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Antithyroid agent

Antithyroid agents are a class of medications designed to treat hyperthyroidism by inhibiting the synthesis, release, or activity of thyroid hormones, such as thyroxine (T4) and triiodothyronine (T3).^[1] These drugs are particularly essential for managing conditions like Graves' disease, the most common cause of hyperthyroidism, where the thyroid gland overproduces hormones leading to symptoms including rapid heartbeat, weight loss, and anxiety.^[2] By normalizing thyroid hormone levels, antithyroid agents help alleviate these symptoms and prevent complications such as heart problems or bone loss.^[3] The primary types of antithyroid agents include thionamides, such as methimazole (MMI) and propylthiouracil (PTU), which are the most commonly prescribed; iodides like potassium iodide or Lugol's solution; and radioactive iodine (sodium iodide I-131).^[4] Thionamides, introduced in the mid-20th century, form the cornerstone of therapy due to their targeted action on thyroid hormone production.^[5] Iodides provide rapid inhibition of hormone release and are often used in acute settings like thyroid storm, while radioactive iodine offers a definitive treatment by ablating overactive thyroid tissue.^[4] These agents primarily work by interfering with key steps in thyroid hormone biosynthesis within the thyroid gland. Thionamides inhibit the enzyme thyroid peroxidase, which is crucial for iodination and coupling of tyrosine residues in thyroglobulin to form T4 and T3, thereby reducing new hormone synthesis without affecting pre-existing hormone stores.^[6] PTU has the additional benefit of blocking the peripheral conversion of T4 to the more active T3.^[2] Iodides temporarily block hormone release via the Wolff-Chaikoff effect, an autoregulatory mechanism that inhibits organification of iodine, though this effect may wane over time.^[4] Radioactive iodine, in contrast, delivers targeted radiation to destroy thyroid cells, leading to reduced hormone production over weeks to months.^[4] Clinically, antithyroid agents are used not only for long-term remission in autoimmune hyperthyroidism but also as preoperative preparation to reduce thyroid vascularity and hormone levels before surgery or radioiodine therapy.^[6] In Graves' disease, thionamide therapy achieves remission in approximately 30-70% of patients after 12-18 months, though relapse is common.^[2] Special considerations include preferring PTU in the first trimester of pregnancy due to MMI's teratogenic risks, and monitoring for rare but serious adverse effects like agranulocytosis or hepatotoxicity, which necessitate prompt patient education on symptoms such as sore throat or jaundice.^[6] Overall, these agents balance efficacy with a favorable safety profile when used judiciously under medical supervision.^[2]

Overview

Definition

Antithyroid agents are pharmacological substances or drugs that reduce the production, release, or peripheral action of thyroid hormones, primarily to manage hyperthyroidism by normalizing excessive hormone levels.^[1]^[7] These agents target key stages in thyroid hormone biosynthesis and function, addressing conditions where overproduction leads to symptoms such as tachycardia, weight loss, and heat intolerance. Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are synthesized in the thyroid gland through a process involving the uptake of iodide, its oxidation to iodine by the enzyme thyroid peroxidase (TPO), and subsequent incorporation into thyroglobulin to form the hormones.^[7] This physiology is central to the action of antithyroid agents, which interfere at specific points to decrease hormone availability and mitigate hyperthyroid effects.^[8] Antithyroid agents are broadly categorized based on their mechanisms: synthesis blockers, such as thioamides that inhibit TPO-mediated iodination; uptake blockers, like perchlorate that competes with iodide transport into thyroid cells (though rarely used clinically due to toxicity risks); and release inhibitors, including high-dose iodine that temporarily halts hormone secretion via the Wolff-Chaikoff effect.^[7]^[4]^[9]

Primary indications

Antithyroid agents are primarily indicated for the management of hyperthyroidism, a condition characterized by excessive thyroid hormone production, to restore euthyroidism and alleviate symptoms such as tachycardia, weight loss, and tremors. They are used in various etiologies, including Graves' disease (the most common cause), toxic multinodular goiter (where multiple thyroid nodules autonomously produce excess hormones), and solitary toxic adenoma (a single hyperfunctioning nodule). In these cases, agents like methimazole (MMI) or propylthiouracil (PTU) inhibit thyroid hormone synthesis, serving as a first-line medical therapy, particularly when definitive treatments like radioactive iodine or surgery are not immediately suitable.^[10]^[11]^[6] These agents also play a key role in preoperative preparation for patients undergoing thyroidectomy, by normalizing thyroid function and reducing thyroid gland vascularity to minimize surgical risks and blood loss. This is particularly relevant for hyperthyroid patients with Graves' disease, toxic multinodular goiter, or solitary toxic adenoma, where antithyroid therapy is combined with beta-blockers for 4-6 weeks prior to surgery. Additionally, in thyroid storm—a life-threatening exacerbation of hyperthyroidism often triggered by infection, surgery, or trauma—antithyroid agents are essential adjuncts in a multimodal approach, with PTU preferred due to its dual action in blocking synthesis and peripheral conversion of T4 to T3, alongside supportive measures like beta-blockade and iodine.^[10]^[12]^[13] Special considerations apply to vulnerable populations to balance maternal/fetal or pediatric risks with therapeutic needs. In pregnancy, antithyroid agents treat hyperthyroidism from Graves' disease, toxic multinodular goiter, or solitary toxic adenoma, with PTU recommended in the first trimester to minimize teratogenic risks (e.g., aplasia cutis), followed by a switch to MMI in the second and third trimesters at the lowest effective dose to maintain maternal euthyroidism while monitoring fetal thyroid function. During breastfeeding, MMI is preferred at doses ≤20 mg/day, as it transfers minimally into breast milk with low risk to the infant's thyroid; PTU is an alternative if MMI is not tolerated, limited to ≤300 mg/day with infant monitoring. In pediatrics, primarily for Graves' disease, MMI is the first-line agent at 0.2-0.5 mg/kg/day for 1-2 years to induce remission, avoiding PTU due to higher hepatotoxicity risk unless MMI is contraindicated.^[10]^[6]^[11]

Historical development

Early discoveries

In the 19th century, goiter was recognized as a prevalent condition associated with iodine deficiency, particularly in inland regions far from marine sources. Swiss physician Jean-François Coindet pioneered the use of iodine for its treatment in 1820, observing that small doses of tincture of iodine reduced goiter size in patients, building on earlier folk remedies involving seaweed and burnt sponge that contained trace iodine.^[14] This marked the initial understanding of iodine as an essential element for thyroid health, though its dual role—beneficial in deficiency but potentially inhibitory in excess—emerged later. By the mid-20th century, the inhibitory mechanism was elucidated through the Wolff-Chaikoff effect, first described in 1948 by Jan Wolff and Israel Lyon Chaikoff, who demonstrated in rat studies that high levels of iodide temporarily block thyroid hormone synthesis by inhibiting organification of iodine within the gland. Early 20th-century research into goitrogenic substances laid foundational insights into chemical inhibition of thyroid function. In the 1940s, experiments revealed that thiourea and its derivatives induced goiter in animals by interfering with thyroid hormone production; for instance, T.H. Kennedy reported in 1942 that thiourea caused pronounced thyroid enlargement in rabbits fed diets supplemented with the compound, attributing this to suppression of iodine utilization in the gland.^[15] These findings, stemming from investigations into natural goitrogens in brassica seeds, highlighted the antithyroid potential of sulfur-containing compounds and paved the way for synthetic thioamides. Similar goitrogenic effects were confirmed in rats by J.B. Mackenzie and colleagues in 1943, who showed that thiourea and sulfonamides enlarged the thyroid without preventing pituitary stimulation.^[16] The discovery of radioactive iodine isotopes in the 1930s provided tools for studying thyroid physiology and eventually therapy. In 1938, Glenn T. Seaborg and John Livingood at the University of California, Berkeley, produced iodine-131 (I-131) by neutron bombardment of tellurium, noting its 8-day half-life suitable for biological tracing.^[17] Initially used for imaging thyroid uptake, I-131's therapeutic application evolved post-World War II; Saul Hertz administered the first doses in 1941 for hyperthyroidism, with widespread adoption after 1946 when large-scale production became feasible, enabling targeted destruction of overactive thyroid tissue.^[18]

Modern agents and milestones

The development of synthetic antithyroid agents marked a significant advancement in the management of hyperthyroidism beginning in the mid-20th century, with thioamides emerging as the cornerstone of medical therapy. Building on the goitrogenic findings, endocrinologist Edward B. Astwood synthesized thiouracil in 1943 and conducted initial clinical trials in 1943-1944, demonstrating its efficacy in reducing thyroid hormone production in hyperthyroid patients and establishing the foundation for thioamide-based treatments.^[19] Propylthiouracil (PTU), the first thioamide, was introduced for clinical use in 1947 to treat Graves' disease, providing a non-surgical option to inhibit thyroid hormone synthesis.^[20] Shortly thereafter, methimazole was approved by the U.S. Food and Drug Administration in 1950, offering improved potency and dosing convenience compared to PTU while sharing the same thioamide class mechanism.^[6] These agents rapidly became standard treatments, revolutionizing care by allowing control of thyrotoxicosis without immediate reliance on ablative therapies. Carbimazole, introduced in 1951 as a prodrug that converts to active methimazole after absorption, gained prominence as a preferred alternative in European practice due to its pharmacokinetic profile and reduced gastrointestinal side effects.^[21] Concurrently, research elucidated additional benefits of PTU, including its unique ability to block peripheral conversion of thyroxine (T4) to the more active triiodothyronine (T3) via inhibition of type 1 deiodinase, a property not shared by methimazole or carbimazole; this recognition, building on discoveries of thyroid hormone metabolism in the early 1970s, enhanced PTU's utility in severe thyrotoxicosis.^[22] Key regulatory and guideline milestones in the 1990s and 2010s reflected evolving safety profiles and practice shifts. This preference for methimazole over PTU for non-pregnant adults due to PTU's higher risk of hepatotoxicity, including rare but severe cases of liver failure, was reinforced in later guidelines.^[23] In the 2010s, the FDA issued a black box warning in 2010 for PTU, highlighting risks of severe liver injury and acute liver failure, leading to recommendations reserving PTU primarily for first-trimester pregnancy.^[24] Post-2000 American Thyroid Association (ATA) guidelines, particularly the 2011 update, further emphasized radioiodine therapy as the definitive treatment for adults with Graves' disease, promoting it over prolonged antithyroid drug use for sustained remission, especially in cases refractory to medical management.^[25]

Pharmacological classification

Synthesis inhibitors

Synthesis inhibitors are a class of antithyroid agents, primarily thioamides, that directly impede the production of thyroid hormones by targeting key enzymatic steps in the thyroid gland. The main agents in this category include methimazole (MMI), carbimazole (a prodrug rapidly converted to MMI in vivo), and propylthiouracil (PTU). These drugs act intracellularly within thyroid follicular cells to block hormone synthesis after iodide uptake has occurred, distinguishing them from agents that affect iodide transport.^[2]^[6] The core mechanism of action for these thioamides involves irreversible inhibition of thyroid peroxidase (TPO), a heme-containing enzyme essential for thyroid hormone biosynthesis. TPO catalyzes the oxidation of iodide to iodine, which then iodinates tyrosine residues on thyroglobulin (organification) and facilitates the coupling of iodotyrosines to form thyroxine (T4) and triiodothyronine (T3). By forming a covalent bond with TPO—often described as suicide inactivation—these agents prevent these processes, leading to depleted hormone stores over time. This covalent interaction contributes to the prolonged duration of action, with effects persisting beyond the drug's plasma half-life due to sustained enzyme blockade and accumulation in the thyroid gland.^[6]^[26]^[27] Structurally, methimazole and its precursor carbimazole feature a five-membered imidazole ring with a methyl group at position 1 and a thione at position 2, which enables the sulfur atom to interact with TPO's catalytic site. In contrast, PTU belongs to the thiouracil class with a six-membered pyrimidine ring containing a thioamide group, allowing similar TPO inhibition but with an additional effect: PTU blocks type 1 iodothyronine deiodinase (D1), reducing the peripheral conversion of T4 to the more active T3, which provides a quicker reduction in circulating active hormone levels compared to MMI alone.^[6]^[28]^[29] Typical initial dosing for methimazole in adults with hyperthyroidism is 10-30 mg orally once daily, often adjusted based on response and sometimes split into divided doses for better efficacy in severe cases. For PTU, the starting dose is usually 300-600 mg per day administered in divided doses (e.g., every 6-8 hours) due to its shorter half-life. These regimens aim to achieve euthyroidism, with clinical improvement often noticeable within days, but normalization of thyroid function typically requiring 1-2 weeks or longer depending on pretreatment hormone levels and disease severity.^[30]^[31]^[32]

Uptake inhibitors

Uptake inhibitors are a class of antithyroid agents that primarily act by blocking the transport of iodide into thyroid follicular cells, thereby reducing the availability of this essential substrate for thyroid hormone synthesis. These agents competitively inhibit the sodium-iodide symporter (NIS), a membrane protein responsible for the active uptake of iodide from the bloodstream into the thyroid gland. By mimicking the structure of iodide as monovalent anions, they bind to NIS and prevent normal iodide accumulation, leading to decreased intrathyroidal iodine levels and subsequent inhibition of hormone production.^[33]^[34] The primary therapeutic agent in this category is potassium perchlorate, which was introduced in the early 1950s for the treatment of hyperthyroidism. It effectively blocks iodide uptake via competitive NIS inhibition and was historically administered at doses ranging from 200 to 1000 mg per day, often starting at 600 mg divided into multiple doses. Despite its efficacy in rapidly reducing thyroid hormone levels, potassium perchlorate is now rarely used due to significant toxicity concerns, including the risk of severe hematologic adverse effects.^[35]^[33]^[36] Other monovalent anions, such as thiocyanate and nitrate, also function as NIS inhibitors through similar competitive mechanisms but are considered obsolete for clinical use owing to their high toxicity and lack of specificity. These compounds were explored in early research but abandoned in favor of safer alternatives. In diagnostic settings, pertechnetate (as technetium-99m pertechnetate) is employed in thyroid scintigraphy because it is taken up by NIS in a manner analogous to iodide, allowing visualization of thyroid function without therapeutic intent.^[37]^[38] The clinical utility of uptake inhibitors like potassium perchlorate is limited to short-term administration, typically lasting only a few days to weeks, as prolonged use carries a substantial risk of aplastic anemia, a potentially fatal condition characterized by bone marrow failure, which led to multiple reported deaths in the 1950s and 1960s and prompted regulatory restrictions on its application.^[39]^[35]^[36]

Release inhibitors

Release inhibitors are a class of antithyroid agents that specifically target the proteolytic release of preformed thyroid hormones (T4 and T3) from thyroglobulin within the thyroid gland, thereby reducing hormone secretion into the bloodstream without primarily interfering with hormone synthesis.^[40] These agents act by impairing the endocytosis and lysosomal degradation processes involved in colloid resorption, leading to accumulation of stored hormones in the follicular lumen.^[41] The primary release inhibitor used clinically is lithium carbonate, administered at doses of 300-900 mg/day to achieve serum levels of 0.6-1.0 mEq/L for antithyroid effects.^[40] Lithium accumulates preferentially in the thyroid gland via the sodium-iodide symporter and exerts its inhibitory action by altering tubulin polymerization, which disrupts microtubule-dependent endocytosis of colloid droplets, and by suppressing TSH-stimulated cAMP production, thereby blocking lysosomal proteolysis and resorption of thyroglobulin.^[41]^[42] This mechanism effectively halts the release of stored T3 and T4 from TSH-stimulated thyroid tissue, as demonstrated in in vitro studies using mouse thyroids where lithium reduced hormone secretion by up to 50% in a dose-dependent manner.^[41] Lithium's utility as a release inhibitor emerged in the 1970s, initially observed in bipolar patients treated with the agent who developed hyperthyroidism due to its antithyroid properties; subsequent trials explored its direct application for thyrotoxicosis management.^[43] It is particularly employed in refractory hyperthyroidism cases unresponsive to thionamide drugs or in situations requiring avoidance of iodine, such as iodine-induced thyrotoxicosis from amiodarone or iodinated contrast media.^[44]^[45] For instance, lithium has been used adjunctively with radioactive iodine therapy to provide rapid control of hormone release in Graves' disease, shortening the time to euthyroidism.^[46] Despite its efficacy, lithium's use is limited by a narrow therapeutic index, necessitating close monitoring of serum levels to avoid toxicity, and its association with adverse effects including hypothyroidism (incidence 5-15%) and goiter (up to 40%) due to prolonged inhibition of hormone release and follicular cell hyperplasia.^[40] These risks are generally reversible upon discontinuation, but long-term administration requires regular thyroid function assessments.^[42]

Iodine-based therapies

Iodine-based therapies exploit the thyroid gland's dependence on iodine for hormone synthesis and uptake, either through pharmacological excess to temporarily inhibit function or via radioactive isotopes to ablate overactive tissue. These approaches are particularly useful in managing hyperthyroidism, preoperative preparation, and thyroid storm, where rapid control of hormone production is needed.^[47] The primary non-radioactive mechanism is the Wolff-Chaikoff effect, an autoregulatory phenomenon in which high doses of iodine (typically exceeding 6 mg per day) inhibit the organification of iodide by thyroid peroxidase, thereby blocking thyroid hormone synthesis for a temporary period of 24 to 48 hours. This effect arises from the generation of inhibitory intrathyroidal compounds, such as iodolactones and iodoaldehydes, which suppress further iodine incorporation into thyroglobulin. Most individuals escape this inhibition within days through downregulation of the sodium-iodide symporter (NIS), restoring normal synthesis, though vulnerable populations like neonates or those with underlying thyroid disease may develop prolonged hypothyroidism.^[48]^[49]^[47] Common agents harnessing the Wolff-Chaikoff effect include Lugol's solution, a mixture of elemental iodine and potassium iodide, administered at 5 to 10 drops per day (providing approximately 40 to 80 mg of iodine) to reduce thyroid vascularity and hormone release before thyroidectomy in hyperthyroid patients. Similarly, saturated solution of potassium iodide (SSKI) is used in thyroid storm at doses of 5 drops every 6 hours orally, rapidly decreasing thyroid hormone synthesis and secretion to stabilize life-threatening thyrotoxicosis. These therapies are initiated only after antithyroid drugs like thionamides to prevent potential exacerbation via the Jod-Basedow phenomenon in iodine-deficient individuals.^[50]^[51]^[52] Radioactive iodine therapy employs iodine-131 (I-131), a beta-emitting isotope with a half-life of 8 days, which is selectively taken up by overactive thyroid cells via NIS and delivers localized radiation to induce DNA damage and cell death, effectively ablating hyperfunctioning tissue over weeks to months. Standard ablative doses range from 4 to 30 millicuries (mCi), calculated via dosimetry formulas that account for 24-hour thyroid uptake and gland size, such as 0.1 to 0.2 mCi per gram of estimated thyroid weight, to achieve a target radiation dose of 80 to 150 Gray while minimizing extrathyroidal exposure. This treatment induces permanent hypothyroidism in 70 to 90% of patients with Graves' disease, necessitating lifelong levothyroxine replacement.^[53]^[54]^[55] In contrast, iodine-123 (I-123), a gamma-emitting isotope with a shorter half-life of 13 hours, serves solely diagnostic purposes in thyroid scintigraphy, where a 0.1 to 0.5 mCi oral dose enables imaging of iodine uptake patterns to differentiate causes of hyperthyroidism, such as hot nodules or diffuse uptake in Graves' disease, without therapeutic intent due to its low beta emission.^[56]^[57]

Receptor antagonists

Receptor antagonists of thyroid hormones function by competitively binding to the ligand-binding domains of thyroid hormone receptors (TRs), primarily the TRα and TRβ isoforms, thereby inhibiting the attachment of endogenous ligands such as triiodothyronine (T3). This blockade disrupts the conformational change required for coactivator recruitment, suppressing transcriptional activation of target genes that regulate metabolic rate, cardiac function, growth, and development. Unlike agents that target thyroid hormone synthesis or release, these antagonists exert their effects peripherally at the cellular level, modulating hormone action without directly altering glandular output.^[58] A prominent example is 1-850, an experimental small-molecule antagonist discovered via computational modeling and high-throughput screening, which exhibits high-affinity binding to both TRα and TRβ with selectivity over other nuclear receptors. This compound effectively blocks T3-mediated coactivator interactions in cellular assays, demonstrating isoform-nonselective antagonism suitable for broad TR inhibition. Additionally, analogs derived from sobetirome, such as NH-3, represent another class of developed antagonists; NH-3, synthesized from sobetirome intermediates, potently inhibits thyroid hormone binding and cofactor recruitment while showing potential for tissue-specific applications in preclinical models. These agents remain primarily investigational, with structure-activity relationship studies guiding further optimization for improved potency and selectivity.^[59]^[60] Clinical application of TR antagonists is currently limited to research contexts, particularly in elucidating mechanisms of thyroid hormone resistance syndromes (RTH), where mutant TRβ receptors exhibit dominant-negative effects on wild-type function; antagonists like 1-850 and NH-3 have been used in vitro and in animal models to probe these interactions and explore therapeutic modulation. They are not established as standard treatments for hyperthyroidism, where conventional therapies dominate due to the antagonists' early-stage development and lack of large-scale human trials. Nonetheless, their peripheral mechanism holds promise for reducing hyperthyroid symptoms—such as tachycardia and weight loss—while minimizing the hypothyroidism risk inherent to gland-suppressive agents, potentially offering a complementary option in refractory cases. Ongoing efforts focus on isoform-selective variants to enhance safety and efficacy profiles.^[61]^[62]

Clinical applications

Hyperthyroidism management

Antithyroid agents, particularly thioamides such as methimazole (MMI) and propylthiouracil (PTU), serve as first-line therapy for managing overt hyperthyroidism in adults, with MMI preferred due to its superior efficacy, once-daily dosing convenience, and lower risk of hepatotoxicity compared to PTU.^[63] PTU is specifically recommended during the first trimester of pregnancy to minimize teratogenic risks associated with MMI and in cases of thyroid storm, where it additionally inhibits peripheral conversion of T4 to T3.^[63] Antithyroid agents are also used preoperatively to normalize thyroid function and decrease vascularity prior to thyroidectomy or as adjunctive therapy before radioactive iodine ablation.^[63] Treatment with antithyroid agents typically lasts 12-18 months, after which therapy is discontinued if the patient achieves euthyroidism, allowing assessment for remission.^[63] Remission rates following this duration range from 20-50%, varying by geographic region and patient factors, with lower rates observed in the United States compared to Europe or Asia.^[63]^[64] Antithyroid agents are often combined with beta-blockers, such as propranolol, to rapidly control adrenergic symptoms like tachycardia and tremors while awaiting normalization of thyroid hormone levels.^[63] For definitive long-term management, especially in cases of relapse or persistent hyperthyroidism, options include radioactive iodine ablation or surgical thyroidectomy following initial control with antithyroid agents.^[63] Monitoring during therapy involves measuring serum TSH and free T4 levels every 4-6 weeks initially until euthyroidism is achieved, then every 2-3 months thereafter to adjust dosing and assess response.^[63] Thyroid-stimulating hormone receptor antibodies (TRAb) should be evaluated at baseline to determine etiology and prior to discontinuation to predict remission likelihood.^[63]

Graves' disease treatment

Graves' disease is an autoimmune disorder characterized by the production of thyroid-stimulating immunoglobulins, known as TSH receptor antibodies (TRAb), which bind to and activate TSH receptors on thyroid follicular cells, leading to excessive thyroid hormone synthesis and release.^[65] Antithyroid agents, such as thionamides, do not directly target the autoimmune process but effectively block the downstream effects by inhibiting thyroid hormone production, thereby controlling hyperthyroidism symptoms and potentially inducing remission.^[66] Methimazole is the preferred first-line antithyroid agent for treating Graves' disease due to its efficacy, once-daily dosing, and favorable safety profile compared to propylthiouracil (PTU), which is reserved primarily for the first trimester of pregnancy or cases of methimazole intolerance.^[67] Treatment typically lasts 12-24 months, with remission rates of approximately 30-50% after discontinuation, though rates vary by treatment duration, geographic region, and patient factors such as TRAb levels; longer durations may improve outcomes.^[68] Achievement of remission requires normalization of thyroid function and TRAb levels during therapy. Several factors influence response and relapse risk following antithyroid therapy. Elevated TRAb levels greater than 10 IU/L at diagnosis or during treatment strongly predict relapse, with approximately 90% of such patients experiencing recurrence upon discontinuation.^[69] Smoking is another key predictor, approximately doubling the risk of relapse by exacerbating TRAb production and impairing treatment response.^[70] In patients with Graves' ophthalmopathy, adjunctive therapies are considered alongside antithyroid agents. Radioactive iodine should be avoided as it can worsen eye disease in 15-20% of cases, particularly in those with active or moderate-to-severe ophthalmopathy.^[65] Selenium supplementation at 200 mcg/day for 6 months has been shown to reduce the progression of mild ophthalmopathy and improve quality of life, based on randomized trials in selenium-deficient regions, though benefits in replete areas require further confirmation.

Adverse effects

Common reactions

Antithyroid agents, particularly thioamides such as methimazole and propylthiouracil, commonly cause mild cutaneous and musculoskeletal reactions. Pruritic maculopapular rashes occur in approximately 5-10% of patients, often presenting as hives or itching that typically emerges within weeks of initiation.^[71] Arthralgia, manifesting as joint or muscle pain, affects about 5% of users and is usually diffuse and self-limited.^[71] Gastrointestinal disturbances, including nausea and upset stomach, are reported in up to 10% of cases and can be mitigated by administering the medication with food.^[6] These reactions generally resolve with dose reduction, antihistamine therapy, or temporary discontinuation, allowing many patients to continue treatment.^[6] Rash incidence specifically with methimazole is around 4-6%, and cross-reactivity between thioamides like methimazole and propylthiouracil occurs in approximately 50% of affected individuals, necessitating careful switching or alternative therapies.^[72]^[73] Iodine-based therapies, such as radioactive iodine or potassium iodide, frequently induce transient salivary and sensory effects. A metallic taste is reported in up to 27% of patients undergoing radioactive iodine treatment for hyperthyroidism, typically resolving within three months as taste buds regenerate.^[74] Sialadenitis, or inflammation of the salivary glands, develops in about 25% of recipients at doses of 100 mCi or higher, presenting as swelling and tenderness that improves with salivary stimulation techniques like lemon drops or massage.^[75] Acneiform rashes may also occur with iodide use, often mild and managed symptomatically with topical agents. Lithium, used off-label as an antithyroid agent, commonly leads to reversible thyroid and neurological effects. Mild hypothyroidism arises in 8-19% of long-term users, characterized by subtle elevations in TSH that often normalize upon discontinuation or levothyroxine supplementation.^[76] Fine hand tremor affects approximately 25% of patients and is typically posture-related, responding to dose adjustment or beta-blockers like propranolol.^[76] These effects underscore the need for regular thyroid function monitoring during lithium therapy.

Serious risks and monitoring

Antithyroid agents, particularly methimazole (MMI) and propylthiouracil (PTU), carry risks of serious hematologic adverse effects, most notably agranulocytosis, which occurs in 0.2-0.5% of patients treated for Graves' disease.^[77] This life-threatening condition, characterized by a severe drop in neutrophils (<500 per mL), typically manifests within the first three months of therapy and presents with symptoms such as high fever, sore throat, pharyngitis, or malaise.^[77]^[6] Upon suspicion, therapy must be discontinued immediately, with white blood cell counts measured and broad-spectrum antibiotics initiated if infection is present.^[10] Hepatic toxicity represents another critical risk, with PTU associated with severe liver failure in approximately 0.1% of cases, often progressing to fulminant hepatic necrosis.^[78] This hepatotoxicity is primarily hepatocellular and may occur at any time during treatment, signaled by jaundice, dark urine, abdominal pain, nausea, or fatigue.^[10] In contrast, MMI more commonly induces cholestatic liver injury, which is generally less severe and reversible upon discontinuation.^[6] Therapy should be halted if alanine aminotransferase (ALT) levels exceed three times the upper limit of normal (ULN), with close weekly monitoring thereafter to prevent progression.^[10] Teratogenicity is a significant concern with MMI use during pregnancy, particularly in the first trimester, where it is linked to congenital anomalies such as aplasia cutis congenita and choanal atresia, with an estimated risk of 2-4% for major birth defects.^[6]^[79] These effects arise from transplacental passage of the drug, potentially disrupting fetal thyroid development between weeks 6 and 10 of gestation.^[10] PTU is preferred in early pregnancy due to a lower teratogenic profile, though it carries its own hepatic risks.^[10] Monitoring strategies emphasize baseline assessments and vigilant symptom surveillance to mitigate these risks. Prior to initiating therapy, a complete blood count (CBC) with differential and liver function tests (LFTs), including ALT, aspartate aminotransferase (AST), and bilirubin, are recommended, though evidence for routine serial testing is insufficient.^[10] Patients should undergo monthly clinical evaluations for symptoms like fever, sore throat, or abdominal discomfort, with immediate CBC and LFTs if any arise; rash may serve as an early indicator warranting agent switching.^[10] Discontinuation and specialist consultation are advised for confirmed abnormalities, such as neutrophil counts below 1000 per mL or ALT exceeding three times ULN.^[10]^[6] Certain contraindications guide agent selection to avoid exacerbating underlying conditions. PTU is contraindicated in patients with active liver disease due to its heightened hepatotoxic potential.^[31] Similarly, perchlorate, an uptake inhibitor occasionally used adjunctively, should be avoided in renal impairment, as it is primarily renally excreted and may accumulate, worsening toxicity.^[80] Prior major adverse reactions to one agent, such as agranulocytosis or severe hepatotoxicity, preclude its use and often warrant alternatives like radioactive iodine or surgery.^[10]

Recent advances

Emerging therapies

Recent advancements in antithyroid therapies have focused on biologics targeting the thyroid-stimulating hormone receptor (TSHR), particularly for Graves' disease, where autoimmune stimulation drives hyperthyroidism. TSHR antagonists, such as the monoclonal antibody K1-70, have shown promise in early clinical studies by blocking TSHR signaling to reduce thyroid hormone overproduction and associated symptoms. In a Phase I trial involving patients with Graves' disease and thyroid eye disease, single doses of K1-70 (25 mg intramuscular or 50-150 mg intravenous) rapidly induced biochemical hypothyroidism, alleviated hyperthyroid symptoms, and improved orbital manifestations in most participants, with a favorable safety profile limited to mild adverse events like fatigue.^[81] Other biologics, including veligrotug (VRDN-001), a monoclonal antibody antagonist targeting insulin-like growth factor-1 receptor (IGF-1R), are in late-stage development for thyroid eye disease in Graves' disease. Phase 3 trials (THRIVE and THRIVE-2), initiated after 2023, demonstrated efficacy in reducing disease activity, with topline results in October 2025 showing significant proptosis reduction and tolerability after 5 IV infusions of 10 mg/kg.^[82] Selective thyroid hormone receptor (TR) modulators represent another emerging class, designed to exert peripheral effects such as lipid regulation without suppressing thyroid gland function, offering adjunctive benefits in hyperthyroidism management. Derivatives and analogs of sobetirome, a TRβ-selective agonist, have advanced in preclinical models, showing targeted activation in liver and peripheral tissues to mitigate metabolic complications of hyperthyroidism while avoiding central cardiac risks. For instance, ZTA-261, a novel selective TRβ agonist, demonstrated high potency in preclinical testing for lipid metabolism disorders, with improved selectivity and reduced toxicity compared to earlier compounds, supporting its investigation for thyroid-related metabolic dysregulation in 2024 studies.^[83] These modulators aim to provide symptom control in hyperthyroid states without the broad suppressive effects of traditional agents.^[84] Combination therapies are gaining traction for refractory Graves' disease, integrating thioamides with immunomodulators to enhance remission rates. The addition of rituximab, a B-cell depleting monoclonal antibody, to standard thioamide treatment (e.g., methimazole) has been explored in recent trials, showing increased remission from 20-30% to 48% at 24 months in young patients, with a single 500 mg dose proving well-tolerated alongside 12 months of antithyroid drugs.^[85] This approach targets autoantibody production, addressing persistent disease in cases unresponsive to monotherapy. Stem cell-based strategies, particularly mesenchymal stem cells (MSCs), are in early preclinical and exploratory phases for autoimmune thyroiditis, by modulating immune responses and reducing inflammation without direct gland suppression. In 2024-2025 studies, MSCs alleviated autoimmune thyroiditis in animal models by inhibiting pro-inflammatory pathways, suggesting potential for regenerating thyroid function and dampening autoimmunity.^[86] Thyroid organoids derived from stem cells have also emerged as tools to model Graves' disease pathology, facilitating targeted therapy development.^[87] The global antithyroid drug market, valued at $2.5 billion in 2025, reflects steady growth driven by these biologics and novel combinations, with a compound annual growth rate (CAGR) of 2.2% from 2024, fueled by rising Graves' disease prevalence and demand for targeted immunotherapies.^[88]

Updated guidelines

Recent clinical guidelines from 2023 to 2025 emphasize antithyroid drugs (ATDs) as a cornerstone of hyperthyroidism management, particularly for Graves' disease, while incorporating updates on pregnancy safety, long-term use, and thyroid eye disease (TED) integration.^[25]^[89] The 2025 Korean Thyroid Association (KTA) guidelines for radioactive iodine therapy in hyperthyroidism, including Graves' disease, recommend monitoring thyroid function post-treatment at 4-6 weeks, then every 2-3 months until stable, and every 6-12 months thereafter. Methimazole remains preferred over propylthiouracil (PTU) for its favorable safety profile in non-pregnant patients, with initial dosing typically ranging from 10 to 30 mg daily, adjusted based on severity; doses exceeding 15-20 mg/day may signal the need for escalation to radioactive iodine (RAI) therapy. For relapse after ATD-induced remission, RAI is strongly recommended (level 1 evidence) when definitive cure is desired, particularly in recurrent hyperthyroidism.^[90] Building on the 2017 American Thyroid Association (ATA) framework, guidelines reinforce PTU as the preferred ATD during the first trimester of pregnancy to minimize teratogenic risks associated with methimazole, such as aplasia cutis and choanal atresia. Long-term ATD use beyond 18-24 months is discouraged without evidence of remission, as prolonged therapy increases adverse event risks without proportional benefits in sustained euthyroidism.^[91]^[25] The 2025 British Journal of Obstetrics and Gynaecology (BJOG) guidelines prioritize PTU preconceptionally and in early pregnancy, recommending an immediate switch from carbimazole or methimazole to PTU upon confirmation of gestation, ideally before 10 weeks, at a 1:20 dose ratio to maintain equivalent efficacy. After the first trimester, switching back to carbimazole may be considered around 20 weeks to avoid PTU-related hepatotoxicity, with ongoing monitoring every 2-4 weeks. Dose titration is essential throughout, targeting free T4 in the upper half of trimester-specific reference ranges using the lowest effective dose to prevent fetal hypothyroidism while controlling maternal hyperthyroidism.^[89] For TED management, the 2022 ATA/European Thyroid Association consensus (endorsed in subsequent 2023-2025 reviews) advises combining ATDs for hyperthyroidism control with intravenous glucocorticoids (e.g., 4.5 g cumulative methylprednisolone over 12 weeks) as first-line for active moderate-to-severe TED without optic neuropathy. Biologics like teprotumumab are preferred over ATD monotherapy for cases with significant proptosis or diplopia, offering superior outcomes in inflammation reduction via IGF-1R inhibition, though relapse monitoring is required post-treatment.^[92]

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