Professional Documents
Culture Documents
review article
drug therapy
Antithyroid Drugs
David S. Cooper, M.D.
a ntithyroid drugs, which have been in use for more than half
a century, remain cornerstones in the management of hyperthyroidism, espe-
cially for patients with Graves disease. Surveys of thyroidologists from the
early 1990s indicate that most practitioners consider antithyroid drugs the treatment of
choice for most young people with Graves disease, both in the United States and in
From the Division of Endocrinology, Sinai
Hospital of Baltimore, the Johns Hopkins
University School of Medicine, Baltimore.
Address reprint requests to Dr. Cooper at
the Division of Endocrinology, Sinai Hos-
pital of Baltimore, 2401 W. Belvedere Ave.,
Baltimore, MD 21215, or at dcooper@
the rest of the world.1,2 A substantial amount of new information, much of it evidence- lifebridgehealth.org.
based,3 has become available since the topic was last summarized in the Journal in 1984.4
The present review considers recent pharmacologic and clinical data related to the use N Engl J Med 2005;352:905-17.
Copyright 2005 Massachusetts Medical Society.
of these compounds.
pharmacology
mechanism of action
Antithyroid drugs are relatively simple molecules known as thionamides, which contain
a sulfhydryl group and a thiourea moiety within a heterocyclic structure (Fig. 1). Propyl-
thiouracil (6-propyl-2-thiouracil) and methimazole (1-methyl-2-mercaptoimidazole,
Tapazole) are the antithyroid drugs used in the United States. Methimazole is used in
most of Europe and Asia, and carbimazole, a methimazole analogue, is used in the Unit-
ed Kingdom and parts of the former British Commonwealth. These agents are actively
concentrated by the thyroid gland against a concentration gradient.5 Their primary
effect is to inhibit thyroid hormone synthesis by interfering with thyroid peroxidase
mediated iodination of tyrosine residues in thyroglobulin, an important step in the
synthesis of thyroxine and triiodothyronine (Fig. 2).
These medications possess other noteworthy effects (Fig. 3). First, propylthioura-
cil, but not methimazole or carbimazole, can block the conversion of thyroxine to tri-
iodothyronine within the thyroid and in peripheral tissues, but this effect is not clinically
important in most instances. Second, antithyroid drugs may have clinically important
immunosuppressive effects. In patients taking antithyroid drugs, serum concentrations
of antithyrotropin-receptor antibodies decrease with time,8 as do other immunolog-
ically important molecules, including intracellular adhesion molecule 19 and soluble
interleukin-2 and interleukin-6 receptors.10,11 In addition, there is evidence that anti-
thyroid drugs may induce apoptosis of intrathyroidal lymphocytes,12 as well as decrease
HLA class II expression.13 Also, most studies show an increased number of circulating
suppressor T cells and a decreased number of helper T cells,14 natural killer cells,15,16
and activated intrathyroidal T cells14 during antithyroid-drug therapy.
Despite these multiple lines of evidence, it has been argued that any change in the
immune system must be viewed in the context of a drug-induced simultaneous improve-
ment in thyroid function that could itself have a beneficial effect on the autoimmune
process in patients with Graves disease.17 However, analyses of animal data18,19 and
human studies20 have also suggested that changes in the immune system may not be
predicated solely on changes in thyroid function.
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
drug therapy
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
choice of drugs
The choice between the drugs available in the
United States, methimazole and propylthiouracil,
has traditionally been a matter of personal prefer-
ence. Nevertheless, methimazole, with its once-
daily schedule, has decided advantages over propyl-
thiouracil, including better adherence27 and more
rapid improvement in serum concentrations of
thyroxine and triiodothyronine.27,39-41 The cost of
low-dose generic methimazole is similar to that
of propylthiouracil. In a recent search of Internet
pharmacies,42 a one-year supply of propylthioura-
cil (300 mg daily) was approximately $408, as com-
pared with a one-year supply of methimazole (15 mg
daily, $360; or 30 mg daily, $720). Finally, differ-
ences in the side-effect profiles of the two drugs fa-
vor methimazole. As discussed below, propylthio-
uracil is preferred during pregnancy.
practical considerations
The usual starting dose of methimazole is 15 to
30 mg per day as a single daily dose, and the usual
starting dose of propylthiouracil is 300 mg daily in
three divided doses. However, the disease of many
patients can be controlled with smaller doses of
methimazole, suggesting that the accepted poten-
cy ratio of 10:1 for methimazole as compared with
propylthiouracil is an underestimate. In one ran-
domized trial, 85 percent of patients had normal
levels of thyroxine and triiodothyronine after six
weeks of treatment with 10 mg of methimazole dai-
ly, as compared with 92 percent of patients receiv-
ing 40 mg daily.43 Indeed, iatrogenic hypothyroid-
ism may develop in patients with relatively mild
hyperthyroidism if methimazole dosing is overly
aggressive.44 On the other hand, inadequate dos-
Figure 3. Effects of Antithyroid Drugs. ing will lead to continuing unmitigated hyperthy-
The multiple effects of antithyroid drugs include inhibition of thyroid hor- roidism.
mone synthesis and a reduction in both intrathyroidal immune dysregulation Once a patient has been started on an antithy-
and (in the case of propylthiouracil) the peripheral conversion of thyroxine to
triiodothyronine. Tyrosine-Tg denotes tyrosine residues in thyroglobulin, I+
roid drug, follow-up testing of thyroid function ev-
the iodinating intermediate, and TPO thyroid peroxidase. ery four to six weeks is recommended, at least until
thyroid function is stable or the patient becomes
euthyroid. After 4 to 12 weeks, most patients have
improved considerably or have achieved normal
therapy,36 which are likely caused by a rise in stim- thyroid function, after which the drug dose can
ulating antithyrotropin-receptor antibodies follow- often be decreased while maintaining normal thy-
ing radioiodine therapy.37 Pretreatment with antithy- roid function. The disease of many patients can be
roid drugs is therefore recommended for patients ultimately controlled with a relatively low dose
with underlying cardiac disease or for the elderly,38 for example, 5 to 10 mg of methimazole or 100 to
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
drug therapy
Hyperthyroidism due
to Graves disease
Relapse Remission
Figure 4. Algorithm for the Use of Antithyroid Drugs among Patients with Graves Disease.
Antithyroid drugs are an option for initial therapy in adults with mild-to-moderate hyperthyroidism or active ophthal-
mopathy and are the therapy of choice for children, adolescents, and pregnant or lactating women. Radioiodine may be
preferable as initial therapy for adults in the United States1 but not for those in the rest of the world.2 Subtotal or near-
total thyroidectomy is also an option for some patients after treatment with antithyroid drugs. In adults who have a re-
lapse, definitive radioiodine therapy is the preferred strategy. Some patients prefer a second course of antithyroid-drug
therapy, and this strategy is preferable for children and adolescents. CBC denotes complete blood count.
200 mg of propylthiouracil daily. Indeed, hypothy- every two to three months and then every four to six
roidism or goiter can develop if the dose is not months. Serum thyrotropin levels remain sup-
decreased appropriately. After the first three to six pressed for weeks or even months, despite a nor-
months, follow-up intervals can be increased to malization of thyroid hormone levels, so a test of
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
thyrotropin levels is a poor early measure. Further- If antithyroid drugs have immunosuppressive
more, patients sometimes continue to have elevat- effects, a higher dose or longer treatment duration
ed serum triiodothyronine levels despite normal or might enhance the chances of remission. At least
even low thyroxine or free thyroxine levels, indicat- six prospective randomized trials have examined
ing the need to increase, not decrease, the antithy- possible benefits of high-dose drug therapy as
roid drug dose.45 compared with lower doses. With the exception of
one trial,55 all have been negative.48,56-59 With re-
remission gard to treatment duration, one prospective trial
Clinicians have long sought clinical and laborato- showed a significant improvement in the rate of re-
ry predictors to improve the selection of patients lapse after 2 years of follow-up in patients treated
so that only those patients most likely to have a re- for 18 months, as compared with those treated for
mission would be subjected to the potential risks 6 months (42 percent vs. 62 percent).60 However,
and inconvenience of antithyroid-drug therapy. In data from other prospective trials with up to four
addition, there have been attempts to develop more years of follow-up do not indicate that treatment
effective strategies for the use of antithyroid drugs for longer than one year has any effect on relapse
to enhance the chances of remission, including al- rates.61,62
tering the dose and treatment duration and com- Given these results, treatment with antithyroid
bining antithyroid drugs with thyroxine therapy. drugs for 12 to 18 months is the usual practice, as
Many retrospective studies clearly show that pa- recommended in a recent systematic, evidence-
tients with more severe degrees of hyperthyroid- based review.63 Some patients opt for long-term
ism, large goiters, or a high triiodothyronine-to- antithyroid drug treatment (i.e., years or even de-
thyroxine ratio in the serum (when unitless, more cades), and there is no theoretical reason why a pa-
than 20) are less likely to enter remission after a tient whose disease is well controlled with a small
course of drug treatment than are those with milder dose of antithyroid drug could not continue anti-
disease and smaller goiters.46-48 In addition, pa- thyroid-drug therapy indefinitely.64 Finally, a Japa-
tients with higher baseline levels of antithyrotropin- nese study showed that a combination of an anti-
receptor antibodies probably have a lower likelihood thyroid drug plus thyroxine for one year, followed
of remission.47,49 by thyroxine alone for three years, decreased the re-
Other clinical features that have been examined lapse rate significantly.65 However, subsequent at-
as possible predictors, but with inconsistent find- tempts to replicate this study have failed.66-68
ings, include the patients age, sex, and history of
cigarette smoking; the presence or absence of oph- discontinuation of drug treatment
thalmopathy; and the duration of symptoms be- With the exception of children and adolescents,
fore diagnosis. A recent prospective study showed who are often treated with antithyroid drugs for
that depression, hypochondriasis, paranoia, mental many years, antithyroid drugs are usually stopped
fatigue, and problems of daily life were risk fac- or tapered after 12 to 18 months of therapy. The
tors for relapse after an average of three years of likelihood of relapse is increased in patients with
antithyroid-drug therapy.50 Unfortunately, none of normal serum levels of free thyroxine and triiodo-
these parameters have sufficient sensitivity or speci- thyronine but suppressed serum thyrotropin lev-
ficity to be clinically useful in predicting the ideal els.69 Relapse usually occurs within the first three
candidates for primary drug therapy. Indeed, a pro- to six months after medication is stopped.47 There-
spective study of more than 300 patients with after, the rate of recurrence decreases and plateaus
Graves disease was unable to identify any clinical after one to two years, for an overall recurrence rate
or biochemical marker that predicted remission or of approximately 50 to 60 percent.48,70,71 About 75
relapse after 12 months of antithyroid-drug ther- percent of women in remission who become preg-
apy.48 Measurement of antithyrotropin-receptor nant will have a postpartum relapse of Graves dis-
antibodies at the end of a course of treatment may ease or the development of postpartum thyroidi-
have predictive value, in that antibody-positive pa- tis.72 Lifelong follow-up is required for patients
tients almost always have a relapse.51,52 However, in remission, since spontaneous hypothyroidism
even those patients whose antibody titers have may develop decades later in some of them.73
normalized have a fairly high rate of relapse (30 to It is important that the possibility of relapse be
50 percent).53,54 discussed so that a treatment strategy will be in
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
drug therapy
place in the event of recurrence. If radioiodine ther- ferential white-cell count should be obtained before
apy is selected after a relapse, the outcome may be initiation of therapy.
influenced by the prior use of antithyroid drugs. Most cases of agranulocytosis occur within the
When used to normalize thyroid function before first 90 days of treatment, but this complication can
radioiodine therapy, propylthiouracil, but not meth- occur even a year or more after starting therapy.
imazole, increases the failure rate of the radioactive Some, but not all, studies have suggested that the
iodine.36,74-76 This radioprotective effect of pro- risk of agranulocytosis is greater in older patients
pylthiouracil may be related to its ability to neutral- and that they have a higher rate of death.82 It is im-
ize iodinated free radicals produced by radiation portant to note that agranulocytosis can develop af-
exposure, a property evidently not shared by meth- ter a prior uneventful course of drug therapy, a find-
imazole.75 The radioprotective effect can be over- ing that is important since renewed exposure to the
come by increasing the radioiodine dose. drug frequently occurs when patients have a re-
lapse and undergo a second course of antithyroid
side effects therapy.
Agranulocytosis is thought to be autoimmune-
Antithyroid drugs are associated with a variety of mediated, and antigranulocyte antibodies are shown
minor side effects, as well as potentially life-threat- by immunofluorescence83 and cytotoxicity84,85
ening or even lethal complications.77-79 Side effects assays. Antineutrophil cytoplasmic antibodies may
of methimazole are dose-related, whereas those of play a role, since antigen targets (e.g., proteinase 3)
propylthiouracil are less clearly related to dose.77 may be expressed on the neutrophil surface.86 Rou-
This may favor use of low-dose methimazole rather tine monitoring of granulocyte counts in patients
than propylthiouracil in the average patient with receiving antithyroid drugs has not been consid-
hyperthyroidism. In a review of the literature, it ered cost-effective, a viewpoint that has been chal-
was found that minor side effects that included lenged by a report indicating that asymptomatic
cutaneous reactions (usually urticaria or macular patients may be detected through monitoring and
rashes), arthralgia, and gastrointestinal upset oc- rescued by stopping the antithyroid drug and ad-
curred in approximately 5 percent of patients, with ministering granulocyte colony-stimulating factor
equal frequency for both drugs.77 Minor cutaneous (G-CSF).87 Nevertheless, most authorities still do
reactions may resolve when an antihistamine is not recommend routine monitoring of the blood
added while drug therapy is continued. As an alter- count.88,89 However, all patients should be instruct-
native, a patient might be switched from one anti- ed to discontinue the antithyroid drug and contact
thyroid drug to the other. However, cross-reactivity a physician immediately if fever or sore throat de-
between the two agents may be as high as 50 per- velops. A white-cell count and differential count
cent. Abandoning antithyroid drugs is a third op- should be obtained immediately and the drug dis-
tion, to be followed by definitive radioiodine therapy. continued if the granulocyte count is less than 1000
The development of arthralgias, while classified as a per cubic millimeter, with close monitoring of the
minor reaction, should prompt drug discontinu- granulocyte count if it is more than 1000 per cubic
ation, since this symptom may be a harbinger of a millimeter but less than 1500 per cubic millimeter.
severe transient migratory polyarthritis known as Fever and sore throat are the most common pre-
the antithyroid arthritis syndrome.80 senting symptoms of agranulocytosis,90 but sepsis
Agranulocytosis is the most feared side effect should be suspected if there is very rapid onset of
of antithyroid-drug therapy. In the largest series, fever, chills, and prostration. In such cases, anti-
agranulocytosis (an absolute granulocyte count of thyroid drugs should be immediately discontinued
less than 500 per cubic millimeter) occurred in 0.37 and the patient should be hospitalized. According
percent of patients receiving propylthiouracil and to one report, Pseudomonas aeruginosa was the spe-
in 0.35 percent receiving methimazole.81 Agranu- cies most commonly isolated from the blood in
locytosis must be distinguished from the transient, agranulocytosis-associated sepsis.90 Therapy for
mild granulocytopenia (a granulocyte count of less agranulocytosis consists of the intravenous admin-
than 1500 per cubic millimeter) that occasionally istration of broad-spectrum antibiotics (includ-
occurs in patients with Graves disease, in some pa- ing coverage for possible pseudomonas infection)
tients of African descent, and occasionally in pa- among patients who are febrile or who have obvi-
tients treated with antithyroid drugs. A baseline dif- ous infections.
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
The administration of G-CSF may shorten the static process.100 Biopsy specimens show preserved
time to recovery and length of hospitalization in hepatocellular architecture, along with intracana-
patients with agranulocytosis due to antithyroid licular cholestasis and mild periportal inflamma-
drugs.91 A bone marrow aspirate may be useful tion. Complete, but slow, recovery is the rule after
prognostically, since severe depression of myeloid drug discontinuation. Since the mechanisms of
precursors suggests a prolonged recovery time and hepatotoxicity for the two antithyroid drugs used in
a failure to respond to G-CSF.92,93 Although a pro- the United States differ, the alternative agent could
spective randomized, controlled trial showed no be used cautiously to treat the underlying hyperthy-
significant difference in recovery time between no roidism in a patient with complicated thyrotoxi-
treatment and G-CSF therapy,94 most authorities cosis and drug-induced hepatic side effects.100,101
recommend using G-CSF for agranulocytosis due Vasculitis is the third major toxic reaction seen
to antithyroid drugs.90-93 Cross-reactivity between with antithyroid-drug treatment, more common-
propylthiouracil and methimazole for agranulocy- ly found in connection with propylthiouracil than
tosis has been well documented, so the use of the with methimazole. Serologic evidence consistent
alternative antithyroid drug is contraindicated. with lupus erythematosus develops in some pa-
Hepatotoxicity is another major side effect of tients, fulfilling the criteria for drug-induced lu-
antithyroid drugs. Estimates regarding the frequen- pus.102 Antineutrophil cytoplasmic antibodypos-
cy of this condition are imprecise, but it probably itive vasculitis has also been reported, especially
ranges from 0.1 percent to 0.2 percent.77 The rec- in Asian patients treated with propylthiouracil.103
ognition of propylthiouracil-related hepatotoxicity Most patients have perinuclear antineutrophil cy-
may be difficult, since in up to 30 percent of pa- toplasmic antibodies, with a majority of them hav-
tients with normal baseline aminotransferase lev- ing antimyeloperoxidase antineutrophil cytoplas-
els who are treated with propylthiouracil, transient mic antibodies.104 It has been hypothesized that
acute increases in those levels develop, ranging antithyroid drugs, especially propylthiouracil, can
from 1.1 to 6 times the upper limit of normal react with myeloperoxidase to form reactive inter-
levels that resolve while therapy is continued.95 Al- mediates that promote autoimmune inflamma-
so, asymptomatic elevations in serum aminotrans- tion.105,106
ferase levels occur frequently in untreated patients The clinical features of drug-induced antineu-
with hyperthyroidism and are not predictive of fur- trophil cytoplasmic antibodypositive vasculitis
ther increases after the institution of propylthio- include acute renal dysfunction, arthritis, skin ul-
uracil therapy.96 cerations, vasculitic rash, and upper and lower res-
The average duration of propylthiouracil ther- piratory symptoms, including sinusitis and hemop-
apy before the onset of hepatotoxicity is approxi- tysis. Although this syndrome generally resolves
mately three months.97 Propylthiouracil-related after drug cessation, high-dose glucocorticoid ther-
hepatotoxicity takes the form of an allergic hepati- apy or cyclophosphamide may be needed in severe
tis accompanied by laboratory evidence of hepa- cases, and some patients have required short-term
tocellular injury often markedly elevated amino- hemodialysis. Some patients with Graves disease
transferase levels and submassive or massive hepatic may have positive tests for antineutrophil cytoplas-
necrosis on biopsy. Therapy consists of immedi- mic antibody before therapy.107,108 In a large cross-
ate cessation of propylthiouracil along with expect- sectional study from the United Kingdom,109 an-
ant management of the potential complications tineutrophil cytoplasmic antibody positivity was
of hepatic failure. Although the literature suggests detected in 5 percent of 649 normal euthyroid con-
a case fatality rate of 25 to 50 percent,98 it is likely trol subjects, 4 percent of untreated patients with
that milder cases that resolve uneventfully are never Graves disease, 33 percent of patients receiving
reported. Liver transplantation may be required,99 propylthiouracil, and 16 percent of patients taking
and referral to a specialized center is reasonable. carbimazole. Thirty percent of patients who had
Routine monitoring of liver-function tests in pa- previously received antithyroid drugs but were no
tients being treated with propylthiouracil is gener- longer receiving them were positive as well. The
ally not recommended, given the frequent benign clinical significance of these intriguing findings is
liver-function abnormalities noted earlier. not known.
The rare hepatic abnormalities associated with Other rare side effects of antithyroid drugs are
methimazole and carbimazole are typical of a chole- listed in Table 1.
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
drug therapy
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
refer enc es
1. Solomon B, Glinoer D, Lagasse R, 9. Sonnet E, Massart C, Gibassier J, Allan- 16. Corrales JJ, Lopez A, Ciudad J, Mories
Wartofsky L. Current trends in the manage- nic H, Maugendre D. Longitudinal study of MT, Miralles JM, Orfao A. Methimazole ther-
ment of Graves disease. J Clin Endocrinol soluble intercellular adhesion molecule-1 apy in Graves disease influences the abnor-
Metab 1990;70:1518-24. (ICAM-1) in sera of patients with Graves mal expression of CD69 (early activation
2. Wartofsky L, Glinoer D, Solomon B, et disease. J Endocrinol Invest 1999;22:430-5. antigen) on T cells. J Endocrinol 1997;155:
al. Differences and similarities in the diag- 10. Tsatsoulis A, Vlachoyiannopoulos PG, 491-500.
nosis and treatment of Graves disease in Dalekos GN, Johnson EO, Moutsopoulos HM. 17. Volpe R. The immunomodulatory effects
Europe, Japan, and the United States. Thy- Increased serum interleukin-1 beta during of anti-thyroid drugs are mediated via actions
roid 1991;1:129-35. treatment of hyperthyroidism with antithy- on thyroid cells, affecting thyrocyte-immu-
3. Cooper DS. Antithyroid drugs in the roid drugs. Eur J Clin Invest 1995;25:654- nocyte signalling: a review. Curr Pharm Des
management of patients with Graves dis- 8. [Erratum, Eur J Clin Invest 1996:26:341.] 2001;7:451-60.
ease: an evidence-based approach to thera- 11. Salvi M, Girasole G, Pedrazzoni M, et al. 18. Davies TF, Weiss I, Gerber MA. Influ-
peutic controversies. J Clin Endocrinol Metab Increased serum concentrations of interleu- ence of methimazole on murine thyroiditis:
2003;88:3474-81. kin-6 (IL-6) and soluble IL-6 receptor in evidence for immunosuppression in vivo.
4. Idem. Antithyroid drugs. N Engl J Med patients with Graves disease. J Clin Endo- J Clin Invest 1984;73:397-404.
1984;311:1353-62. crinol Metab 1996;81:2976-9. 19. Reinhardt W, Appel MC, Alex S, Yang YN,
5. Marchant B, Alexander WD, Robertson 12. Mitsiades N, Poulaki V, Tseleni-Bal- Braverman LE. The inhibitory effect of large
JWK, Lazarus JH. Concentration of 35S-pro- afouta S, Chrousos GP, Koutras DA. Fas lig- doses of methimazole on iodine induced
pylthiouracil by the thyroid gland and its and expression in thyroid follicular cells from lymphocytic thyroiditis and serum anti-thy-
relationship to anion trapping mechanism. patients with thionamide-treated Graves roglobulin antibody titers in BB/Wor rats.
Metabolism 1971;20:989-99. disease. Thyroid 2000;10:527-32. J Endocrinol Invest 1989;12:559-63.
6. Davidson B, Soodak M, Neary JT, et al. 13. Zantut-Wittmann DE, Tambascia MA, 20. Wilson R, McKillop JH, Pearson C, Bur-
The irreversible inactivation of thyroid per- da Silva Trevisan MA, Pinto GA, Vassallo J. nett AK, Thomson JA. Differential immuno-
oxidase by methylmercaptoimidazole, thio- Antithyroid drugs inhibit in vivo HLA-DR suppressive action of carbimazole and pro-
uracil, and propylthiouracil in vitro and its expression in thyroid follicular cells in pylthiouracil. Clin Exp Immunol 1988;73:
relationship to in vivo findings. Endocrinol- Graves disease. Thyroid 2001;11:575-80. 312-5.
ogy 1978;103:871-82. 14. Totterman TH, Karlsson FA, Bengtsson 21. Cooper DS, Saxe VC, Meskell M, Maloof
7. Taurog A. Hormone synthesis and M, Mendel-Hartvig I. Induction of circu- F, Ridgway EC. Acute effects of propylthio-
secretion. In: Braverman LE, Utiger RD, eds. lating activated suppressor-like T cells by uracil (PTU) on thyroidal iodide organifica-
Werner and Ingbars the thyroid: a funda- methimazole therapy for Graves disease. tion and peripheral iodothyronine deiodi-
mental and clinical text. Philadelphia: Lip- N Engl J Med 1987;316:15-22. nation: correlation with serum PTU levels
pincott-Raven, 1996:47-80. 15. Wang PW, Luo SF, Huang BY, Lin JD, measured by radioimmunoassay. J Clin Endo-
8. McGregor AM, Petersen MM, McLachlan Huang MJ. Depressed natural killer activity crinol Metab 1982;54:101-7.
SM, Rooke P, Smith BR, Hall R. Carbimazole in Graves disease and during antithyroid 22. Cooper DS, Bode HH, Nath B, Saxe V,
and the autoimmune response in Graves medication. Clin Endocrinol (Oxf ) 1988;28: Maloof F, Ridgway EC. Methimazole phar-
disease. N Engl J Med 1980;303:302-7. 205-14. macology in man: studies using a newly
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
drug therapy
developed radioimmunoassay for methima- prospective randomized study. J Clin Endo- 50. Fukao A, Takamatsu J, Murakami Y, et
zole. J Clin Endocrinol Metab 1984;58:473- crinol Metab 2001;86:3488-93. al. The relationship of psychological fac-
9. 37. Nakazato N, Yoshida K, Mori K, et al. tors to the prognosis of hyperthyroidism
23. Barnes HV, Bledsoe T. A simple test for Antithyroid drugs inhibit radioiodine- in antithyroid drug-treated patients with
selecting the thioamide schedule in thyro- induced increases in thyroid autoantibod- Graves disease. Clin Endocrinol (Oxf ) 2003;
toxicosis. J Clin Endocrinol Metab 1972;35: ies in hyperthyroid Graves disease. Thyroid 58:550-5.
250-5. 1999;9:775-9. 51. Feldt-Rasmussen U, Schleusener H, Car-
24. Jansson R, Dahlberg PA, Johansson H, 38. Singer PA, Cooper DS, Levy EG, et al. ayon P. Meta-analysis evaluation of the
Lindstrom B. Intrathyroidal concentrations Treatment guidelines for patients with hyper- impact of thyrotropin receptor antibodies
of methimazole in patients with Graves dis- thyroidism and hypothyroidism: Standards on long-term remission after medical ther-
ease. J Clin Endocrinol Metab 1983;57:129- of Care Committee, American Thyroid Asso- apy of Graves disease. J Clin Endocrinol
32. ciation. JAMA 1995;273:808-12. Metab 1994;78:98-102.
25. McCruden DC, Hilditch TE, Connell 39. Kallner G, Vitols S, Ljunggren JG. Com- 52. Schott M, Morgenthaler NG, Fritzen R,
JMC, McLellan AR, Robertson J, Alexander parison of standardized initial doses of two et al. Levels of autoantibodies against human
WD. Duration of antithyroid action of meth- antithyroid drugs in the treatment of Graves TSH receptor predict relapse of hyperthy-
imazole estimated with an intravenous per- disease. J Intern Med 1996;239:525-9. roidism in Graves disease. Horm Metab Res
chlorate discharge test. Clin Endocrinol 40. Homsanit M, Sriussadaporn S, Vanna- 2004;36:92-6.
(Oxf ) 1987;26:33-9. saeng S, Peerapatdit T, Nitiyanant W, Vichay- 53. Nedrebo BG, Holm PI, Uhlving S, et al.
26. Mashio Y, Beniko M, Ikota A, Mizumoto anrat A. Efficacy of single daily dosage of Predictors of outcome and comparison of
H, Kunita H. Treatment of hyperthyroidism methimazole vs. propylthiouracil in the different drug regimens for the prevention
with a small single daily dose of methima- induction of euthyroidism. Clin Endocrinol of relapse in patients with Graves disease.
zole. Acta Endocrinol (Copenh) 1988;119: (Oxf ) 2001;54:385-90. Eur J Endocrinol 2002;147:583-9.
139-44. 41. He CT, Hsieh AT, Pei D, et al. Compari- 54. Teng CS, Yeung RTT. Changes in thy-
27. Nicholas WC, Fischer RG, Stevenson son of single daily dose of methimazole and roid-stimulating antibody activity in Graves
RA, Bass JD. Single daily dose of methima- propylthiouracil in the treatment of Graves disease treated with antithyroid drug and its
zole compared to every 8 hours propylthio- hyperthyroidism. Clin Endocrinol (Oxf ) relationship to relapse: a prospective study.
uracil in the treatment of hyperthyroidism. 2004;60:676-81. J Clin Endocrinol Metab 1980;50:144-7.
South Med J 1995;88:973-6. 42. DestinationRx home page. (Accessed 55. Werner RS, Romaldini JH, Farah CS,
28. Hoffman WH, Miceli JN. Pharmacoki- January 13, 2005, at http://www.destinationrx. Werner MC, Bromberg N. Serum thyroid
netics of propylthiouracil in children and com.) stimulating antibody, thyroglobulin levels,
adolescents with Graves disease in the hyper- 43. Reinwein D, Benker G, Lazarus JH, Alex- and thyroid suppressibility measurement as
thyroid and euthyroid states. Dev Pharmacol ander WD. A prospective randomized trial predictors of the outcome of combined meth-
Ther 1988;11:73-81. of antithyroid drug dose in Graves disease imazole and triiodothyronine therapy in
29. Kampmann JP, Mortensen HB, Bach B, therapy. J Clin Endocrinol Metab 1993;76: Graves disease. Thyroid 1991;1:293-9.
Waldorff S, Kristensen MB, Hansen JM. 1516-21. 56. Jorde R, Ytre-Arne K, Stormer J, Sunds-
Kinetics of propylthiouracil in the elderly. 44. Page SR, Sheard CE, Herbert M, Hop- fjord J. Short-term treatment of Graves dis-
Acta Med Scand Suppl 1979;624:93-8. ton M, Jeffcoate WJ. A comparison of 20 or ease with methimazole in high versus low
30. Jansson R, Lindstrom B, Dahlberg PA. 40 mg per day of carbimazole in the initial doses. J Intern Med 1995;238:161-5.
Pharmacokinetic properties and bioavail- treatment of hyperthyroidism. Clin Endo- 57. Wilson R, Buchanan L, Fraser WD,
ability of methimazole. Clin Pharmacokinet crinol (Oxf ) 1996;45:511-6. [Erratum, Clin McKippop JH, Thomsen JA. Do higher doses
1985;10:443-50. Endocrinol (Oxf ) 1997;46:240.] of carbimazole improve remission in Graves
31. Cooper DS, Steigerwalt S, Migdal S. 45. Hegeds L, Hansen JM, Bech K, et al. disease? QJM 1996;89:381-5.
Pharmacology of propylthiouracil in thyro- Thyroid stimulating immunoglobulins in 58. Grebe SKG, Feek CM, Ford HC, et al.
toxicosis and chronic renal failure. Arch Graves disease with goitre growth, low thy- A randomized trial of short-term treatment
Intern Med 1987;147:785-6. roxine and increasing triiodothyronine dur- of Graves disease with high-dose carbima-
32. Giles HG, Roberts EA, Orrego H, Sellers ing PTU treatment. Acta Endocrinol (Copenh) zole plus thyroxine versus low-dose carbim-
EM. Determination of free propylthiouracil 1984;107:482-8. azole. Clin Endocrinol (Oxf ) 1998;48:585-
clearance and single sample prediction of 46. Schleusener H, Schwander J, Fischer C, 92.
steady state. J Pharm Pharmacol 1982;34: et al. Prospective multicentre study on the 59. Paschke R, Vogg M, Kristoferitsch R, et
62-4. prediction of relapse after antithyroid drug al. Methimazole has no dose-related effect
33. Tallstedt L, Lundell G, Torring O, et al. treatment in patients with Graves disease. on the intensity of the intrathyroidal autoim-
Occurrence of ophthalmopathy after treat- Acta Endocrinol (Copenh) 1989;120:689-701. mune process in relapsing Graves disease.
ment for Graves hyperthyroidism. N Engl [Erratum, Acta Endocrinol (Copenh) 1989; J Clin Endocrinol Metab 1995;80:2470-4.
J Med 1992;326:1733-8. 121:304.] 60. Allannic H, Fauchet R, Orgiazzi J, et al.
34. Torring O, Tallstedt L, Wallin G, et al. 47. Vitti P, Rago T, Chiovato L, et al. Clini- Antithyroid drugs and Graves disease: a pro-
Graves hyperthyroidism: treatment with cal features of patients with Graves disease spective randomized evaluation of the effi-
antithyroid drugs, surgery, or radioiodine undergoing remission after antithyroid drug cacy of treatment duration. J Clin Endo-
a prospective, randomized study. J Clin treatment. Thyroid 1997;7:369-75. crinol Metab 1990;70:675-9.
Endocrinol Metab 1996;81:2986-93. 48. Benker G, Rienwein D, Kahaly G, et al. 61. Garcia-Mayor RVG, Paramo C, LunaCano
35. Ljunggren JG, Torring O, Wallin G, et al. Is there a methimazole dose effect on remis- R, Perez Mendez LF, Galofre JC, Andrade A.
Quality of life aspects and costs in treatment sion rate in Graves disease? Results from a Antithyroid drug and Graves hyperthyroid-
of Graves hyperthyroidism with antithyroid long-term prospective study. Clin Endo- ism: significance of treatment duration and
drugs, surgery, or radioiodine: results from crinol (Oxf ) 1998;49:451-7. TRAb determination on lasting remission.
a prospective, randomized study. Thyroid 49. Michelangeli V, Poon C, Taft J, Newn- J Endocrinol Invest 1992;15:815-20.
1998;8:653-9. ham H, Topliss D, Colman P. The prognostic 62. Maugendre D, Gatel A, Campion L, et al.
36. Andrade VA, Gross JL, Maia AL. Effect value of thyrotropin receptor antibody mea- Antithyroid drugs and Graves disease
of methimazole pretreatment on the effi- surement in the early stages of treatment of prospective randomized assessment of
cacy of radioactive iodine therapy in Graves Graves disease with antithyroid drugs. Thy- long-term treatment. Clin Endocrinol (Oxf )
hyperthyroidism: one-year follow-up of a roid 1998;8:119-24. 1999;50:127-32.
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
The new england journal of medicine
63. Abraham P, Avenell A, Watson WA, Park ical trial. J Clin Endocrinol Metab 2004;89: growth factor in antithyroid-drug-induced
CM, Bevan JS. Antithyroid drug regimen for 4439-44. agranulocytosis. QJM 2001;94:423-8.
treating Graves hyperthyroidism. Cochrane 77. Cooper DS. The side effects of antithy- 92. Julia A, Olona M, Bueno J, et al. Drug-
Database Syst Rev 2004;2:CD003420. roid drugs. Endocrinologist 1999;9:457-76. induced agranulocytosis: prognostic fac-
64. Slingerland DW, Burrows BA. Long- 78. Ducornet B, Duprey J. Effects secon- tors in a series of 168 episodes. Br J Haema-
term antithyroid treatment in hyperthyroid- daires des antithyroidiens de synthese. Ann tol 1991;79:366-71.
ism. JAMA 1979;242:2408-10. Med Interne 1988;139:410-31. 93. Tajiri J, Noguchi S, Okamura S, et al.
65. Hashizume K, Ichikawa I, Sakurai A, et 79. Meyer-Gessner M, Benker G, Olbricht Granulocyte colony-stimulating factor treat-
al. Administration of thyroxine in treated T, et al. Nebenwirkungen der antithyreoi- ment of antithyroid drug-induced granulo-
Graves disease: effects on the level of anti- dalen Therapie der hyperthyreose. Dtsch cytopenia. Arch Intern Med 1993;153:509-
bodies to thyroid-stimulating hormone recep- Med Wochenschr 1989;114:166-71. 14.
tors and on the risk of recurrence of hyper- 80. Shabtai R, Shapiro MS, Orenstein D, 94. Fukata S, Kuma K, Sugawara M. Granu-
thyroidism. N Engl J Med 1991;324:947-53. Taragan R, Shenkman L. The antithyroid locyte colony-stimulating factor (G-CSF)
66. McIver B, Rae P, Beckett G, Wilkinson E, arthritis syndrome reviewed. Arthritis Rheum does not improve recovery from antithyroid
Gold A, Toft A. Lack of effect of thyroxine in 1984;27:227-9. drug-induced agranulocytosis: a prospective
patients with Graves hyperthyroidism who 81. Tajiri J, Noguchi S. Antithyroid drug- study. Thyroid 1999;9:29-31.
are treated with an antithyroid drug. N Engl induced agranulocytosis: special reference 95. Liaw Y-F, Huang M-J, Fan K-D, Li K-L,
J Med 1996;334:220-4. to normal white blood cell count agranulo- Wu S-S, Chen T-J. Hepatic injury during pro-
67. Rittmaster RS, Zwicker H, Abbott EC, et cytosis. Thyroid 2004;14:459-62. pylthiouracil therapy in patients with hyper-
al. Effect of methimazole with or without 82. Pearce SH. Spontaneous reporting of thyroidism. Ann Intern Med 1993;118:424-
exogenous L-thyroxine on serum concentra- adverse reactions to carbimazole and pro- 8.
tions of thyrotropin (TSH) receptor antibod- pylthiouracil in the UK. Clin Endocrinol 96. Gurlek A, Cobaukara V, Bayraktar M.
ies in patients with Graves disease. J Clin (Oxf ) 2004;61:589-94. Liver tests in hyperthyroidism: effect of anti-
Endocrinol Metab 1996;81:3283-8. 83. Toth EL, Mant MJ, Shivji S, Ginsberg J. thyroid therapy. J Clin Gastroenterol 1997;
68. Pfeilschifter J, Zeigler R. Suppression of Propylthiouracil-induced agranulocytosis: 24:180-3.
serum thyrotropin with thyroxine in patients an unusual presentation and a possible 97. Williams KV, Nayak S, Becker D, Reyes J,
with Graves disease: effects on recurrence mechanism. Am J Med 1988;85:725-7. Burmeister LA. Fifty years of experience
of hyperthyroidism and thyroid volume. Eur 84. Berkman EM, Orlin JB, Wolfsdorf J. with propylthiouracil-associated hepatotox-
J Endocrinol 1997;136:81-6. An anti-neutrophil antibody associated with icity: what have we learned? J Clin Endo-
69. Cho BY, Shong MH, Yi KH, Lee HK, Koh a propylthiouracil-induced lupus-like syn- crinol Metab 1997;82:1727-33.
CS, Min HK. Evaluation of serum basal thy- drome. Transfusion 1983;23:135-8. 98. Ruiz JK, Rossi GV, Vallejos HA, Brenet
rotrophin levels and thyrotrophin receptor 85. Fibbe WE, Claas FHJ, Van der Star-Dijk- RW, Lopez IB, Escribano AA. Fulminant
antibody activities as prognostic markers for stra W, Schaafsma MR, Meyboom RH, Falk- hepatic failure associated with propylthiou-
discontinuation of antithyroid drug treat- enburg JH. Agranulocytosis induced by pro- racil. Ann Pharmacother 2003;37:224-8.
ment in patients with Graves disease. Clin pylthiouracil: evidence of a drug dependent 99. Russo MW, Galanko JA, Shrestha R,
Endocrinol (Oxf ) 1992;36:585-90. antibody reacting with granulocytes, mono- Fried MW, Watkins P. Liver transplantation
70. Hedley AJ, Young RE, Jones SJ, Alex- cytes and haematopoietic progenitor cells. for acute liver failure from drug induced liver
ander WD, Bewsher PD. Antithyroid drugs in Br J Haematol 1986;64:363-73. injury in the United States. Liver Transpl
the treatment of hyperthyroidism of Graves 86. Akamizu T, Ozaki S, Hiratani H, et al. 2004;10:1018-23.
disease: long-term follow-up of 434 patients. Drug-induced neutropenia associated with 100. Arab DM, Malatjalian DA, Rittmaster
Clin Endocrinol (Oxf ) 1989;31:209-18. anti-neutrophil cytoplasmic antibodies RS. Severe cholestatic jaundice in uncompli-
71. Berglund J, Christensen SB, Dymling JF, (ANCA): possible involvement of comple- cated hyperthyroidism treated with methim-
Hallengren B. The incidence of recurrence ment in granulocyte cytotoxicity. Clin Exp azole. J Clin Endocrinol Metab 1995;80:
and hypothyroidism following treatment Immunol 2002;127:92-8. 1083-5.
with antithyroid drugs, surgery or radioio- 87. Tajiri J, Noguchi S, Murakami N. Use- 101. Parker WA. Propylthiouracil-induced
dine in all patients with thyrotoxicosis in fulness of granulocyte count measurement hepatotoxicity. Clin Pharm 1982;1:471-4.
Malm during the period 19701974. J Intern four hours after injection of granulocyte col- 102. Horton RC, Sheppard MC, Emery P.
Med 1991;229:435-42. ony-stimulating factor for detecting recov- Propylthiouracil-induced systemic lupus
72. Amino N, Tanizawa O, Mori H, et al. ery from antithyroid drug-induced granulo- erythematosus. Lancet 1989;2:568.
Aggravation of thyrotoxicosis in early preg- cytopenia. Thyroid 1997;7:575-8. 103. Gunton JE, Stiel J, Caterson RJ, McElduff
nancy and after delivery in Graves disease. 88. Cooper DS. Antithyroid drugs for the A. Anti-thyroid drugs and antineutrophil
J Clin Endocrinol Metab 1982;55:108-12. treatment of hyperthyroidism caused by cytoplasmic antibody positive vasculitis:
73. Wood LC, Ingbar SH. Hypothyroidism Graves disease. Endocrinol Metab Clin a case report and review of the literature.
as a late sequela in patient with Graves dis- North Am 1998;27:225-47. J Clin Endocrinol Metab 1999;84:13-6.
ease treated with antithyroid agents. J Clin 89. Vanderpump MP, Ahlquist JA, Franklyn 104. Sera N, Ashizawa K, Ando T, et al.
Invest 1979;64:1429-36. JA, Clayton RN. Consensus statement for Treatment with propylthiouracil is associ-
74. Braga M, Walpert N, Burch HB, Solo- good practice and audit measures in the ated with appearance of antineutrophil cyto-
mon BL, Cooper DS. The effect of methima- management of hypothyroidism and hyper- plasmic antibodies in some patients with
zole on cure rates after radioiodine treatment thyroidism: the Research Unit of the Royal Graves disease. Thyroid 2000;10:595-9.
for Graves hyperthyroidism: a randomized College of Physicians of London, the Endo- 105. Case Records of the Massachusetts
clinical trial. Thyroid 2002;12:135-9. crinology and Diabetes Committee of the General Hospital (Case 21-2002.) N Engl
75. Santos RB, Romaldini JH, Ward LS. Royal College of Physicians of London, and J Med 2002;347:122-30.
Propylthiouracil reduces the effectiveness the Society for Endocrinology. BMJ 1996; 106. Waldhauser L, Uetrecht J. Oxidation of
of radioiodine treatment in hyperthyroid 313:539-44. propylthiouracil to reactive metabolites by
patients with Graves disease. Thyroid 2004; 90. Sheng WH, Hung CC, Chen YC, et al. activated neutrophils: implications for agran-
14:525-30. Antithyroid-drug-induced agranulocytosis ulocytosis. Drug Metab Dispos 1991;19:354-
76. Bonnema SJ, Bennedbk FN, Veje A, complicated by life-threatening infections. 9.
Marving J, Hegedus L. Propylthiouracil before QJM 1999;92:455-61. 107. Sato H, Hattori M, Fujieda M, et al.
131I therapy of hyperthyroid disease: effect 91. Andres E, Kurtz JE, Perrin AE, Dufour P, High prevalence of antineutrophil cytoplas-
on cure rate evaluated by a randomized clin- Schlienger JL, Maloisel F. Haematopoietic mic antibody positivity in childhood onset
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
drug therapy
Graves disease treated with propylthiouracil. K. Effects of propylthiouracil and methima- methimazole or propylthiouracil in utero.
J Clin Endocrinol Metab 2000;85:4270-3. zole on fetal thyroid status in mothers with Eur J Pediatr 1992;151:558-9.
108. Guma M, Salinas I, Reverter JL, et al. Graves hyperthyroidism. J Clin Endocrinol 125. Hamburger JL. Diagnosis and man-
Frequency of antineutrophil cytoplasmic Metab 1997;82:3633-6. agement of Graves disease in pregnancy.
antibody in Graves disease patients treated 117. Wing DA, Millar LK, Koonings PP, Thyroid 1992;2:219-24.
with methimazole. J Clin Endocrinol Metab Montoro MN, Mestman JH. A comparison 126. Momotani N, Yamashita R, Makino F,
2003;88:2141-6. of propylthiouracil and methimazole in the Noh JY, Ishikawa N, Ito K. Thyroid function
109. Harper L, Chin L, Daykin J, et al. Propyl- treatment of hyperthyroidism in pregnancy. in wholly breast-feeding infants whose moth-
thiouracil and carbimazole associated-anti- Am J Obstet Gynecol 1994;170:90-5. ers take high doses of propylthiouracil. Clin
neutrophil cytoplasmic antibodies (ANCA) 118. Mandel SJ, Brent GA, Larsen PR. Review Endocrinol (Oxf ) 2000;53:177-81.
in patients with Graves disease. Clin Endo- of antithyroid drug use during pregnancy 127. Azizi F, Hedayati M. Thyroid function
crinol (Oxf ) 2004;60:671-5. and report of a case of aplasia cutis. Thyroid in breast-fed infants whose mothers take
110. Ikeda S, Schweiss JF. Excessive blood 1994;4:129-33. high doses of methimazole. J Endocrinol
loss during operation in the patient treated 119. Di Gianantonio E, Schaefer C, Mas- Invest 2002;25:493-6.
with propylthiouracil. Can Anaesth Soc troiacovo PP, et al. Adverse effects of prena- 128. Azizi F, Bahrainian M, Khamseh ME,
J 1982;29:477-80. tal methimazole exposure. Teratology 2001; Khoshniat M. Intellectual development and
111. Uchigata Y, Eguchi Y, Takayama- 64:262-6. thyroid function in children who were breast-
Hasumi S, Omori Y. Insulin autoimmune 120. Momotani N, Ito K, Hamada N, Ban Y, fed by thyrotoxic mothers taking methima-
syndrome (Hirata disease): clinical features Nishikawa Y, Mimura T. Maternal hyperthy- zole. J Pediatr Endocrinol Metab 2003;16:
and epidemiology in Japan. Diabetes Res roidism and congenital malformation in the 1239-43.
Clin Pract 1994;22:89-94. offspring. Clin Endocrinol (Oxf ) 1984;20: 129. American Academy of Pediatrics Com-
112. Taguchi M, Yokota M, Koyano H, Endo 695-700. mittee on Drugs. Transfer of drugs and other
Y, Ozawa Y. Acute pancreatitis and parotitis 121. Cheron RG, Kaplan MM, Larsen PR, chemicals into human milk. Pediatrics 2001;
induced by methimazole in a patient with Selenkow HA, Crigler JF Jr. Neonatal thyroid 108:776-89.
Graves disease. Clin Endocrinol (Oxf ) 1999; function after propylthiouracil therapy for 130. Jongjaroenprasert W, Akarawut W,
51:667-70. maternal Graves disease. N Engl J Med 1981; Chantasart D, Chailurkit L, Rajatanavin R.
113. Mandel SJ, Cooper DS. The use of anti- 304:525-8. Rectal administration of propylthiouracil in
thyroid drugs in pregnancy and lactation. 122. Momotani N, Noh J, Oyanagi H, Ishi- hyperthyroid patients: comparison of sus-
J Clin Endocrinol Metab 2001;86:2354-9. lawa N, Ito K. Antithyroid drug therapy for pension enema and suppository form. Thy-
114. Gardner DF, Cruikshank DP, Hays PM, Graves disease during pregnancy: optimal roid 2002;12:627-31.
Cooper DS. Pharmacology of propylthioura- regimen for fetal thyroid status. N Engl 131. Nabil N, Miner DJ, Amatruda JM.
cil (PTU) in pregnant hyperthyroid women: J Med 1986;315:24-8. Methimazole: an alternative route of ad-
correlation of maternal PTU concentrations 123. Messer PM, Hauffa BP, Olbricht T, ministration. J Clin Endocrinol Metab
with cord serum thyroid function tests. Benker G, Kotulla P, Reinwein D. Antithy- 1982; 54:180-1.
J Clin Endocrinol Metab 1986;62:217-20. roid drug treatment of Graves disease in 132. Junik R, Sowinski J, Zamyslowska H,
115. Mortimer RH, Cannell GR, Addison pregnancy: long-term effects on somatic Gembicki M. Effect of intravenous methim-
RS, Johnson LP, Roberts MS, Bernus I. Meth- growth, intellectual development and thy- azole on serum levels of thyroid hormones
imazole and propylthiouracil equally cross roid function of the offspring. Acta Endo- in patients with hyperthyroidism resistant
the perfused human term placental lobule. crinol (Copenh) 1990;123:311-6. to oral thyrostatic drugs. Endokrynol Pol
J Clin Endocrinol Metab 1997;82:3099-102. 124. Eisenstein Z, Weiss M, Katz Y, Bank H. 1989;40:307-13. (In Polish.)
116. Momotani N, Noh JY, Ishikawa N, Ito Intellectual capacity of subjects exposed to Copyright 2005 Massachusetts Medical Society.
The New England Journal of Medicine as published by New England Journal of Medicine.
Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.