring during nearly 10 years of follow-up were significantly greater in patients with hypothyroidism after radioiodine therapy, as compared with those on continuous long-term methimazole treatment. In a retrospective study, 32% of patients receiving levothyroxine replacement had abnormal TSH concentrations, while 92% of them had seen a health care provider the previous year (27). In the Colorado Thyroid Disease Prevalence Study of patients who reported taking thyroid medication, nearly 40% had an abnormal serum TSH level (21). Therefore, patients under replacement therapy may be at risk of organic consequences of under- and over-treatment. However, the extent of this problem may differ in various clinics and depends on the proper replacement therapy and patient education by physicians and the social and cultural behavior of the patients.

At the end of 10 years of follow-up, the difference in bone mineral density between MMI- and radioiodine-treated groups was not statistically significant. Thyroid hormones exert their effect on osteoblasts via nuclear receptors to stimulate osteoclastic bone resorption (28). Even a slight increase in thyroid hormones to a level of subclinical hyperthyroidism results in accelerated bone turnover and calcium excretion (29). Of interest is the report of a decrease in bone turnover and conversion of the mineral balance to positive early during antithyroid treatment of patients with hyperthyroidism (30). Although bone turnover will increase following the early decline during antithyroid treatment (31), there are no reports of changes in bone mineral density during long-term continuous antithyroid drug therapy.

Important changes in hemodynamic regulation may occur in both clinical and subclinical thyroid diseases and treatment of these conditions may prevent cardiac dysfunction and improve the quality of life (32–34). In the present study cardiovascular hemodynamic data were within the normal range and comparable in the two study groups.

This study had a few limitations. First, patients were selected from those aged over 40 years with diffuse toxic goiter, who had recurrence of hyperthyroidism after initial treatment with antithyroid drugs for one and a half years, and the results cannot be applied to all patients with hyperthyroidism, in particular, to the more common younger Graves’ patients. Secondly, the drop-out rate of this study was rather high and might have affected the results. Thirdly, the number of patients available for study was not powered to detect significant differences in cardiovascular, bone and lipid alterations between the treatment groups. Fourthly, we were not able to investigate changes in immunological features during follow-up. Fifthly, the cost comparison is based on the need for follow-up in groups 1 and 2 being the same – every 6 months –but some clinicians may argue that group 1 patients needs more frequent follow-up than those in group 2. In addition, 9 patients required an additional radioiodine dose, which added to the cost in group 2 and may have been avoided by the adiministration of larger doses of radioiodine.

In spite of almost 60 years experience in the use of antithyroid drugs and radioiodine for the treatment of Graves’ disease, the rationale for choice of therapy is often obscure (6, 35). Very often the choice has to be made between prolonged treatment with antithyroid drugs on the one hand and lifetime therapy with thyroid hormone for thyroid failure on the other (36).

The major drawback of antithyroid drug treatment for hyperthyroidism is the frequent reappearance of hyperthyroidism when therapy is discontinued. However, there is, of course, no need to discontinue antithyroid drug therapy, but rather this therapy can be continued indefinitely. Except for mild side effects, serious reactions are rare (37), and the risks of occurrence of cardiac and bone complications are equal to or less than those of radioiodine therapy. The cost of long-term continuous antithyroid drug therapy does not exceed that of the continuous care given following radioiodine therapy. Therefore, a possible approach to the therapy of hyperthyroidism may be to control the disease, for a lifetime, with antithyroid drugs. The remarkable lack of MMI side effects and the apparent high treatment compliance in this study prompt the adoption of an alternative approach such as this.


   Acknowledgements
 
We are indebted to Mrs Niloufar Shiva for English editing, Ms Mojgan Padyab for statistical help and Mrs Tahereh Fakhimi for preparation of the manuscript.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

    1. Astwood EB & Vanderlaan WP. Thiouracil derivatives of greater activity for the treatment of hyperthyroidism. Journal of Clinical Endocrinology 1945 5 424–430.

    2. Weetman AP, McGregor AM & Hall R. Evidence for an effect of antithyroid drugs on the natural history of Graves’ desease. Clinical Endocrinology 1984 21 163–172.[Medline]

    3. Reinwein D, Benker G, Lazarus JH & Alexander WD. The European Multicenter Study Group on Antithyroid Drug Treatment. A prospective randomized trial of antithyroid drug dose in Graves’ disease. Journal of Clinical Endocrinology and Metabolism 1993 6 1516–1521.

    4. Allannic H, Fauchet R, Orgiazzi J, Madec AM, Genetet B, Lorcy Y, Le Guerrier AM, Delambre C & Derennes V. Antithyroid drugs and Graves’ disease: a prospective randomized evaluation of the efficacy of treatment duration. Journal of Clinical Endocrinology and Metabolism 1990 70 675–679.[Abstract]

    5. Vitti P, Rago T, Chiovato L, Pallini S & Santini F. Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid 1997 7 369–375.[ISI][Medline]

    6. Wartofsky L. Has the use of antithyroid drugs for Graves’ disease become obsolete? Thyroid 1993 3 335–344.[Medline]

    7. Reynolds LR & Kotchen TA. Antithyroid drugs and radioiodine: fifteen years’ experience with Graves’ disease. Archives of Internal Medicine 1979 139 651–653.[Abstract]

    8. Watson AB, Brownlie BEW, Frampton CM, Turner JG & Rogers TGH. Outcome following standardized 185 MB dose 131I therapy for Graves’ disease. Clinical Endocrinology 1988 2 487–496.

    9. Kendall-Taylor PK, Keir MJ & Ross WM. Ablative radioiodine therapy for hyperthyroidism: l long term follow up study. British Medical Journal 1984 28 9361–9363.

    10. Solomon B, Glinoer D, Lagasse R & Wartofsky L. Current trends in the management of Graves’ disease. Journal of Clinical Endocrinology 1990 70 1518–1524.

    11. Wartofsky L, Glinoer D, Solomon B, Nagataki S, Lagasse R, Nagayama Y & Izumi M. Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan, and the United States. Thyroid 1991 1 129–135.[Medline]

    12. Dunn JT & Chapman EM. Rising incidence of hypothyroidism after radioactive iodine therapy in hyperthyroidism. New England Journal of Medicine 1964 271 1037–1042.

    13. Holm LE. Changing annual incidence of hypothyroidism after 131I therapy for hyperthyroidism, 1951–1975. Journal of Nuclear Medicine 1982 23 108–112.[Abstract/Free Full Text]

    14. Biondi B, Fazio S, Carella C, Amato G, Cittadini A, Lupoli G, Sacca L, Bellastella A & Lombardi G. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. Journal of Clinical Endocrinology and Metabolism 1993 77 334–338.[Abstract]

    15. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson P, Benjamin EJ & D’Agostino RB. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. New England Journal of Medicine 1994 331 1249–1252.[Abstract/Free Full Text]

    16. Adlin EV, Maurer AH, Marks AD & Channick BJ. Bone mineral density in postmenopausal women treated with L-thyroixine. American Journal of Medicine 1991 90 360–366.[ISI][Medline]

    17. Faber J & Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis. European Journal of Endocrinology 1994 130 350–356.[Abstract]

    18. Rennie D. Thyroid storm. Journal of the American Medical Association 1997 277 1238–1243.[CrossRef][ISI][Medline]

    19. Dong BJ, Hauek WW, Gambertogllo JG, Gee L, White JR, Bubp JL & Greenspan FS. Bioequivalance of generic and brand-name levothyroxine products in the treatment of hypothyroidism. Journal of the American Medical Association 1997 277 1205–1213.[Abstract]

    20. Jones SJ, Hedley AJ, Curtis B, Allisons SP, Woolfson AM, Steel R, Bewsher PD & Weir RD. We need thyroid follow-up registers? A cost effective study. Lancet 1982 1 1229–1233.[Medline]

    21. Canaris GJ, Manowitz NR, Mayor G & Chester Ridgway E. The Colorado thyroid disease prevalence study. Archives of Internal Medicine 2000 160 526–534.[Abstract/Free Full Text]

    22. Ekelund LG, Haskell WL, Johnson JL, Whaley FS, Criqui MH & Sheps DS. Physical fitness as a predictor of cardiovascular mortality in asymptomatic North American men. The Lipid Research Clinics Mortality Follow-up Study. New England Journal of Medicine 1988 319 1379–1384.[Abstract]

    23. Jenkinson C, Couller A & Wright L. Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. British Medical Journal 1993 306 1437–1440.

    24. WHO/UNICEF/ICCIDD Assessment of the iodine deficiency disorders and monitoring their elemination. Report of consultation, May. 4–6 WHO/NHD/01.1, Geveva, 2001.

    25. Becker DV. Choice of therapy for Graves’ hyperthyroidism. New England Journal of Medicine 1984 311 464–466.[ISI][Medline]

    26. Sridama A, McCormick M, Kaplan EL, Fauchet R & DeGrool LJ. Long-term follow up study of compensated low dose 131I therapy. New England Journal of Medicine 1984 311 426–432.[Abstract]

    27. Ross DS, Daniels GH & Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic. Journal of Clinical Endocrinology and Metabolism 1990 71 764–769.[Abstract]

    28. Sato K, Han DC, Fujii Y, Tsushima T & Shizume K. Thyroid hormone stimulates alkaline phosphatase activity in cultured rat osteoblastic cells (ROS 17/2.8) through 3,5,3'- triiodo-L-thyronine nuclear receptors. Endocrinology 1987 120 1873–1881.[Abstract]

    29. Kumeda Y, Inaba M, Tahara H, Kurioka Y, Ishikawa T, Morii H & Nishizawa Y. Persistent increase in bone turnover in Graves’ patients with subclinical hyperthyroidism. Journal of Clinical Endocrinology and Metabolism 2000 85 4157–4161.[Abstract/Free Full Text]

    30. Mosekilde L, Eriksen EF & Charles P. Effects of thyroid hormones on bone and mineral metabolism. Endocrinology and Metabolism Clinics of North America 1990 19 35–63.[ISI][Medline]

    31. Pantazi H & Papapetrou PD. Changes in parameters of bone and mineral metabolism during therapy for hyperthyroidism. Journal of Clinical Endocrinology and Metabolism 2000 85 1099–1106.[Abstract/Free Full Text]

    32. Klein I & Ojamaa K. Thyroid hormone and the cardiovascular system. New England Journal of Medicine 2001 344 501–509.[Free Full Text]

    33. Petretta M, Bonaduce D, Spinelli L, Vicario ML, Nuzzo V, Marciano F, Camuso P, De Sanctis V & Lupoli G. Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. European Journal of Endocrinology 2001 145 691–696.[Abstract]

    34. Faber J, Petersen L, Wiinberg N, Schifter S & Mehlsen J. Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism. Thyroid 2002 12 319–324.[CrossRef][ISI][Medline]

    35. Franklyn JA, Daykin J, Droic Z, Farmer M & Sheppard MC. Long-term follow up of treatment of hyperthyroidism by three different methods. Clinical Endocrinology 1991 34 71–76.[Medline]

    36. Astwood EB. Use of antithyroid drugs. In Hyperthyroidism, pp 85–98. Ed. WJ Irvine. Baltimore, MD: Williams & Wilkins, 1967.

    37. Cooper DS. The side effects of antithyroid drugs. Endocrinologist 1999 9 457–467.

Received 18 January 2005
Accepted 4 February 2005




This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
P. Laurberg, G. Wallin, L. Tallstedt, M. Abraham-Nordling, G. Lundell, and O. Torring
TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study
Eur. J. Endocrinol., January 1, 2008; 158(1): 69 - 75.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
A. Toft and T. C Sandeep
Radioiodine treatment of hyperthyroidism
BMJ, March 10, 2007; 334(7592): 483 - 484.
[Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
P. Laurberg
Remission of Graves' disease during anti-thyroid drug therapy. Time to reconsider the mechanism?
Eur. J. Endocrinol., December 1, 2006; 155(6): 783 - 786.
[Abstract] [Full Text] [PDF]

Home page
 DTBHome page
Radioiodine therapy for hyperthyroidism
DTB, June 1, 2006; 44(6): 44 - 48.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
P. Abraham, A. Avenell, C. M Park, W. A Watson, and J. S Bevan
A systematic review of drug therapy for Graves' hyperthyroidism
Eur. J. Endocrinol., October 1, 2005; 153(4): 489 - 498.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Azizi, F
Right arrow Articles by Sheikholeslami, F
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Azizi, F
Right arrow Articles by Sheikholeslami, F

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS