J Endocrinol Invest (2014) 37:10411048
DOI 10.1007/s40618-014-0136-z
SHORT REVIEW
An update on the medical treatment of Graves hyperthyroidism
Michele Marino Francesco Latrofa
Francesca Menconi Luca Chiovato
Paolo Vitti
Received: 30 June 2014 / Accepted: 9 July 2014 / Published online: 4 September 2014
Italian Society of Endocrinology (SIE) 2014
Abstract Medical treatment of Graves hyperthyroidism
is based on the use of thionamides; namely, methimazole
and propylthiouracil. In the past, methimazole was pre-
ferred by European endocrinologists, whereas propylthio-
uracil was the first choice for the majority of their North
American colleagues. However, because of the recent
definition of a better side-effect profile, methimazole is
nowadays the first choice world while. Although thiona-
mides are quite effective for the short-term control of
Graves hyperthyroidism, a relatively high proportion of
patients relapses after thionamide withdrawal. Other pos-
sible medical treatments, include iodine and compounds
containing iodine, perchlorate, lithium (as an adjuvant in
patients undergoing radioiodine therapy), b-adrenergic
antagonists, glucocorticoids, and some new molecules still
under investigation. Management of Graves hyperthy-
roidism using thionamides as well as the other available
medical treatments is here reviewed in detail, with a special
mention of situations such as pregnancy and lactation, as
well as neonatal and fetal thyrotoxicosis.
M. Marino
F. Latrofa
F. Menconi
P. Vitti
Department of Clinical and Experimental Medicine, University
of Pisa, Pisa, Italy
M. Marino (&)
F. Latrofa
F. Menconi
P. Vitti
Endocrinology Unit, University Hospital of Pisa, Via Paradisa 2,
56124 Pisa, Italy
e-mail: michele.marino@med.unipi.it
L. Chiovato
Department of Internal Medicine and Medical Therapy,
University of Pavia, Pavia, Italy
L. Chiovato
Unit of Endocrinology, Fondazione Salvatore Maugeri IRCCS,
Pavia, Italy
Keywords Graves disease
Hyperthyroidism

Thyrotoxicosis
Methimazole
Propylthiouracil
Introduction
Since its first descriptions, management of Graves disease
(GD) on the therapeutic side has always puzzled endocri-
nologists all over the world. The major limitations derive
from the fact that causal treatments are not available,
because the pathogenesis of GD is poorly known in spite of
the efforts of investigators in the field since more than one
century. Thus, whereas it is well known that the two major
thyroid manifestations of GD, namely, hyperthyroidism
and goiter, are due to autoantibodies binding to the TSH
receptor and mimicking the actions of TSH, the events
responsible for the loss of immunological tolerance against
thyroid antigens in general and the TSH receptor in par-
ticular are known only in part. The major aim of the
available treatment methods is correction of thyrotoxicosis,
and treatment of Graves ophthalmopathy when present
and severe. Here we review the current medical treatments
available to manage Graves hyperthyroidism based on the
recent advancements in the field.
Medical treatment of graves hyperthyroidism
Correction of hyperthyroidism can be achieved both by
inhibition of hormone synthesis and/or release, or by
elimination of functional thyroid tissue, by surgery, radi-
oiodine or both [1]. In addition, peripheral metabolism of
thyroid hormone can be modified favorably by several
drugs [1]. Irrespective of the methods, the choice of the
right option among those available should be made after
123
1042 J Endocrinol Invest (2014) 37:10411048

Table 1 Comparison between the pharmacological properties of taken the lead also in North America, especially, if not
methimazole and propylthiouracil only, because of its superior side-effect profile [57]. Thus,
Property Methimazole Propylthiouracil nowadays propylthiouracil is used only in peculiar cir-
cumstances, namely allergy to methimazole or pregnancy
Relative potency [10 (up to 50) 1
[57]. The main reason for the switch towards methimazole
Route of administration Oral Oral of North American endocrinologists is the increasing
Extent of absorption Almost complete Almost complete numbers of reports of severe liver toxicity in patients given
Serum protein binding Negligible 75 % propylthiouracil, in some cases leading to liver transplan-
Half life (h) 46 12 tation, and in a few cases to death due to fulminant hepatic
Action duration (h) [24 \6 failure [57].
Transplacental passage Low Low
Breast milk levels Low Lower Outcome of hyperthyroidism after treatment
Type I deiodinase inhibition No Yes with thionamides

A major issue concerning treatment with thionamides is the

careful consideration of several variables in any given
patient [1]. However, the patient should be involved in the
decision-making process, and thus he/she has to be
informed adequately on the therapeutic alternatives.
Thionamides
Thionamides, also known as anti-thyroid drugs, which
include methimazole, carbimazole, and propylthiouracil,
were described and introduced into the clinical practice as
early as in 1940s [2]. Thionamides act mainly by inhibiting
iodine organification and coupling of iodotyrosines to
thyroglobulin molecules, thereby reducing synthesis of
thyroid hormones [3]. Carbimazole is not active as it is, but
is virtually completely converted into methimazole, having
ultimately similar effects [3]. In addition to this action in
the thyroid, unlike methimazole, propylthiouracil has the
additional effect of inhibiting to some extent the conver-
sion of T4 to T3 in peripheral tissues, an effect that, how-
ever, seems of limited clinical value [3]. The
pharmacologic properties of the two major thionamides are
reported in Table 1. Both drugs are effective in controlling
hyperthyroidism, but methimazole is at least 10 times more
potent [3].
Once treatment with thionamides is initiated, because
they do not block the release of preformed hormones,
euthyroidism is usually not obtained before 16 weeks, the
time needed for intrathyroidal hormone and iodine stores to
be depleted, depending on several variables such as disease
activity, initial levels of hormones and intrathyroidal hor-
mone and iodine stores [3]. Thus, large goiters that have
remarkable deposits of hormones often require a relatively
long period of time for hyperthyroidism to be controlled
[3].
In the early 1990s, surveys showed that propylthiouracil
was favored by North American endocrinologists, whereas
most of their European colleagues preferred methimazole
[4]. Nevertheless, in more recent years, methimazole has
relatively high rate of relapse of hyperthyroidism after
withdrawal of the drugs [3]. The frequency of relapse was
as low as *30 % of patients in a few studies [8, 9].
However, in the majority of studies hyperthyroidism
recurred in up to *50 to *80 % of Graves patients,
depending on the duration of treatment and of the follow-
up period [3, 10, 11]. It seems that over the years, possibly
because of an increased iodine supply in the diet, remission
rates have decreased [12, 13]. Unfortunately, there are no
single tests or combination of tests that can identify accu-
rately patients who will relapse. Size of the goiter, HLA-
DR3 typing, anti-TSH receptor (TRAb) or anti-thyroper-
oxidase (TPOAb) antibodies serum levels, serum thyro-
globulin, thyroid echogenicity by ultrasound, circulating
activated T cells, T cell subset ratios and presence of
Graves Ophthalmopathy, have all been considered as
possible risk factors, but none has been shown to have a
sensitivity or a specificity sufficient to predict relapse of
hyperthyroidism in individual patients [813]. Among
those variables, a large goiter seems to be the most sig-
nificant predictor of hyperthyroidism relapse (Fig. 1) [10].
A longer initial duration of euthyroidism following anti-
thyroid drugs administration seems to be the only variable
related to the risk of relapse in children [11]. A relatively
reliable variable to help predict hyperthyroidism relapse is
a positive test for TSH receptor stimulating antibodies
(TSAbs) before treatment withdrawal, regardless of the age
[14]. Nevertheless, even when TSAbs become undetect-
able, there are still relatively high chances of relapse,
ranging from *20 to *50 % [14].
In most instances, relapse of hyperthyroidism occurs
within 36 months after thionamide withdrawal, and,
overall, more than 60 % of patients who relapse do so
within 2 years from thionamide withdrawal, although
hyperthyroidism can recur also much later [813]. A late,
spontaneous switch to primary hypothyroidism can be also
observed, especially in patients who do not relapse after
thionamide withdrawal [15, 16]. Generally, relapse of

123
J Endocrinol Invest (2014) 37:10411048
Fig. 1 Goiter size and thyroid-stimulating hormone receptor anti-
body (TRAb) level at the time of antithyroid drug discontinuation and
incidence of relapses of hyperthyroidism in a cohort of patients with
Graves disease (modified from Ref. [10])
hyperthyroidism after a full cycle of thionamides lasting 1
or 2 years, is seen as a quite strong indication for alterna-
tive treatments to be considered, namely, radioiodine or
thyroidectomy [813]. However, a second course of thi-
onamides can also be administered, for example to children
or adolescents, keeping in mind that patients who have
relapsed once are more prone to do so after a second cycle
[813].
Side-effects of thionamides
Thionamides minor side-effects have been reported in
115 % of patients, although the overall average appears
to be *6 % [3]. The most common are pruritus and skin
rash, whereas urticaria and arthralgias are rarer [3, 17,
18]. These side-effects generally resolve spontaneously
and therapy can be continued [3]. Nevertheless, it is
generally advisable to switch from one thionamide to the
other, although cross-sensitivity between these drugs may
occur. Antihistamine medications can be used to control
these mild side-effects [3]. A slight elevation in liver
enzyme has also been reported as a mild side-effect, and
sometimes it is difficult to distinguish whether this is due
to the medication or it results from thyrotoxicosis itself
[3]. When detected, alterations in liver function tests must
be monitored closely because toxic hepatitis may develop
suddenly [3].
Fortunately, serious side-effects of thionamides are rel-
atively rare, as they are observed in approximately 0.3 %
of patients [3]. Agranulocytosis, namely a granulocyte
1043
count below 500/mm3, can be observed both with meth-
imazole and propylthiouracil and is more frequent in
elderly patients, although it can occur at any age [3].
Generally, agranulocytosis appears within the first
34 months of treatment, after which is usually observed
quite rarely [3]. Agranulocytosis develops quite suddenly,
in that even weekly white blood cell counts may not detect
it [3]. Because the first manifestation is usually high fever
due to infections, most often of the upper respiratory tract,
the best prevention of this side-effect is probably to instruct
patients to report these symptoms immediately [3].
Although routine white blood cell counts are not useful,
they should be always performed before initiation of
treatment, because mild leukopenia is a relatively common
manifestation of Graves hyperthyroidism and it has to be
distinguished from a thionamide side-effect [3]. When
agranulocytosis occurs, prompt discontinuation of the drug
is recommended, followed by a specific treatment, which
can include broad-spectrum antibiotics and eventually
growth factors to stimulate bone marrow [3]. Usually
patients recover completely within 23 weeks, although
some deaths have been reported.
Hepatitis, either cholestatic (mostly observed with
methimazole) or necrotic (mostly observed with propyl-
thiouracil), is another rare, but very severe complication of
thionamides and it is associated with significant mortality
and sometimes with the requirement of liver transplanta-
tion [3]. Other, more rare, severe side-effects of thiona-
mides are vasculitis, lupus-like syndromes and aplastic
anemia [3].
When a major adverse reaction to thionamides occurs,
prompt withdrawal of the drug is mandatory. Because of
the risk of cross-reactivity, switching from one thionamide
to the other is not recommended in the presence of severe
side-effects, such as agranulocytosis, hepatitis or vasculitis,
so that alternative treatments must be sought.
Possible immune suppressive actions of thionamides
Achievement of a stable euthyroid condition is the purpose
of antithyroid drug treatment of Graves hyperthyroidism.
Thionamides can be used either as a preparatory treatment
before surgery or radioiodine, or as a primary tool in the
attempt of inducing long-term remission of hyperthyroid-
ism. In this regard, a direct effect of thionamides on the
immune system has been postulated to explain the fact that
a minority of patients undergo long-lasting remission of
thyrotoxicosis after withdrawal of the drugs [19]. In sup-
port of this hypothesis, in certain studies patients treated
with antithyroid drugs had a higher remission rate than
patients treated with b-blockers [3], but no randomized
studies on this issue are available. Still on the same line,
the treatment of Graves disease with thionamides has been
123
1044
shown to be followed by a reduction in the levels of cir-
culating autoantibodies [(TRAb, TPOAb and anti-thyro-
globulin (TgAb)] [20]. Finally, in vitro experiments have
suggested a downregulating effect of methimazole on
antigen presentation [21] and in vivo studies have shown
that the drug is able to reduce the severity of experimental
thyroiditis [22, 23]. Nevertheless, despite these observa-
tions, the postulated immunosuppressive actions of thi-
onamides, especially methimazole, remain controversial. A
reduction in serum antibody levels has been reported also
in patients treated with perchlorate, a drug with completely
different pharmacologic properties [24]. In addition, res-
toration of euthyroidism per se may be responsible for the
reduction in serum autoantibodies, possibly because of a
direct effect of thyroid hormone on the immune system.
Finally, the natural history of the disease, which like that of
many other autoimmune disorders is characterized by
cycles of spontaneous relapse and remission, may explain
the reduction in antibody levels. Therefore, a course of
thionamide treatment would be merely a way of keeping
the patient euthyroid while waiting for the autoimmune
process to subside or vanish.
Thionamide treatment modalities
Treatment is generally started with relatively high doses of
thionamides (2040 mg/day of methimazole or
200400 mg/day of propylthiouracil) [3]. Greater doses are
rarely necessary. Despite the anecdotic equivalence of
1 mg of methimazole to 10 mg of propylthiouracil, it has
been shown that methimazole is more effective in con-
trolling hyperthyroidism when compared with tenfold
higher doses of propylthiouracil, another reason for
choosing methimazole as the first line treatment [25]. It
was recently shown that a combination between methim-
azole and potassium bromide may result in a more rapid
control on hyperthyroidism, although further studies are
needed to confirm this observation [26].
When long-term treatment is planned, one of two
strategies is currently used [3]: (1) maintenance of euthy-
roidism with the minimum effective dose, with thyroid
tests performed every 13 months; the minimum dose is
derived by back-titration every 46 weeks; (2) Admin-
istration of a fixed, relatively high dose of the drugs in
combination with levothyroxine, to avoid iatrogenic
hypothyroidism, the so-called block-and-replace regimen.
The latter was proposed mainly because of the postulated
immunosuppressive effect of higher doses of thionamides
and because of studies suggesting a greater remission rate
of hyperthyroidism in patients treated with high doses of
thionamides (60 vs. 15 mg of methimazole per day) [27].
The administration of levothyroxine supposedly provides
an extra advantage, in that very high remission rates were
123
J Endocrinol Invest (2014) 37:10411048
reported in patients treated with methimazole for 6 months
and then given a combination of methimazole and levo-
thyroxine for an additional year, followed by levothyrox-
ine alone for 3 years [27, 28]. However, these findings
were not been reproduced by subsequent studies [2932],
and a prospective randomized trial of low (10 mg/day) vs.
high (40 mg/day) doses of methimazole, no differences
were observed in terms of decrease in TRAb levels or on
the rate of hyperthyroidism remission, whereas side-
effects were more common in the group given methima-
zole 40 mg/day [8]. Therefore, based on the current
knowledge, the block-and-replace regimen has no proven
advantages, although one point in favor of it is that it
probably requires less testing. However, the block-and-
replacement protocol can be useful in those rare patients
who switch from hyperthyroidism to hypothyroidism and
vice versa after minimal changes in the thionamide dosage
(brittle hyperthyroidism).
Still when long-term use of thionamides is planned,
treatment is maintained for 1224 months, after which
therapy is usually withdrawn. Indefinite treatment even
with low doses of thionamides is not a common practice.
Iodine and compounds containing iodine
Pharmacologic doses of inorganic iodine [as Lugols
solution or saturated solution of potassium iodide
(SSKI)] cause a reduction of its own transport into the
thyroid, thereby inhibiting iodine organification (the so-
called WolffChaikoff effect), ultimately blocking the
release of hormones [33]. In addition, iodine decreases
to some extent the vascularity of the thyroid gland [34,
35]. However, these effects are transient and last only
for a few days or weeks, after which hyperthyroidism
recurs or worsens. Thus, treatment with iodine is used
only for short periods of time in the preparation for
surgery, once euthyroidism has been achieved with
thionamides. The usual dose of Lugols solution, the
way iodine is given mostly, is 35 drops three times a
day, whereas that of SSKI is 13 drops three times a
day [3335].
Oral cholecystographic agents, namely iopanoic acid
and sodium ipodate, cause a very rapid fall in serum thy-
roid hormones levels, by inhibition of the peripheral con-
version of T4 to T3, and also due to a reduction of hormone
secretion because of the inorganic iodine released from the
drug [36]. However, both iopanoic acid and sodium ipodate
are of limited value in long-term treatment of hyperthy-
roidism, because of the escape of hormone synthesis from
the blocking effect of iodine [36]. These agents were ide-
ally used in emergency situations, such as thyroid storm.
However, their commerce was recently discontinued in
most Countries.
J Endocrinol Invest (2014) 37:10411048
Perchlorate
Perchlorate competes with transport of iodine into the
thyroid gland and it therefore can be used in the treatment
of hyperthyroidism [37]. Apart from minor side-effects,
such as gastric irritation, major adverse effects, in partic-
ular aplastic anemia, are common [38], because of which
long-term use of perchlorate is not recommended, whereas
its use is limited to special situations such as thyroid storm.
Although in the past potassium perchlorate was mostly
used, more recently sodium perchlorate became more
easily available.
Lithium
The use of lithium has been introduced recently as this
compound renders radioiodine therapy somehow more
effective [39, 40]. Thus, if lithium is given on the day
of thionamide withdrawal, namely 5 days before radio-
iodine for a period of approximately 3 weeks, thyro-
toxicosis, either due to thionamide withdrawal before
radioiodine or to radioiodine itself after its administra-
tion, is reduced in extent. The required dosage is
900 mg/day, although even doses of 450 mg/day seem
to be effective [39, 40]. The effects likely reflect an
inhibitory action on hormone release or on intrathyroi-
dal iodine turnover.
b-Adrenergic antagonists
Several symptoms of thyrotoxicosis, especially concerning
the cardiovascular system, reflect hyperactivity or hyper-
sensitivity of the sympathetic nervous system. Therefore,
blockade of b-adrenergic receptors with b-adrenergic
antagonists can ameliorate symptoms such as tachycardia,
palpitation, tremor, and anxiety [41]. The effect of b-
adrenergic antagonists is actually much faster than that of
thionamides, because of which b-blockers are important in
the early management of hyperthyroidism [41]. These
drugs do not affect hormone synthesis or secretion and
therefore should not be used alone, with the exception of
short periods before and/or after radioiodine therapy [41].
The drugs used are propranolol, atenolol, metoprolol,
bisoprolol and nadolol, none of which seems to have par-
ticular advantages over the others [41]. Thus, the choice
depends mostly on the personal experience of the physi-
cian. Although propranolol is capable of inhibiting to some
extent the peripheral conversion of T4 to T3 [42], the real
clinical advantage provided by this pharmacologic property
is unclear. The usual contraindications to b-blockers should
be taken into account. b-adrenergic antagonists can be
rapidly tapered and discontinued once stable euthyroidism
is obtained.
1045
Glucocorticoids
If used at high dosage, glucocorticoids can inhibit the
peripheral conversion of T4 to T3 [1]. In addition, in
Graves disease they seem to decrease T4 secretion by the
thyroid, possibly by immune suppression, although the
efficacy and duration of this effect are unknown. Because
of the well known, significant side-effects associated with
their long-term use and of the effectiveness of other med-
ical treatments, the use of glucocorticoids is not justified in
Graves hyperthyroidism, with the exception of thyroid
storm, where they are used as a general supportive
measure.
Perspectives
Recently, a low molecular weight compound capable of
binding to the TSH receptor and therefore of competing
with autoantibodies has been developed [43], although no
clinical studies are available. Rituximab, an anti-CD20
monoclonal antibody, has been reported to prevent, but not
to cure, hyperthyroidism in an animal model of Graves
disease and, in addition, to have some beneficial action on
the rate of hyperthyroidism relapse after thionamides
withdrawal in a phase II trial [44, 45]. Nevertheless, the
potential toxicity of rituximab raises concerns on whether it
should be used in a benign condition such as Graves
disease. Finally, selenium, an anti-oxidant agent shown to
have a beneficial effect in Graves Ophthalmopathy [46,
47], seems to have a beneficial effect also on hyperthy-
roidism, by reducing some of the symptoms by mecha-
nisms that are yet to be understood [48].
Medical treatment of Graves disease in pregnancy
and lactation
Thionamides are the first choice of treatment in a pregnant
woman with Graves hyperthyroidism [4951]. Usually, a
clinical improvements of thyrotoxic symptoms occurs after
the first week of treatment, whereas biochemical euthy-
roidism is reached within 24 weeks. Both propylthiouracil
and methimazole have been used during pregnancy and are
equally effective, but propylthiouracil is preferred. Meth-
imazole was reported to cross the placenta and the breast
epithelium to a greater extent than propylthiouracil [52],
which, however, was later excluded [4951]. Nevertheless,
the association between the use of methimazole and aplasia
cutis as well as other malformations, have prompted the
use of propylthiouracil as the first choice during pregnancy
[4953]. Aplasia cutis is a congenital localized absence of
skin that is observed in *1 in 2,000 births [54]. A few
cases of this and other malformations have been reported in
the offspring of mothers who had taken methimazole
123
1046
during pregnancy, therefore suggesting a possible associa-
tion [4952]. In a recent study performed in quite large
number of pregnancies, it was shown that methimazole,
unlike propylthiouracil, is associated with a significantly
greater frequency of congenital anomalies when compared
with an untreated control group (4.1 vs. 2.1 %) [54]. Mal-
formations included aplasia cutis, omphalocele and
omphalomesenteric duct anomaly [54]. In addition, malfor-
mations such as choanal and esophageal atresia, minor facial
abnormalities and psychomotor delay, either isolated or
associated in rare cases with aplasia cutis, thereby defining a
conditions named methimazole embryopathy, have been
reported in newborns exposed to methimazole during the
first trimester of pregnancy [4952]. Therefore, propylthio-
uracil is nowadays largely preferred to methimazole. Taking
these findings into considerations, in hyperthyroid pregnant
women the first priority should always be the control of
hyperthyroidism, because of the risk of abortion. Therefore
in countries, where propylthiouracil is not promptly avail-
able, our recommendation is still to continue methimazole
and then switch to propylthiouracil once available.
The aim of thionamide treatment in a pregnant woman is
to keep maternal FT4 within the high normal range, which
ensures fetal euthyroidism because FT4 levels in the
mother are correlated with those in the fetus, as assessed by
assays in cord blood [55]. In this regard, a low TSH level is
not a reliable index to judge the adequacy of treatment, as it
may not necessarily reflect changes in thyroid function as
promptly as FT4, although it is still important because a
high level always indicates excessive thionamide treat-
ment, thereby prompting an adjustment of the thionamide
dose. Because of the immunosuppressive effect of preg-
nancy, partial and transient remission of Graves disease
may occur in the second and third trimesters and allow a
reduction and even discontinuation of thionamide treat-
ment. On the other hand, relapse of hyperthyroidism is
frequent in the postpartum period [56].
In general, the block-and-replace regimen is not recom-
mended in pregnancy, because much more thionamide than
levothyroxine will cross the placenta and therefore cause
fetal hypothyroidism. Iodine is avoided because of the risk
of fetal hypothyroidism and goiter due to the greater sen-
sitivity of the fetal thyroid to the WolffChaikoff effect.
The use of b-blockers is controversial, but most will not
recommend them, at least for prolonged periods.
Both thionamides are secreted in breast milk in small
amounts [50, 51]. Nevertheless, treatment with thiona-
mides during lactation appears to be safe, whether it is
continued after gestation or initiated in the postpartum.
When concerning methimazole, doses up to 20 mg daily
have been documented not to affect infants thyroid func-
tion [57], whereas available data for propylthiouracil are
scanty, with the consequent recommendation of using low
123
J Endocrinol Invest (2014) 37:10411048
doses [51]. Irrespective of the drug used, the mother should
take her pills just after breast feeding, thereby providing a
34 h interval before she lactates again. Although maternal
hormone levels must be monitored with appropriate anti-
thyroid drug adjustment, the childs thyroid function does
not need to be checked regularly as long as somatic and
mental development progress normally.
Treatment of neonatal and fetal thyrotoxicosis
Because during the last trimester of pregnancy immuno-
globulins cross the placenta, maternal TSAbs can also do
so, which can result in fetal and/or neonatal thyrotoxicosis
in the offspring of pregnant women with Graves disease
[58]. Even mothers who have had Graves disease and are
euthyroid after thyroidectomy or radioiodine treatment
may still have circulating TSAbs capable of causing fetal
and/or neonatal thyrotoxicosis. Thus, the possibility of this
event should be considered in all pregnant women with a
current or past history of Graves disease.
Neonatal thyrotoxicosis requires prompt treatment.
Thionamides, methimazole (0.51 mg/kg/day) or propyl-
thiouracil (510 mg/kg/day) should be administered every
8 h. Propranolol may be added to slow the heart rate and
reduce hyperactivity. Iodine (one drop of Lugols solution,
equivalent to 8 mg of iodine every 8 h) is also used in
addition to thionamides, to inhibit the release of preformed
thyroid hormones. In severely ill infants, glucocorticoids
may be added as a general supportive measure and to block
conversion of T4 to T3. Fetal thyrotoxicosis is treated by
giving antithyroid drugs to the mother. The dose of thi-
onamide should be adjusted to maintain a fetal heart rate of
about 140 beats/min.
Conflict of interest None.
References
1. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC,
Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA,
Ross DS, Sosa JA, Stan MN (2011) Hyperthyroidism and other
causes of thyrotoxicosis: management guidelines of the American
Thyroid Association and American Association of Clinical
Endocrinologists. Thyroid 21:593646
2. Astwood EB (1943) Treatment of of hyperthyroidism with thio-
urea and thiouracil. JAMA 122:78
3. Cooper DS (2005) Antithyroid drugs. N Engl J Med 352:905917
4. Wartofsky L, Glinoer D, Solomon B, Lagasse R (1991) Differ-
ences and similarities in the diagnosis and treatment of Graves
disease in Europe, Japan and the United States. Thyroid 1:129135
5. Emiliano AB, Governale L, Parks M, Cooper DS (2010) Shifts in
propylthiouracil and methimazole prescribing practices: antithy-
roid drug use in the United States from 1991 to 2008. J Clin
Endocrinol Metab 95:22272233
6. Glinoer D, Cooper DS (2012) The propylthiouracil dilemma.
Curr Opin Endocrinol Diabet Obes 19:402407
J Endocrinol Invest (2014) 37:10411048
7. Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein
IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA,
Stan MN (2009) The role of propylthiouracil in the management
of Graves disease in adults: report of a meeting jointly sponsored
by the American Thyroid Association and the Food and Drug
Administration. Thyroid 19:673674
8. Reinwein D, Benker G, Lazarus JH, Alexander WD (1993) A
prospective randomized trial of antithyroid drug dose in Graves
disease therapy. European Multicenter Study Group on Antithy-
roid Drug Treatment. J Clin Endocrinol Metab 76:15161521
9. Konishi T, Okamoto Y, Ueda M, Fukuda Y, Harusato I, Tsu-
kamoto Y, Hamada N (2011) Drug discontinuation after treat-
ment with minimum maintenance dose of an antithyroid drug in
Graves disease: a retrospective study on effects of treatment
duration with minimum maintenance dose on lasting remission.
Endocr J 58:95100
10. Vitti P, Rago T, Chiovato L, Pallini S, Santini F, Fiore E, Rocchi
R, Martino E, Pinchera A (1997) Clinical features of patients with
Graves disease undergoing remission after antithyroid drug
treatment. Thyroid 7:369375
11. Kaguelidou F, Alberti C, Castanet M, Guitteny MA, Czernichow
P, Leger J (2008) Predictors of autoimmune hyperthyroidism
relapse in children after discontinuation of antithyroid drug
treatment. J Clin Endocrinol Metab 93:38173826
12. Wartofsky L (1973) Low remission after therapy for Graves
disease. Possible relation of dietary iodine with antithyroid
therapy results. JAMA 226:10831088
13. Solomon BL, Evaul JE, Burman KD, Wartofsky L (1987)
Remission rates with antithyroid drug therapy: continuing influ-
ence of iodine intake? Ann Intern Med 107:510512
14. Barbesino G, Tomer Y (2013) Clinical utility of TSH receptor
antibodies. J Clin Endocrinol Metab 98:22472255
15. Lamberg BA, Salmi J, Wagar G, Makinen T (1981) Spontaneous
hypothyroidism after antithyroid treatment of hyperthyroid
Graves disease. J Endocrinol Invest 4(3):99402
16. Feldt-Rasmussen U, Schleusener H, Carayon P (1994) Meta-
analysis evaluation of the impact of thyrotropin receptor anti-
bodies on long term remission after medical therapy of Graves
disease. J Clin Endocrinol Metab 78:98102
17. Tripodi PF, Ruggeri RM, Campenn A, Cucinotta M, Mirto A, Lo
Gullo R, Baldari S, Trimarchi F, Cucinotta D, Russo GT (2008)
Central nervous system vasculitis after starting methimazole in a
woman with Graves disease. Thyroid 18:10111013
18. Ruggeri RM, Imbesi S, Saitta S, Campenn A, Cannavo S,
Trimarchi F, Gangemi S (2013) Chronic idiopathic urticaria and
Graves disease. J Endocrinol Invest 36:531536
19. Weetman AP, McGregor AM, Hall R (1984) Evidence for an
effect of antithyroid drugs on the natural history of Graves dis-
ease. Clin Endocrinol 21:163172
20. Marcocci C, Marino M (2005) Thyroid directed antibodies. In:
Braverman LE, Utiger RD (eds) Werner and Ingbars the thyroid:
a fundamental and clinical text, 9th edition. Lippincott, Williams
& Wilkins, Philadelphia, pp 360372
21. Weetman AP, McGregor AP, Hall R (1983) Methimazole inhibits
thyroid autoantibody production by an action on accessory cells.
Clin Immunol Immunopathol 28:3945
22. Weiss I, Davies TF (1981) Inhibition of immunoglobulin-
secreting cells by antithyroid drugs. J Clin Endocrinol Metab
53:12231228
23. Rennie DP, McGregor AM, Keast D, Weetman AP, Foord SM,
Dieguez C, Williams ED, Hall R (1983) The influence of meth-
imazole on thyroglobulin-induced autoimmune thyroiditis in the
rat. Endocrinology 112:326330
24. Wenzel KW, Lente JR (1984) Similar effects of thionamide drugs
and perchlorate on thyroid-stimulating immunoglobulins in
1047
Graves disease: evidence against an immunosuppressive action
of thionamide drugs. J Clin Endocrinol Metab 58:6269
25. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N
(2007) Comparison of methimazole and propylthiouracil in
patients with hyperthyroidism caused by Graves disease. J Clin
Endocrinol Metab 92:21572162
26. Li D, Pei H, Li X, Liu X, Li X, Xie Y (2012) Short-term effects
of combined treatment with potassium bromide and methimazole
in patients with Graves disease. J Endocrinol Invest 35:971974
27. Hashizume K, Ichikawa K, Sakurai A, Suzuki S, Takeda T,
Kobayashi M, Miyamoto T, Arai M, Nagasawa T (1991)
Administration of thyroxine in treated Graves diseaseeffects
on the level of antibodies to thyroid stimulating hormone
receptors and on the risk of recurrence of hyperthyroidism.
N Engl J Med 324:947953
28. Romaldini JH, Bromberg N, Werner RS, Tanaka LM, Rodrigues
HF, Werner MC, Farah CS, Reis LC (1983) Comparison of
effects of high and low dosage regimens of antithyroid drugs in
the management of Graves hyperthyroidism. J Clin Endocrinol
Metab 57:563570
29. Tamai H, Hayaki I, Kawai K, Komaki G, Matsubayashi S, Kuma
K, Kumagai LF, Nagataki S (1995) Lack of effect of thyroxine
administration on elevated thyroid stimulating hormone receptor
antibody levels in treated Graves disease patients. J Clin Endo-
crinol Metab 80:14811484
30. Rittmaster RS, Zwicker H, Abbott EC, Douglas R, Givner ML,
Gupta MK, Lehmann L, Reddy S, Salisbury SR, Shlossberg AH,
Tan MH, York SE (1996) Effect of methimazole with or without
exogenous L-thyroxine on serum concentrations of thyrotropin
(TSH) receptor antibodies in patients with Graves disease. J Clin
Endocrinol Metab 81:32833288
31. Rizvi A, Crapo LM (1996) Failure of thyroxine therapy for
Graves disease (letter). Ann Intern Med 124:694
32. Rittmaster RS, Abbott EC, Douglas R, Givner ML, Lehmann L,
Reddy S, Salisbury SR, Shlossberg AH, Tan MH, York SE (1998)
Effect of methimazole, with or without L-thyroxine, on remission
rates in Graves disease. J Clin Endocrinol Metab 83:814818
33. Emerson CH, Anderson AJ, Howard WJ, Utiger RD (1975)
Serum thyroxine and triiodothyronine concentrations during
iodide treatment of hyperthyroidism. J Clin Endocrinol Metab
40:3336
34. Marigold JH, Morgan AK, Earle DJ, Young AE, Croft DN (1985)
Lugols iodine: its effect on thyroid blood flow in patients with
thyrotoxicosis. Br J Surg 72:4547
35. Chang DC, Wheeler MH, Woodcock JP, Curley I, Lazarus JR,
Fung H, John R, Hall R, McGregor AM (1987) The effect of
preoperative Lugols iodine on thyroid blood flow in patients with
Graves hyperthyroidism. Surgery 102:10551061
36. Laurberg P, Boye N (1987) Inhibitory effect of various radio-
graphic contrast agents on secretion of thyroxine by the dog
thyroid and on peripheral and thyroidal deiodination of thyroxine
to tri-iodothyronine. J Endocrinol 112:387390
37. DeGroot LJ, Buhler U (1971) Effect of perchlorate and meth-
imazole on iodine metabolism. Acta Endocrinol (Copenh)
68:696706
38. Barzilai D, Sheinfeld M (1966) Fatal complications following use
of potassium perchlorate in thyrotoxicosis. Report of two cases
and a review of the literature. Isr J Med Sci 2:453456
39. Bogazzi F, Giovannetti C, Fessehatsion R, Tanda ML, Campo-
mori A, Compri E, Rossi G, Ceccarelli C, Vitti P, Pinchera A,
Bartalena L, Martino E (2010) Impact of lithium on efficacy of
radioactive iodine therapy for Graves disease: a cohort study on
cure rate, time to cure, and frequency of increased serum thy-
roxine after antithyroid drug withdrawal. J Clin Endocrinol
Metab 95:201208
123
1048
40. Martin NM, Patel M, Nijher GM, Misra S, Murphy E, Meeran K
(2012) Adjuvant lithium improves the efficacy of radioactive
iodine treatment in Graves and toxic nodular disease. Clin
Endocrinol (Oxf) 77:621627
41. Henderson JM, Portmann L, Van Melle G, Haller E, Ghika JA
(1997) Propranolol as an adjunct therapy for hyperthyroid tremor.
Eur Neurol 37:182185
42. Wiersinga WM (1991) Propranolol and thyroid hormone metab-
olism. Thyroid 1:273277
43. Neumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C,
Monaco F, Huang W, Gershengorn MC (2011) A new small-
molecule antagonist inhibits Graves disease antibody activation
of the TSH receptor. J Clin Endocrinol Metab 96:548554
44. Ueki I, Abiru N, Kobayashi M, Nakahara M, Ichikawa T, Eguchi
K, Nagayama Y (2011) B cell-targeted therapy with anti-CD20
monoclonal antibody in a mouse model of Graves hyperthy-
roidism. Clin Exp Immunol 163:309317
45. Heemstra KA, Toes RE, Sepers J, Pereira AM, Corssmit EP,
Huizinga TW, Romijn JA, Smit JW (2008) Rituximab in
relapsing Graves disease, a phase II study. Eur J Endocrinol
159:609615
46. Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M,
Stahl M, Altea MA, Nardi M, Pitz S, Boboridis K, Sivelli P, von
Arx G, Mourits MP, Baldeschi L, Bencivelli W, Wiersinga W
(2011) Selenium and the course of mild Graves orbitopathy.
N Engl J Med 364:19201931
47. Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L (2013)
Prevalence and natural history of Graves orbitopathy in the XXI
century. J Endocrinol Invest 36:444449
48. Bulow Pedersen I, Knudsen N, Carle A, Schomburg L, Kohrle J,
Jrgensen T, Rasmussen LB, Ovesen L, Laurberg P (2013) Serum
selenium is low in newly diagnosed Graves disease: a popula-
tion-based study. Clin Endocrinol (Oxf) 79:584590
49. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman
J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wier-
singa W (2011) Guidelines of the American Thyroid Association
for the diagnosis and management of thyroid disease during
pregnancy and postpartum. Thyroid 21:10811125
123
J Endocrinol Invest (2014) 37:10411048
50. Lazarus JH (2012) Antithyroid drug treatment in pregnancy.
J Clin Endocrinol Metab 97:22892291
51. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L,
Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ,
Mestman J, Rovet J, Sullivan S (2012) Management of thyroid
dysfunction during pregnancy and postpartum: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab
97:25432565
52. Marchant B, Brownlie BE, Hart DM, Horton PW, Alexander WD
(1977) The placental transfer of propylthiouracil, methimazole
and carbimazole. J Clin Endocrinol Metab 45:11871193
53. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K,
Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N,
Mukasa K, Ito K, Ito K (2012) Treatment of Graves disease with
antithyroid drugs in the first trimester of pregnancy and the
prevalence of congenital malformation. J Clin Endocrinol Metab
97:23962403
54. Ribuffo D, Costantini M, Gullo P, Houseman ND, Taylor GI
(2003) Aplasia cutis congenita of the scalp, the skull, and the
dura. Scand J Plast Reconstr Surg Hand Surg 37:176180
55. Santini F, Chiovato L, Ghirri P, Lapi P, Mammoli C, Montanelli
L, Scartabelli G, Ceccarini G, Coccoli L, Chopra IJ, Boldrini A,
Pinchera A (1999) Serum iodothyronines in the human fetus and
the newborn: evidence for an important role of placenta in fetal
thyroid hormone homeostasis. J Clin Endocrinol Metab
84:493498
56. Rotondi M, Cappelli C, Pirali B, Pirola I, Magri F, Fonte R,
Castellano M, Rosei EA, Chiovato L (2008) The effect of preg-
nancy on subsequent relapse from Graves disease following a
successful course of anti-thyroid drug therapy. J Clin Endocrinol
Metab 93:39853988
57. Azizi F, Amouzegar A (2011) Management of hyperthyroidism
during pregnancy and lactation. Eur J Endocrinol 164:871876
58. Zakarija M, McKenzie JM (1983) Pregnancy-associated changes
in the thyroid-stimulating antibody of Graves disease and the
relationship to neonatal hyperthyroidism. J Clin Endocrinol
Metab 57:10361040