Antithyroid agents (ATDs) are the principal pharmacological treatment capable of reducing the synthesis of thyroid hormones and controlling hyperthyroidism, particularly in Graves disease. In modern clinical practice, ATDs are not merely a bridge to radioactive iodine or surgery. They often represent a complete strategy that can be adjusted over time, may induce immunological remission in a proportion of patients, and remains essential when rapid and reversible control of thyroid function is required, such as during pregnancy or in the presence of comorbidities that make other options hazardous.
This group includes the thionamides used in most countries: methimazole, also known as thiamazole, carbimazole, and propylthiouracil (PTU). Methimazole and carbimazole share the same therapeutic rationale and are generally preferred because of their efficacy and safety, whereas PTU retains selected indications, particularly during the first trimester of pregnancy and in situations in which methimazole cannot be used. The choice of ATD, initial dose, titration regimen, and monitoring must be based on the balance between biochemical control, risk of relapse, and prevention of iatrogenic complications, including agranulocytosis and hepatotoxicity.
Thionamides act by inhibiting thyroid peroxidase, the key enzyme involved in iodine organification and iodotyrosine coupling, which are central steps in the synthesis of T4 and T3 within the thyroid follicle. This mechanism does not destroy the gland and does not immediately eliminate hormones that have already been synthesised and stored in the colloid. Clinical improvement is therefore progressive and depends both on inhibition of new hormone synthesis and on depletion of the preformed hormone pool. This physiological delay explains why symptomatic treatment, particularly with beta-blockers, is often required during the initial stages to control the adrenergic manifestations of thyrotoxicosis.
Propylthiouracil shares the inhibitory effect on thyroid peroxidase but, compared with methimazole, also reduces the peripheral conversion of T4 into T3 by inhibiting deiodination. This property may be clinically useful in severe thyrotoxicosis when a more rapid reduction in circulating T3 is required, although its safety profile must remain a central consideration, particularly the stronger association between PTU and severe liver injury. In the routine management of Graves disease, methimazole is generally preferred because it provides effective control with a simpler dosing schedule and a more favourable overall risk profile.
Biochemical control during ATD treatment follows a typical course. FT4 and FT3 decrease during the first few weeks, whereas TSH may remain suppressed for longer because of delayed recovery of pituitary feedback. Correct interpretation of this dynamic is essential to avoid inappropriate dose adjustments. During the initial stages, treatment should not be directed at normalising TSH, but at normalising free thyroid hormone concentrations and achieving clinical stabilisation. TSH becomes a more reliable indicator of the restored euthyroid state only at a later stage.
Furthermore, the therapeutic effect in Graves disease is not exclusively biochemical. By reducing hormone excess and controlling the immune activation cycle associated with the disease, ATD treatment may promote a progressive reduction in TSH receptor autoantibodies and increase the likelihood of remission. This outcome reflects a complex relationship between treatment duration, disease severity, antibody levels, and relapse risk. In this respect, the medication acts as a modulator of an endocrine and immune system rather than merely producing enzymatic blockade.
According to international guidelines, Graves disease may be treated with antithyroid therapy, radioactive iodine, or thyroidectomy, and the choice depends on clinical characteristics, comorbidities, and informed patient preferences. Within this range of options, ATDs are often the initial treatment, particularly when reversible therapy is desired, surgical risk is high, thyrotoxicosis must be stabilised before definitive treatment, or pregnancy requires selective pharmacological control. European guidelines also emphasise the role of TSH receptor antibody measurement in diagnosis and in supporting decisions concerning treatment withdrawal and relapse risk.
In toxic nodules and toxic multinodular goitre, ATDs control thyrotoxicosis but rarely produce stable remission because the underlying substrate is nodular functional autonomy. In these cases, ATD treatment is often used for stabilisation, to reduce perioperative risk, or as preparation for radioactive iodine treatment. It may also become chronic therapy in selected patients who are unsuitable for, or unwilling to undergo, definitive treatment. The clinical rationale is different: in Graves disease, treatment seeks a balance that may ultimately lead to remission, whereas in autonomous disease the aim is often sustainable control while awaiting, or as an alternative to, definitive treatment.
Hyperthyroidism must be distinguished from other forms of thyrotoxicosis that are not sustained by increased hormone synthesis, such as destructive thyroiditis or low T3 syndrome, because ATDs are ineffective in these settings. Appropriate treatment therefore requires an accurate aetiological diagnosis before therapy is initiated or continued. In practical terms, antithyroid treatment is effective when the underlying problem is excessive hormone production, not when the predominant mechanism is the release of preformed hormones due to follicular injury.
The choice between methimazole and PTU is based on a widely accepted principle: methimazole is generally preferred for most patients, whereas PTU is reserved for selected situations, particularly during the first trimester of pregnancy and in cases of methimazole intolerance or contraindication. This approach reflects the risk-benefit balance, with particular consideration of the risk of severe PTU-associated hepatotoxicity and the different teratogenic profiles of the medications during early pregnancy.
Initiating antithyroid therapy requires an assessment of the severity of hyperthyroidism and the speed at which control must be achieved. In moderate or severe Graves disease, the initial methimazole dose is selected to reduce FT4 and FT3 rapidly and is then progressively decreased according to a titration strategy based on restoration of euthyroidism. This approach minimises exposure to higher doses, which are associated with a greater risk of dose-dependent adverse effects, while maintaining stable biochemical control.
An alternative model, historically used, is the block-and-replace regimen, in which a higher ATD dose is administered to block hormone synthesis and levothyroxine is added to prevent iatrogenic hypothyroidism. In contemporary practice, many guidelines favour titration because it reduces exposure to high antithyroid doses and tends to limit the risk of serious adverse events. When this alternative regimen is considered, the choice must account for the patient’s clinical profile, likelihood of adherence, and the need to avoid wide fluctuations between hyperthyroidism and hypothyroidism.
During the initial stages, titration must be guided primarily by FT4 and FT3 because TSH may remain suppressed for weeks or months. Treating TSH as an immediate target may lead to excessive dose reduction, followed by an increase in thyroid hormone concentrations and clinical instability. TSH becomes more useful for confirming the restored balance only after FT4 and FT3 have remained within the reference range and the patient is clinically stable.
In autonomous nodules and toxic multinodular goitre, titration follows a similar principle of biochemical control, but the objective is not immunological remission. In these settings, the decision to maintain long-term treatment must be accompanied by periodic monitoring designed to minimise both undertreatment and overtreatment, while recognising that the natural history of autonomous disease makes definitive treatment more likely to be required over the long term.
Monitoring of ATD treatment must be structured around two objectives: ensuring stable biochemical control and identifying clinically significant adverse events at an early stage. During the initial phase, FT4 and FT3 measurements allow assessment of the response and gradual dose reduction, thereby avoiding progression to iatrogenic hypothyroidism. As previously discussed, TSH may remain suppressed and should not be used as the sole parameter guiding initial dose decisions.
In Graves disease, follow-up also includes identifying a possible point at which treatment may be discontinued and estimating the risk of relapse. European guidelines recommend measuring TSH receptor antibodies to support clinical decisions regarding ATD withdrawal and management during pregnancy. In general, stable clinical status, thyroid hormone concentrations within the reference range on low doses, and declining autoantibody levels suggest a greater probability of remission. Conversely, severe thyrotoxicosis, a large goitre, high antibody levels, and persistent hyperthyroidism despite adequate treatment indicate a higher risk of relapse.
Follow-up must also consider the quality of long-term control. Repeated fluctuations between hyperthyroidism and hypothyroidism are not clinically neutral. They may increase arrhythmic risk, worsen symptoms, and impair adherence. Well-conducted monitoring aims to achieve stable euthyroidism by addressing not only dosage, but also adherence, concomitant pharmacological interactions, and, when required, the overall therapeutic strategy, including consideration of radioactive iodine or surgery.
In patients receiving prolonged treatment, surveillance must include periodic reassessment of the indication. Stable control with low doses may support continued therapy, whereas persistent instability, adverse events, or a low probability of remission make transition to definitive treatment more appropriate. Follow-up therefore becomes an active component of therapeutic decision-making rather than a simple laboratory assessment.
Antithyroid medications are generally effective and well tolerated, but their safety profile is dominated by rare and potentially serious adverse events. The most feared complication is agranulocytosis, defined by severe neutropenia, which can predispose patients to rapidly progressive infections. Observational studies involving large patient cohorts have shown that agranulocytosis occurs most frequently during the first few months of treatment and that the risk is higher with larger doses and older age. Its rarity does not diminish the clinical importance of early recognition. Management is based on immediate withdrawal of the ATD and urgent medical assessment, because continued treatment in the presence of fever or sore throat may expose the patient to severe infectious complications.
PTU is associated with a higher risk of severe hepatotoxicity than methimazole, including cases of fulminant liver failure that prompted regulatory safety communications. This evidence directly influences treatment selection. PTU is reserved for selected indications, whereas methimazole is preferred for most patients. Mild and transient abnormalities in liver enzyme concentrations, which may also occur during thyrotoxicosis, must be distinguished from clinical presentations consistent with severe liver injury, which require treatment withdrawal and urgent assessment.
Other adverse events include cutaneous reactions, arthralgia, low-grade fever, gastrointestinal disturbances, and, more rarely, antineutrophil cytoplasmic antibody-associated vasculitis, particularly with PTU. Clinical management requires severity stratification. Minor events may be managed through reassessment and, in some cases, a change of agent, whereas serious events require permanent withdrawal and planning of an alternative strategy for controlling hyperthyroidism. In particular, after an episode of agranulocytosis, substitution with another thionamide is not considered safe because of the risk of cross-reactivity.
Prevention of the most serious outcomes depends primarily on patient education and appropriate monitoring. Because agranulocytosis may develop abruptly, the most effective clinical recommendation is to instruct patients clearly to stop treatment and obtain an urgent complete blood count if fever or pharyngeal symptoms occur. In parallel, the initial assessment and subsequent clinical reviews must consider signs of hepatotoxicity, including pruritus, jaundice, right upper quadrant pain, or marked unexplained fatigue. Safety is therefore not entrusted to occasional testing, but to a coherent system of prevention and early recognition.
Pregnancy is a clinical setting in which control of thyrotoxicosis is essential, but treatment must minimise fetal risk. International guidelines recommend a trimester-specific approach. During the first trimester, propylthiouracil is often preferred to reduce the risk of methimazole-associated malformations during organogenesis, whereas a switch to methimazole is generally recommended from the second trimester to limit prolonged exposure to PTU and its hepatic risk. The objective is to maintain FT4 within a safe range while avoiding both uncontrolled maternal hyperthyroidism, which is associated with obstetric complications, and iatrogenic fetal hypothyroidism caused by an excessive ATD dose.
During pregnancy, titration requires the lowest possible dose that adequately controls the disease, with frequent assessments and recognition that physiological changes may alter disease severity over time. A specific feature of Graves disease is the role of TSH receptor antibodies, which can cross the placenta and affect fetal thyroid function. Antibody assessment and coordinated obstetric and endocrine care are therefore integral components of management. Follow-up must integrate maternal biochemical findings, clinical status, and assessment of fetal risk.
During breastfeeding, ATDs may be used cautiously at appropriate doses, with methimazole preferred in many settings and clinical monitoring, as well as neonatal thyroid function testing when indicated. The underlying principle is to achieve effective maternal control with the lowest possible pharmacological exposure, avoiding both recurrence of thyrotoxicosis, which may compromise maternal health, and excessive exposure of the infant. In this setting as well, titration and stable maternal euthyroidism are central to safety.
In Graves disease, the typical duration of ATD treatment is often measured in months, with the objective of achieving and maintaining euthyroidism and subsequently assessing whether treatment can be discontinued when signs of remission are present. The probability of remission varies widely and depends on clinical and immunological factors. Treatment withdrawal therefore cannot be automatic. European guidelines emphasise the use of TSH receptor antibodies to estimate relapse risk and guide treatment discontinuation. Relapse is not uncommon and may require another course of ATD therapy or transition to radioactive iodine or surgery, depending on the patient’s clinical profile and treatment history.
An important consideration is the possibility of long-term treatment with low-dose methimazole in selected patients, particularly when definitive treatment is to be avoided or when the disease relapses repeatedly but remains controllable with minimal doses. In this setting, the quality of control and safety become the principal considerations. Prolonged treatment must be accompanied by regular follow-up and periodic reassessment of cumulative risk, taking into account age, cardiovascular comorbidities, and informed patient preferences.
In toxic nodules and toxic multinodular goitre, long-term antithyroid therapy is more often a compromise than a therapeutic objective because nodular autonomy tends to persist. The decision to continue chronic treatment is based on feasibility, surgical risk, willingness to undergo radioactive iodine treatment, and stability of biochemical control. In frail older patients, a chronic strategy may be reasonable when appropriately monitored, but it must be made clear that treatment does not alter the anatomical substrate of autonomous disease.
When pharmacological treatment does not ensure stability, significant adverse events occur, or the risk of relapse is high, the most coherent strategy is to plan definitive treatment, selecting radioactive iodine or surgery according to the clinical profile. Antithyroid treatment consequently becomes one component of a broader therapeutic pathway rather than indefinite treatment continued by inertia, and the final decision remains grounded in the balance between efficacy, safety, and patient preferences.