Левотироксин

Кратко

Избыток левотироксина может вызывать фибрилляцию предсердий, стенокардию, сердечную недостаточность и инфаркт, а дозы, при которых уровень гормона гипофиза ТТГ становится очень низким, связаны с более частыми инсультами, переломами, нарушениями памяти и более высокой смертностью; при недостаточности надпочечников левотироксин, назначенный раньше заместительной терапии стероидными гормонами, может спровоцировать адреналовый криз, а у детей избыточная доза может вызвать преждевременное заращение швов черепа или закрытие зон роста костей. Гормон щитовидной железы влияет также на обновление костной ткани, обмен холестерина в печени, расход энергии в мышцах, работу мозга и регуляцию уровня сахара в крови. В испытаниях у людей с незначительно повышенным уровнем ТТГ препарат приводил этот показатель к норме, но не уменьшал симптомы и не улучшал качество жизни, а у пожилых людей значимо не влиял на частоту сердечно-сосудистых осложнений и смертность.

Серьёзные нежелательные последствия

Левотироксин назначают, когда щитовидная железа вырабатывает слишком мало гормонов, а при раке щитовидной железы — для подавления тиреотропного гормона (ТТГ), гормона гипофиза, стимулирующего эту железу ¹².

Состояние	Частота	У кого и когда риск выше	Источник
Фибрилляция предсердий и другие нарушения ритма сердца	367 случаев среди 17 684 человек, принимавших препарат, при медиане наблюдения 4,5 года; отношение рисков 1,6 при уровне ТТГ 0,03 mU/l и ниже	У пожилых людей	³⁴
Сердечно-сосудистые события и смерть	2144 события у тех же пациентов, отношение рисков 1,37 при том же уровне ТТГ; 75 963 случая смерти от сердечно-сосудистых причин среди 705 307 ветеранов при медиане наблюдения 4 года, отношение рисков 1,39 при ТТГ ниже 0,1 mIU/l	Также при недостаточной дозе: отношение рисков 2,67 при ТТГ выше 20	³⁵
Инсульт	41 931 из 663 809 ветеранов при медиане наблюдения 59 месяцев; отношение шансов 1,33 при ТТГ ниже 0,1 mIU/l	Также при ТТГ выше 5,5	⁶
Стенокардия, сердечная недостаточность, инфаркт миокарда, остановка сердца	Не установлена	У пожилых людей; при сердечно-сосудистых заболеваниях	⁴
Остеопоротические переломы	562 перелома у тех же пациентов, отношение рисков 2,02 при том же уровне ТТГ; 10,4% из 213 511 человек в возрасте 70 лет и старше, принимавших препарат, при среднем сроке наблюдения 3,8 года	При более высоких дозах; у женщин в постменопаузе	³⁷⁴
Когнитивные нарушения или деменция	Среди 65 931 человека к 75 годам — 11,0% после периода низкого ТТГ против 6,4% без него	В возрасте 65 лет и старше; отношение рисков 1,34, если ТТГ снизился в результате лечения	⁸
Смерть	Среди 160 439 человек при медиане наблюдения 6 лет отношение рисков 1,18 при ТТГ ниже 0,1 mIU/l и 2,21 при ТТГ выше 10 mIU/l по сравнению с 2–2,5 mIU/l	При избыточной и недостаточной дозе	⁹
Острая надпочечниковая недостаточность (адреналовый криз)	Не установлена	При нелеченой надпочечниковой недостаточности	⁴
Эмболия сосудов головного мозга, шок, кома, смерть	Описаны при передозировке	При передозировке, в том числе при приёме для снижения массы тела	⁴
Краниосиностоз, преждевременное закрытие зон роста костей, псевдоопухоль головного мозга, юношеский эпифизеолиз головки бедренной кости	Не установлена	У младенцев и детей	⁴
Судороги; ангионевротический отёк и сывороточная болезнь	Редко; частота не установлена	В начале лечения; при повышенной чувствительности к вспомогательным веществам	⁴

Большинство нежелательных реакций обусловлено избытком гормона, который может повышать частоту сердечных сокращений, толщину стенки сердца и сократимость миокарда ⁴. Избыточная заместительная терапия встречается часто: у 41,0% из 339 человек в возрасте 65 лет и старше, принимавших препарат, уровень ТТГ был ниже 0,45 mU/l ¹⁰. У человека гипертиреоз смещает ремоделирование кости в сторону резорбции, и итоговая потеря костной ткани за каждый цикл ремоделирования составляет около 10% ¹¹. Полный эффект изменения дозы может проявиться лишь через 4–6 недель ¹.

Нерешённые вопросы

Результаты независимых когортных исследований расходятся: по данным британской базы THIN, уровень ТТГ ниже 0,1 mIU/l был связан со смертностью, но не с фибрилляцией предсердий и не с переломами, а авторы допускают обратную причинно-следственную связь ⁹. Среди 8 573 313 жителей Швеции приём левотироксина был связан с развитием рака (отношение рисков 1,08 у женщин и 1,06 у мужчин); сведения о финансировании этого исследования получить не удалось ¹².

Другие пути, на которые влияет препарат

Гормон щитовидной железы действует через два рецептора — TRα и TRβ, — содержание которых в разных тканях неодинаково ¹³.

Ткань	Механизм	Что показано у людей
Костная ткань	У мышей T3 оказывает анаболическое действие на растущий скелет и катаболическое — на скелет взрослых животных, главным образом через TRα1 ¹¹	Избыточная заместительная доза может усиливать резорбцию и снижать минеральную плотность кости ⁴
Печень	T3 стимулирует транскрипцию генов рецептора ЛПНП и ГМГ-КоА-редуктазы; многие подобные механизмы установлены у грызунов ¹³	У 286 пожилых людей через 12 месяцев уровень холестерина ЛПНП значимо не изменился (апостериорный анализ) ¹⁴
Мышцы и жировая ткань	T3 стимулирует кальциевую АТФазу SERCA, гидролизующую АТФ ¹³	У 138 взрослых, получавших лечение, расход энергии в покое изменялся вместе с тиреоидным статусом, а масса тела в группах не различалась ¹⁵
Головной мозг	DIO2 активирует T4 в гипоталамусе ¹³	Дозы, при которых средний уровень ТТГ составил от 1,85 до 9,49 mU/l, не изменили настроение и память ¹⁶
Глюкоза и кортизол	Ускоряет клиренс глюкокортикоидов ⁴	Может ухудшать гликемический контроль при сахарном диабете ⁴

Для чего назначают и как действует

Левотироксин — синтетический тироксин (T4), основной гормон, который выделяет щитовидная железа ¹¹⁸. При субклиническом гипотиреозе уровень ТТГ повышен, а концентрация свободного T4 остаётся нормальной ¹⁹.

Тиреоидная пероксидаза йодирует тиреоглобулин и катализирует конденсацию его йодтирозильных остатков с образованием T4; DIO1 и DIO2 превращают T4 в активный T3, а DIO3 инактивирует оба гормона ²⁰¹⁸. В гипофизе DIO2 образует T3, через который T4 подавляет секрецию ТТГ, поэтому при первичном гипотиреозе дозу подбирают по уровню ТТГ ¹⁸¹.

Синтез и активация гормонов щитовидной железыФолликул щитовидной железы, затем ткани-мишени

Йодид в плазме крови
Натрий-йодидный симпортер (SLC5A5)2 Na+ПерхлоратТиреотропный гормон (ТТГ) усиливает экспрессию симпортера
Йодид в фолликуле щитовидной железы
Тиреоидная пероксидаза (TPO)Гем b, H2O2, образуемая двойной оксидазой 2 (DUOX2)Моно- и дийодтирозильные остатки образуются в полости фолликула
Йодтирозильные остатки тиреоглобулина
Тиреоидная пероксидаза (TPO)H2O2Два дийодтирозила соединяются, остаётся дегидроаланин; образуется и немного T3
Тироксиновые остатки тиреоглобулина
Катепсины B, K и LПротеолиз тиреоглобулина в полости фолликула и после эндоцитоза
Тироксин (T4)
Йодтирониндейодиназы 1 и 2 (DIO1, DIO2)Дейодирование наружного кольца; у человека DIO2 образует большую часть T3 крови
Трийодтиронин (T3)
Йодтирониндейодиназа 3 (DIO3)Дейодирование внутреннего кольца инактивирует T3; из T4 DIO3 даёт реверсивный T3
3,3′-Дийодтиронин

В организме

Левотироксин лучше всего всасывается натощак и выводится медленно: период полувыведения составляет 6–7 дней ¹.

Всасывание препарата могут уменьшать ингибиторы протонной помпы, антациды, кальция карбонат, железа сульфат, секвестранты желчных кислот и пищевые волокна ⁴. При совместном приёме с трициклическими антидепрессантами левотироксин может повышать риск аритмий, а с симпатомиметиками — риск коронарной недостаточности у больных ишемической болезнью сердца ⁴. Европейское агентство лекарственных средств (EMA) признало причинную связь между приёмом биотина и искажением результатов анализов функции щитовидной железы и сочло, что это создаёт значительный риск ошибок в ведении пациентов ²¹.

Генетические различия

На примере редких мутаций видно, какие ткани зависят от каждого из рецепторов тиреоидных гормонов ²³.

У ребёнка с доминантно-негативной мутацией гена THRA отмечались задержка роста, запоры и брадикардия при почти нормальных показателях функции щитовидной железы; тироксин подавил секрецию ТТГ, но рост, частота сердечных сокращений и работа кишечника улучшились незначительно ²³. Вариант DIO2 Thr92Ala был связан с меньшей скоростью ферментативной реакции в щитовидной железе и мышцах человека ¹⁸.

Соотношение пользы и вреда

В 21 испытании с участием 2192 взрослых с незначительно повышенным уровнем ТТГ лечение гормонами щитовидной железы в течение 3–18 месяцев нормализовало этот показатель, но не улучшило качество жизни ²⁴.

Группа	Польза	Серьёзный вред
Возраст 65 лет и старше, ТТГ 4,60–19,99 mIU/l (737 человек)	Через год баллы по шкалам симптомов и утомляемости различались на 0,0 и 0,4 балла при минимальной клинически значимой разнице 9 баллов ¹⁹	Смерть: 10 из 368 (2,7%) против 5 из 369 (1,4%); отношение рисков 1,91 (0,65–5,60) ¹⁹
Возраст 65 лет и старше, два испытания, медиана наблюдения 17 месяцев (842 человека)	Сердечно-сосудистые события: отношение рисков 0,74 (0,41–1,35) ²⁵	Смерть: отношение рисков 1,28 (0,54–3,03) ²⁵
Эутиреоз, антитела к тиреоидной пероксидазе, выкидыши или бесплодие в анамнезе (952 женщины)	Живорождение на сроке 34 недели и более: 37,4% против 37,9% ²⁶	Серьёзные нежелательные явления: 5,9% против 3,8% ²⁶

Как указывают авторы испытания TRUST, его статистическая мощность была недостаточной для оценки сердечно-сосудистых событий и смертности ¹⁹.

Без лекарств

Таблетки селена не улучшили самочувствие: у 412 взрослых жителей Дании с аутоиммунным гипотиреозом, получавших левотироксин, баллы качества жизни через 12 месяцев составили 28,8 против 28,0 в группе плацебо ²⁸.

Как разрабатывались рекомендации

У людей без заболеваний щитовидной железы уровень ТТГ с возрастом повышается ³⁰.

Среди 52 298 взрослых в Великобритании медиана уровня ТТГ на момент начала лечения в период с 2001 по 2009 год снизилась с 8,7 до 7,9 mIU/l ³¹. Из 58 706 человек, начавших приём препарата в США в 2008–2018 годах, у 30,5% функция щитовидной железы была нормальной ³².

Консенсусные заявления

Американская экспертная группа в 2004 году не рекомендовала рутинное лечение при уровне ТТГ 4,5–10 mIU/l ³³. Национальный институт здравоохранения и совершенствования медицинской помощи Великобритании (NICE) в рекомендациях 2019 года советует рассмотреть лечение при уровне ТТГ 10 mIU/l и выше, а соотношение пользы и вреда у людей моложе 65 лет комитет оценил на основании собственного опыта ³⁴. В рекомендациях Европейской тиреоидной ассоциации (ETA) 2013 года цитируется исследование на основе базы данных, выполненное двумя авторами самих рекомендаций ³⁵.

Прекращение приёма

У части людей функция щитовидной железы после прекращения приёма остаётся нормальной, причём чаще — если лечение было начато по поводу незначительного повышения ТТГ, а не манифестного гипотиреоза ³⁶.

В 17 обсервационных исследованиях с умеренным или высоким риском систематической ошибки, включавших в общей сложности 1103 пациента, эутиреоз сохранился у 35,6% тех, кого изначально лечили по поводу субклинического гипотиреоза, и у 11,8% — по поводу манифестного ³⁶. Среди 370 взрослых жителей Нидерландов в возрасте 60 лет и старше при открытом поэтапном снижении дозы через год полностью прекратили приём 95 человек (25,7%); у 142 человек снижение дозы остановили, когда уровень ТТГ достиг 10 mIU/l и более ³⁷.

Назначение лекарства изменяют вместе с врачом, который его выписал.

Источники

Регуляторное
AbbVie Inc.; approved by the US Food and Drug Administration. SYNTHROID (levothyroxine sodium) tablets, for oral use US Food and Drug Administration, Drugs@FDA, NDA 021402, prescribing information revised February 2024, 2024.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021402s038lbl.pdf
Финансирование и результат
Финансирование
Labelling prepared by the applicant, AbbVie Inc., and approved by the US Food and Drug Administration as supplement 038 to NDA 021402 on 20 February 2024.
Результат
Synthetic T4, chemically identical to thyroidal T4, indicated for primary, secondary and tertiary hypothyroidism and as an adjunct for TSH suppression in thyrotropin-dependent well-differentiated thyroid cancer. Narrow therapeutic index. Once daily on an empty stomach, half to one hour before breakfast, and at least 4 hours apart from drugs that interfere with absorption, including phosphate binders such as calcium carbonate and ferrous sulfate; gastric acidity is required for absorption, and proton pump inhibitors, sucralfate and antacids may reduce it. Absorption 40% to 80%, mostly in the jejunum and upper ileum, increased by fasting. T4 is 99.96% protein-bound; half-life 6 to 7 days in euthyroid patients, 9 to 10 days in hypothyroidism and 3 to 4 days in hyperthyroidism. About 80% of circulating T3 derives from peripheral monodeiodination of T4. Adult full replacement 1.6 mcg/kg/day, titrated by 12.5 to 25 mcg every 4 to 6 weeks; TSH is checked 6 to 8 weeks after a dose change; peak effect may take 4 to 6 weeks; in primary hypothyroidism the dose is titrated to a normal TSH, in secondary or tertiary hypothyroidism to free T4. Atrial fibrillation is the most common arrhythmia of overtreatment in the elderly; over-replacement may increase bone resorption and decrease bone mineral density, particularly in postmenopausal women. If cardiac symptoms develop or worsen, the dose is reduced or withheld for one week and restarted lower. Replacement therapy is generally taken for life.
Независимое
Brent GA. Mechanisms of thyroid hormone action Journal of Clinical Investigation, 2012.
doi:10.1172/JCI60047 PubMed 22945636
Финансирование и результат
Финансирование
This work was supported by Veterans Affairs Merit Review Funds and NIH grant R01 CA89364.
Результат
Review. Thyroid hormone is synthesised in thyroid follicles by iodination of tyrosine residues in thyroglobulin; TSH, secreted by the anterior pituitary in response to feedback from circulating thyroid hormone, acts on the TSH receptor of follicular cells and regulates iodide uptake by the sodium/iodide symporter. T4 is a prohormone activated to T3; humans derive circulating T3 primarily from type 2 deiodinase and rodents from type 1; type 3 deiodinase inactivates T4 to reverse T3; selenium is required by all three deiodinases. Unliganded thyroid hormone receptor heterodimerises with RXR, binds a thyroid hormone response element and then a corepressor such as NCoR or SMRT; T3 binding disrupts corepressor binding and promotes coactivator binding. TR-beta mediates thyroid hormone feedback to TRH and TSH; resistance to thyroid hormone, caused by TR-beta mutations, features elevated circulating thyroid hormone and nonsuppressed serum TSH.
Независимое
Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy Journal of Clinical Endocrinology and Metabolism, 2010.
doi:10.1210/jc.2009-1625 PubMed 19906785
Финансирование и результат
Участники
17 684
Наблюдение
median 4.5 years; 78,518 person-years
Финансирование
We thank Chest Heart Stroke Scotland and the Anonymous Trust, University of Dundee, for providing grants to support this work.
Результат
There were 2144 cardiovascular events, 367 dysrhythmias and 562 osteoporotic fractures. Against TSH 0.4 to 4.0 mU/l, suppressed TSH (0.03 or lower) carried adjusted hazard ratios of 1.37 (95% CI 1.17 to 1.60) for cardiovascular disease, 1.6 (1.10 to 2.33) for dysrhythmia and 2.02 (1.55 to 2.62) for fracture; raised TSH (above 4.0) 1.95 (1.73 to 2.21), 1.80 (1.33 to 2.44) and 1.83 (1.41 to 2.37); low but unsuppressed TSH (0.04 to 0.4) 1.1 (0.99 to 1.123), 1.13 (0.88 to 1.47) and 1.13 (0.92 to 1.39). Free T4 was not available.
Регуляторное
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets, for oral use: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label set 1e11ad30-1041-4520-10b0-8f9d30d30fcc, version 1537, published 29 February 2024; initial US approval 2002, 2024.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e11ad30-1041-4520-10b0-8f9d30d30fcc
Финансирование и результат
Финансирование
not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, AbbVie Inc.
Результат
Boxed warning: thyroid hormones, including Synthroid, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss; in euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction; larger doses may produce serious or even life-threatening manifestations of toxicity, particularly with sympathomimetic amines used for their anorectic effects. Contraindicated in uncorrected adrenal insufficiency. Warnings and precautions: narrow therapeutic index; overtreatment or undertreatment may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function and glucose and lipid metabolism; in children overtreatment is associated with craniosynostosis and acceleration of bone age. Over-treatment may increase heart rate, cardiac wall thickness and contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and elderly patients, who start at lower doses; arrhythmias are monitored during surgery in patients with coronary artery disease on suppressive therapy. Initiation before glucocorticoids may precipitate acute adrenal crisis in adrenal insufficiency, because thyroid hormone increases metabolic clearance of glucocorticoids. Addition of levothyroxine may worsen glycaemic control in diabetes. Over-replacement may increase bone resorption and decrease bone mineral density, particularly in post-menopausal women. Adverse reactions are primarily those of hyperthyroidism from overdosage, including arrhythmias, heart failure, angina, myocardial infarction, cardiac arrest, muscle weakness, decreased bone mineral density, impaired fertility; seizures reported rarely with institution of therapy; pseudotumor cerebri and slipped capital femoral epiphysis in pediatric patients; premature epiphyseal closure with compromised adult height; hypersensitivity reactions to inactive ingredients, including angioedema and serum sickness. Overdosage: confusion and disorientation; cerebral embolism, shock, coma and death have been reported; seizures occurred in a 3-year-old child ingesting 3.6 mg; symptoms may not appear until several days after ingestion. Interactions: increases the response to oral anticoagulants; may reduce the effect of digitalis glycosides; with tricyclic or tetracyclic antidepressants, increased risk of arrhythmias and central nervous system stimulation; with ketamine, marked hypertension and tachycardia; with sympathomimetics, risk of coronary insufficiency in coronary artery disease; phosphate binders including calcium carbonate and ferrous sulfate, bile acid sequestrants, ion exchange resins, orlistat, proton pump inhibitors, sucralfate and antacids may reduce absorption; phenobarbital and rifampin accelerate metabolism; soybean flour, cottonseed meal, walnuts, dietary fibre and grapefruit juice may reduce absorption; biotin interferes with TSH, T4 and T3 immunoassays and is stopped at least 2 days before testing. Atrial fibrillation is the most common arrhythmia of levothyroxine overtreatment in the elderly. Long-term carcinogenicity, mutagenicity and animal fertility studies have not been performed.
Независимое
Evron JM, Hummel SL, Reyes-Gastelum D, Haymart MR, Banerjee M, Papaleontiou M. Association of thyroid hormone treatment intensity with cardiovascular mortality among US veterans JAMA Network Open, 2022.
doi:10.1001/jamanetworkopen.2022.11863 PubMed 35552725
Финансирование и результат
Участники
705 307
Наблюдение
median 4 years (IQR 2 to 9)
Финансирование
This work was supported by the National Institute on Aging of the National Institutes of Health under award K08 AG049684 and by a pilot grant cofunded by the Claude D. Pepper Older Americans Independence Center, the Michigan Institute for Clinical and Health Research, and the Michigan Biology of Cardiovascular Aging (Dr Papaleontiou).
Результат
75,963 patients (10.8%) died of cardiovascular causes. Against euthyroidism (TSH 0.5 to 5.5 mIU/l, free T4 0.7 to 1.9 ng/dl), adjusted hazard ratios for cardiovascular mortality were 1.39 (95% CI 1.32 to 1.47) for TSH below 0.1 mIU/l and 1.29 (1.20 to 1.40) for free T4 above 1.9 ng/dl, and 2.67 (2.55 to 2.80) for TSH above 20 mIU/l and 1.56 (1.50 to 1.63) for free T4 below 0.7 ng/dl.
Независимое
Papaleontiou M, Levine DA, Reyes-Gastelum D, Hawley ST, Banerjee M, Haymart MR. Thyroid hormone therapy and incident stroke Journal of Clinical Endocrinology and Metabolism, 2021.
doi:10.1210/clinem/dgab444 PubMed 34137866
Финансирование и результат
Участники
733 208
Наблюдение
median 59 months
Финансирование
This work was supported by the National Institute on Aging of the NIH under Award Number K08 AG049684 and by a pilot grant co-funded by the Claude D. Pepper Older Americans Independence Center, the Michigan Institute for Clinical and Health Research and the Michigan Biology of Cardiovascular Aging to Dr. Papaleontiou. Dr. Haymart is supported by AHRQ R01 HS024512 and R01 CA201198 from the National Cancer Institute. The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit this manuscript for publication.
Результат
Incident atrial fibrillation occurred in 71,333 of 643,687 (11.08%) and stroke in 41,931 of 663,809 (6.32%). Against euthyroidism, stroke was associated with TSH below 0.1 mIU/l (OR 1.33, 95% CI 1.24 to 1.43) and free T4 above 1.9 ng/dl (OR 1.17, 1.06 to 1.30), and with TSH above 5.5 mIU/l (OR 1.29, 1.26 to 1.33) and free T4 below 0.7 ng/dl (OR 1.29, 1.22 to 1.35), adjusted for age, sex and prior atrial fibrillation. Risk of atrial fibrillation and stroke was cumulative over time for exogenous hyper- and hypothyroidism.
Независимое
Turner MR, Camacho X, Fischer HD, Austin PC, Anderson GM, Rochon PA, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study BMJ, 2011.
doi:10.1136/bmj.d2238 PubMed 21527461
Финансирование и результат
Участники
213 511
Наблюдение
mean 3.8 years
Финансирование
This work was supported by a team grant (OTG-88591) from the Canadian Institutes of Health Research (CIHR) and by a CIHR interdisciplinary capacity enhancement grant (HOA-80075). LLL is supported by a Canadian Diabetes Association/CIHR clinician scientist award. PCA is supported by a career investigator award from the Heart and Stroke Foundation of Ontario. GMA is supported by the University of Toronto chair in health management strategies. No endorsement by the Ministry of Health and Long-Term Care or by the Institute for Clinical Evaluative Sciences is intended.
Результат
Of 213,511 levothyroxine users aged 70 or more, 22,236 (10.4%; 88% women) had a fracture over a mean 3.8 years. Current against remote use: adjusted odds ratio 1.88 (95% CI 1.71 to 2.05). Among current users, high (more than 0.093 mg/day) and medium (0.044 to 0.093 mg/day) against low (less than 0.044 mg/day) cumulative doses in the preceding year: adjusted odds ratios 3.45 (3.27 to 3.65) and 2.62 (2.50 to 2.76). Serum thyroid stimulating hormone was not available in the databases.
Независимое
Adams R, Oh ES, Yasar S, Lyketsos CG, Mammen JS. Endogenous and exogenous thyrotoxicosis and risk of incident cognitive disorders in older adults JAMA Internal Medicine, 2023.
doi:10.1001/jamainternmed.2023.5619 PubMed 37870843
Финансирование и результат
Участники
65 931
Наблюдение
primary care records from 1 January 2014 to 6 May 2023
Финансирование
This work was supported by the Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, including significant contributions from the Richman Family Foundation, the Rick Sharp Alzheimer's Foundation, the Sharp Family Foundation, and others. The work was also supported by National Institutes of Health grants R01AG064256, P30 AG066507, R01AG076525 and R01AG057725. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Результат
Cumulative incidence of cognitive disorder (mild cognitive impairment or dementia) by age 75 years was 11.0% (95% CI 8.4% to 14.2%) with exposure to low TSH against 6.4% (6.0% to 6.8%) without. Adjusted hazard ratio 1.39 (1.18 to 1.64) for all-cause thyrotoxicosis and 1.34 (1.10 to 1.63) for exogenous thyrotoxicosis from thyroid hormone, with point estimates suggestive of a dose response.
Независимое
Thayakaran R, Adderley NJ, Sainsbury C, Torlinska B, Boelaert K, Šumilo D, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study BMJ, 2019.
doi:10.1136/bmj.l4892 PubMed 31481394
Финансирование и результат
Участники
160 439
Наблюдение
median 6 years
Финансирование
Funding: None.
Результат
Against TSH 2 to 2.5 mIU/l, mortality hazard ratios were 1.18 (95% CI 1.08 to 1.28) for TSH below 0.1, 1.29 (1.22 to 1.36) for 4 to 10 and 2.21 (2.07 to 2.36) above 10 mIU/l. Neither the lowest nor the highest TSH category was associated with atrial fibrillation or with all fractures; fragility fractures HR 1.15 (1.01 to 1.31) above 10 mIU/l. Heart failure HR 1.42 (1.21 to 1.67) above 10 and 0.79 (0.64 to 0.99) below 0.1 mIU/l.
Независимое
Somwaru LL, Arnold AM, Joshi N, Fried LP, Cappola AR. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over Journal of Clinical Endocrinology and Metabolism, 2009.
doi:10.1210/jc.2008-1696 PubMed 19126628
Финансирование и результат
Участники
339
Финансирование
This work was supported by National Institute on Aging Grant K23 AG19161 (to A.R.C.), and contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01 HC-15103 from the National Heart, Lung, and Blood Institute.
Результат
339 of 3678 (9.2%) took a thyroid hormone preparation. Of these, 41.0% had TSH below 0.45 mU/l, 16.2% above 4.5 and 42.8% in the euthyroid range. For every 10 kg lower body weight the odds of low TSH rose by 65% (OR 1.65, 95% CI 1.31 to 2.07); diabetes was associated with low (OR 3.35, 1.46 to 7.65) and high TSH (OR 2.66, 1.14 to 6.21). The authors cite a British study in which physicians failed to adjust the dose in 89% of those with low TSH.
Независимое
Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance Endocrine Reviews, 2016.
doi:10.1210/er.2015-1106 PubMed 26862888
Финансирование и результат
Финансирование
This work was supported by grants from the Medical Research Council (G108/502, G0501486, and G800261), the Wellcome Trust (GR076584), Arthritis Research UK (18292 and 19744), the European Union Marie-Curie Fellowship (509311), the Sir Jules Thorn Trust, the Society for Endocrinology, and the British Thyroid Foundation.
Результат
Review. In genetically modified mice T3 is anabolic in the developing skeleton and catabolic in adult bone, mediated predominantly by TRα1, and DIO2 in osteoblasts optimises mineralisation and strength; effects of altered T3 action in bone predominate over skeletal responses to TSH. In humans hyperthyroidism shortens the bone remodelling cycle in favour of resorption, reducing formation and mineralisation time more than resorption time, with a net 10% loss of bone per remodelling cycle. Thyrotoxicosis is an established cause of secondary osteoporosis in adults, fracture risk is increased in subclinical hyperthyroidism, and thyroid status at the upper end of the euthyroid reference range is associated with fracture in postmenopausal women.
Финансирование не установлено
Wändell P, Carlsson AC, Li X, Sundquist J, Sundquist K. Levothyroxine treatment is associated with an increased relative risk of overall and organ specific incident cancers - a cohort study of the Swedish population Cancer Epidemiology, 2020.
doi:10.1016/j.canep.2020.101707 PubMed 32222650
Финансирование и результат
Участники
8 573 313
Наблюдение
2009 to 2015
Финансирование
Funding statement not read: the publisher's full text returned a captcha to automated access. The PubMed record gives the competing interest statement only.
Результат
399,751 incident cancers. Levothyroxine treatment was associated with a slightly higher overall cancer risk, adjusted HR 1.06 (95% CI 1.03 to 1.10) in men and 1.08 (1.07 to 1.10) in women, with higher risks in women for cancers of breast, endometrium, stomach, colon, liver, pancreas, bladder and skin and for leukaemia. Indication, TSH and dose were not reported in the abstract. Results read from the PubMed abstract.
Независимое
Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism Physiological Reviews, 2014.
doi:10.1152/physrev.00030.2013 PubMed 24692351
Финансирование и результат
Финансирование
This work was supported by Veterans Affairs Merit Review Funds and National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1 DK98576.
Результат
Review. Thyroid hormone receptor isoforms alpha and beta are differentially expressed in tissues and have distinct roles; local activation of T4 to T3 by D2, expressed in hypothalamus, white fat, brown fat and skeletal muscle, is a key mechanism of metabolic regulation and is required for adaptive thermogenesis. Thyroid hormone acts on metabolism mainly through brain, white fat, brown fat, skeletal muscle, liver and pancreas. Excess raises resting energy expenditure and lipolysis and lowers cholesterol; deficiency does the reverse. In liver T3 stimulates transcription of the LDL receptor gene, SREBP-2, HMG-CoA reductase and CYP7A1, which TR stimulates directly in human liver; LDL receptor induction is a major pathway of cholesterol lowering after T4 treatment of hypothyroid patients. T3 stimulates SERCA in muscle, which hydrolyses ATP and increases energy expenditure, and modulates hepatic insulin sensitivity and gluconeogenesis. Many mechanisms are drawn from rodent models, such as SREBP-2 suppression in hypothyroid rats and pancreatic beta-cell maturation in rats; the importance of brown fat in adult humans is stated to remain controversial.
Независимое
Ao L, Noordam R, Trompet S, van Vliet NA, Sattar N, Rodondi N, et al. Levothyroxine treatment response of cardiometabolic biomarkers in older adults with subclinical hypothyroidism Journal of Clinical Endocrinology and Metabolism, 2026.
doi:10.1210/clinem/dgag155 PubMed 41965091
Финансирование и результат
Участники
286
Наблюдение
12 months
Финансирование
L.A. is supported by the China Scholarship Council. This work was supported by a research grant (666869, THYRAGE) from the European Union Horizon 2020 program. The IEMO trial was supported by ZonMw and the Swiss National Science Foundation; the TRUST trial by the European Union FP7-HEALTH-2011 program and the Swiss National Science Foundation.
Поддержка в натуральной форме
Levothyroxine and matching placebo supplied free of charge by the healthcare business of Merck KGaA, acknowledged as nonfinancial support.
Результат
Levothyroxine against placebo at 12 months: apolipoprotein B -0.03 g/l (95% CI -0.07 to 0.00), total cholesterol -0.17 mmol/l (-0.34 to 0.00), non-HDL cholesterol -0.15 (-0.31 to 0.00), remnant cholesterol -0.09 (-0.16 to -0.01), LDL cholesterol -0.07 (-0.15 to 0.02), triglycerides -0.07 (-0.15 to 0.01); the authors concluded there were no effects overall. In 27 participants with TSH of 10 mIU/l or more, lipid changes were nominally favourable but not significant after correction for multiple testing.
Независимое
Samuels MH, Kolobova I, Niederhausen M, Purnell JQ, Schuff KG. Effects of altering levothyroxine dose on energy expenditure and body composition in subjects treated with LT4 Journal of Clinical Endocrinology and Metabolism, 2018.
doi:10.1210/jc.2018-01203 PubMed 30165520
Финансирование и результат
Регистрация
NCT00565864
Участники
138
Наблюдение
6 months
Финансирование
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant R01 DK075496 to M.H.S.) and National Center for Advancing Translational Sciences (Grant UL1 RR024120; OHSU Clinical and Translational Science Award).
Результат
With final mean TSH 1.85, 3.93 and 9.49 mU/l in the three arms, there were no substantial differences in metabolic outcomes, weight or body composition, although falls in thyroid status correlated with falls in resting energy expenditure across all subjects. The authors conclude that lowering TSH below 2.50 mU/l is unlikely to benefit weight or body composition in hypothyroid patients.
Независимое
Samuels MH, Kolobova I, Niederhausen M, Janowsky JS, Schuff KG. Effects of altering levothyroxine (L-T4) doses on quality of life, mood, and cognition in L-T4 treated subjects Journal of Clinical Endocrinology and Metabolism, 2018.
doi:10.1210/jc.2017-02668 PubMed 29509918
Финансирование и результат
Участники
138
Наблюдение
6 months
Финансирование
This work was supported by National Institutes of Health Grants R01 DK075496 (to M.H.S.) and UL1 RR024120 (to OHSU).
Результат
Doses were adjusted double-blind to TSH targets of 0.34 to 2.50, 2.51 to 5.60 or 5.61 to 12.0 mU/l; final mean doses were 1.50, 1.32 and 0.78 µg/kg and mean TSH 1.85, 3.93 and 9.49 mU/l. Quality of life, mood, memory and executive function did not differ after correction for multiple comparisons. Participants could not tell how their dose had changed (P = 0.55), yet preferred the dose they perceived as higher (P < 0.001): 68% preferred the final dose when they thought it had risen and 96% the initial dose when they thought it had fallen.
Независимое
Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients PLoS One, 2011.
doi:10.1371/journal.pone.0022552 PubMed 21829633
Финансирование и результат
Участники
5 686
Финансирование
This study has been sponsored by the University of Catania and was supported also by a grant from AIRC (Associazione Italiana Ricerca Cancro) to RV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Результат
Despite TSH in the normal range, levothyroxine-treated athyreotic patients had higher free T4 and lower free T3 than matched controls (P < 0.001); 15.2% had free T3 below and 7.2% free T4 above the control range. Free T3 to free T4 ratios varied widely between individuals, and the relation between thyroid hormones and TSH indicated an altered pituitary feedback with reduced sensitivity.
Независимое
Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling Endocrine Reviews, 2008.
doi:10.1210/er.2008-0019 PubMed 18815314
Финансирование и результат
Финансирование
This work was supported by Hungarian Scientific Research Fund Grant OTKA T049081; Sixth EU Research Framework Program Grant LSHM-CT-2003-503041; János Bolyai Research Scholarship of the Hungarian Academy of Sciences; and National Institute of Diabetes, Digestive and Kidney Disorders Grants DK76117, DK58538, DK65055, DK78560, DK078476, DK076099, and DK064643.
Результат
Review. T4 is the main secretory product of the thyroid, and most circulating T3 derives from extrathyroidal deiodination of T4. D1 and D2 remove an outer-ring iodine to form T3; D3 removes an inner-ring iodine, forming rT3 from T4 and inactivating T3 to T2. The three deiodinases are dimeric thioredoxin-fold selenoproteins with selenocysteine in the active centre; D1 and D3 sit in the plasma membrane and D2 in the endoplasmic reticulum. D1 is sensitive to propylthiouracil and amiodarone. D2 has a half-life of about 40 minutes; T4 binding to its active centre accelerates ubiquitination by WSB1 and TEB4 and proteasomal degradation. Expression of D2 in the pituitary converts T4 to T3 locally and mediates the effect of serum T4 on TSH secretion; Dio2-null mice have raised serum T4 and TSH. Mutations in SECIS-binding protein 2 impair deiodinase activity; MCT8 mutations cause Allan-Herndon-Dudley syndrome with high free T3, low to below normal free T4 and normal TSH. DIO2 Thr92Ala (rs225014) has an allele frequency of 0.35 in Caucasians; it does not change the kinetics of transiently expressed D2 but was associated with lower enzyme velocity in human thyroid and skeletal muscle; associations with insulin resistance and hypertension are conflicting; it was not correlated with response to T4/T3 combination therapy.
Независимое
Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism New England Journal of Medicine, 2017.
doi:10.1056/NEJMoa1603825 PubMed 28402245
Финансирование и результат
Регистрация
NCT01660126
Участники
737
Наблюдение
primary outcomes at 12 months; median follow-up 18.0 months with levothyroxine and 17.3 months with placebo
Финансирование
Supported by a research grant (278148) from the European Union FP7-HEALTH-2011 program and by grants from the Swiss National Science Foundation (SNSF 320030-150025, P2BEP3_165409 and PZ00P3-167826) and the Swiss Heart Foundation and Velux Stiftung (974a). The European Union FP7 provided primary financial support. The funder, the trial sponsors (NHS Greater Glasgow and Clyde Health Board, University of Glasgow, University College Cork, Leiden University Medical Center, University of Bern and Bern University Hospital) and Merck played no role in the design, analysis or reporting of the trial; the main sponsor contributed to the writing of the protocol.
Поддержка в натуральной форме
Merck (Darmstadt, Germany) provided levothyroxine and matching placebo free of charge.
Результат
Levothyroxine starting at 50 mcg (25 mcg below 50 kg or with coronary heart disease), median 50 mcg at 1 year, against placebo with mock titration. At 12 months thyrotropin 3.63 against 5.48 mIU/l (difference -1.92, 95% CI -2.24 to -1.59). Change in Hypothyroid Symptoms score 0.2 in both groups (difference 0.0, 95% CI -2.0 to 2.1) and in Tiredness score 3.8 against 3.2 (difference 0.4, -2.1 to 2.9); minimum clinically important difference 9 points. New atrial fibrillation 11 of 368 (3.0%) against 13 of 369 (3.5%), hazard ratio 0.80 (0.35 to 1.80); fracture 9 (2.4%) against 8 (2.2%), 1.06 (0.41 to 2.76); death 10 (2.7%) against 5 (1.4%), 1.91 (0.65 to 5.60). Of 2647 people screened, 1645 had reversion of thyrotropin to below 4.60 mIU/l.
Справочное издание
Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. The Reactome Pathway Knowledgebase 2024 Nucleic Acids Research, 2024.
doi:10.1093/nar/gkad1025 PubMed 37941124
Финансирование и результат
Финансирование
The development of Reactome is supported by grants from the National Institutes of Health [U41HG003751, U24HG012198, U24HG011851, U54GM114833, U01CA239069]; European Bioinformatics Institute (EMBL-EBI), Open Targets (The Target Validation Platform) and Medicine by Design (University of Toronto). Funding for open access charge: National Institutes of Health [U24HG012198].
Результат
Pathway R-HSA-209968, Thyroxine biosynthesis (review status five stars, externally reviewed), and its reactions, read through the Reactome Content Service on 2026-10-21. SLC5A5 (NIS) transports iodide from blood serum into thyroid cells using the inward movement of Na+, which the Na+/K+-ATPase drives; TSH stimulates the uptake; SLC5A5 mutations cause thyroid dyshormonogenesis 1. DUOX1 and DUOX2 form the H2O2 that thyroid peroxidase requires. TPO, with cofactors Ca2+ and haem b, in a complex on the extracellular side of the apical plasma membrane, iodinates tyrosine residues of thyroglobulin with iodide and H2O2 and transfers the iodophenyl group of a donor DIT to an acceptor DIT (T4) or MIT (T3), leaving dehydroalanine on the donor; TPO mutations cause thyroid dyshormonogenesis 2A. Iodinated thyroglobulin is taken into follicular cells and cleaved in lysosomes, releasing T4, T3 and iodotyrosines; released iodide is recycled, and T4 and T3 are exported to the blood. DIO3 converts T4 to reverse T3 and T3 to 3,3'-diiodothyronine (T2), both inactive.
Регуляторное
European Medicines Agency, Pharmacovigilance Risk Assessment Committee and Coordination Group for Mutual Recognition and Decentralised Procedures (human). Levothyroxine: CMDh scientific conclusions and grounds for variation, amendments to the product information and timetable for the implementation (PSUSA/00001860/202201) European Medicines Agency, periodic safety update single assessment PSUSA/00001860/202201; CMDh position adopted October 2022, 2022.
https://www.ema.europa.eu/en/documents/psusa/levothyroxine-cmdh-scientific-conclusions-and-grounds-variation-amendments-product-information-and-timetable-implementation-psusa00001860202201_en.pdf
Финансирование и результат
Финансирование
European Medicines Agency
Результат
Biotin interference with thyroid function tests was judged causal from spontaneous reports and literature, with results normalising after biotin withdrawal or a different assay; the PRAC saw significant potential for clinical mismanagement of patients whose dose is titrated by periodic tests, particularly pregnant women, children, the elderly and patients monitored for thyroid cancer. St John's Wort, a potent CYP3A inducer, was added as an interaction that may increase hepatic clearance of levothyroxine, based on spontaneous reports and literature including cases with a positive dechallenge. Proton pump inhibitors may decrease absorption of levothyroxine, particularly as tablets, by raising intragastric pH; marketing authorisation holders identified cases with increased TSH or hypothyroidism; regular monitoring is recommended during concomitant treatment and care is taken when the PPI is stopped. The CMDh judged the benefit-risk balance unchanged subject to these product information changes, with variations to be submitted by marketing authorisation holders by 26 January 2023.
Консенсус
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement Thyroid, 2014.
doi:10.1089/thy.2014.0028 PubMed 25266247
Финансирование и результат
Финансирование
The task force members volunteered their time and expertise and did not receive funds from the ATA. No funds were received from commercial sources for the development of this document. J.J. is partially supported by federal funds (UL1TR000101) from the National Center for Advancing Translational Science, NIH; A.S. holds a Health Services Research Chair funded by Cancer Care Ontario.
Результат
Levothyroxine is recommended as the preparation of choice (strong recommendation, moderate-quality evidence). Levothyroxine should be taken consistently 60 minutes before breakfast or at bedtime, 3 or more hours after the evening meal (weak, moderate). It should be separated from interfering medicines and supplements such as calcium carbonate and ferrous sulfate; a 4-hour separation is traditional but untested (weak). Absorption studies support a role of coffee in reducing absorption. Routine combination of levothyroxine with liothyronine is recommended against, given conflicting trial results and a paucity of long-term outcome data (weak, moderate); across 13 trials benefits were heterogeneous, yet combination was preferred in four of five blinded crossover preference trials, whose four positive trials had 128 completers. Genetic testing of deiodinase polymorphisms to guide therapy is not recommended (strong, moderate); a secondary analysis of 552 patients found an interaction between DIO2 Thr92Ala and combination therapy, with 16% homozygous, while a secondary analysis of 92 patients from another trial found no association with well-being, neurocognitive functioning or preference.
Независимое
Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, et al. A mutation in the thyroid hormone receptor alpha gene New England Journal of Medicine, 2012.
doi:10.1056/NEJMoa1110296 PubMed 22168587
Финансирование и результат
Участники
1
Финансирование
Supported by grants from the Wellcome Trust, the National Institutes of Health Research Cambridge Biomedical Research Centre, the Medical Research Council Centre for Obesity and Related Metabolic Disease, and the Great Ormond Street Children's Charity.
Результат
A de novo heterozygous nonsense mutation in THRA produced a dominant negative TRα1 that inhibited wild-type receptor action. The child had growth retardation affecting the lower body segment, delayed tooth eruption, skeletal dysplasia with wormian bones and epiphyseal dysgenesis, severe constipation, bradycardia and low blood pressure, with near-normal thyroid hormone levels, disproportionately low free T4, high-normal or slightly raised free T3 and a low T4 to T3 ratio. The authors attribute resistance to tissues in which TRα predominates, such as skeleton, gastrointestinal tract and myocardium, while organs containing mainly TRβ, such as pituitary and liver, remained sensitive. After thyroxine 50 µg daily for 9 months, free T4, free T3 and IGF-1 rose to normal or supraphysiological levels, TSH was fully suppressed and basal metabolic rate normalised, but pulse and blood pressure stayed low and growth and gastrointestinal function improved little.
Независимое
Feller M, Snel M, Moutzouri E, Bauer DC, de Montmollin M, Aujesky D, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis JAMA, 2018.
doi:10.1001/jama.2018.13770 PubMed 30285179
Финансирование и результат
Участники
2 192
Наблюдение
3 to 18 months
Финансирование
The Swiss National Science Foundation funded this study (grant SNSF 320030_172676 to Dr Rodondi). The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Результат
Thyroid hormone lowered mean TSH into the reference range (0.5 to 3.7 against 4.6 to 14.7 mIU/l on placebo) but was not associated with benefit in general quality of life (n = 796; standardised mean difference -0.11, 95% CI -0.25 to 0.03) or thyroid-related symptoms (n = 858; SMD 0.01, -0.12 to 0.14). Risk of bias low; GRADE quality moderate to high.
Независимое
Zijlstra LE, Jukema JW, Westendorp RGJ, Du Puy RS, Poortvliet RKE, Kearney PM, et al. Levothyroxine treatment and cardiovascular outcomes in older people with subclinical hypothyroidism: pooled individual results of two randomised controlled trials Frontiers in Endocrinology, 2021.
doi:10.3389/fendo.2021.674841 PubMed 34093444
Финансирование и результат
Участники
842
Финансирование
The TRUST trial was supported by a research grant (278148) from the European Union FP7-HEALTH-2011 program and by grants from the Swiss National Science Foundation, the Swiss Heart Foundation and Velux Stiftung. Study medication was supplied free of charge by Merck KGaA. The IEMO trial was supported by research grant (627001001) from ZonMw and by grants from the Swiss National Science Foundation. The funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.
Поддержка в натуральной форме
Levothyroxine and matching placebo donated by Merck KGaA, which did not receive or provide financial contributions.
Результат
Mean TSH fell from 6.38 mIU/l to 3.66 at 1 year on levothyroxine (median dose 50 µg) against 5.66 on placebo. Over a median 17 months, levothyroxine did not significantly change cardiovascular events (44 events in total; HR 0.74, 95% CI 0.41 to 1.35 in the results text and 0.41 to 1.25 in the abstract), atrial fibrillation (HR 0.69, 0.32 to 1.52), heart failure (HR 0.41, 0.13 to 1.35) or all-cause mortality (HR 1.28, 0.54 to 3.03), irrespective of history of cardiovascular disease and age.
Независимое
Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception New England Journal of Medicine, 2019.
doi:10.1056/NEJMoa1812537 PubMed 30907987
Финансирование и результат
Регистрация
ISRCTN15948785
Участники
952
Наблюдение
from before conception to the end of pregnancy
Финансирование
Supported by the United Kingdom NIHR efficacy and mechanism evaluation program (project number 09/100/10). Generic levothyroxine and placebo were packaged and supplied by Sharp HealthCare (formerly Bilcare United Kingdom), which had no role in the design of the trial; the collection, analysis or interpretation of the data.
Результат
Levothyroxine 50 µg daily or placebo. Live birth after at least 34 weeks: 176 of 470 (37.4%) against 178 of 470 (37.9%); relative risk 0.97 (95% CI 0.83 to 1.14), absolute difference -0.4 percentage points (-6.6 to 5.8). Pregnancy loss, preterm birth and neonatal outcomes did not differ. Serious adverse events in 28 women (5.9%) on levothyroxine and 18 (3.8%) on placebo (P = 0.14).
Консенсус
Bekkering GE, Agoritsas T, Lytvyn L, Heen AF, Feller M, Moutzouri E, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline BMJ, 2019.
doi:10.1136/bmj.l2006 PubMed 31088853
Финансирование и результат
Финансирование
This guideline was not funded.
Результат
BMJ Rapid Recommendation (MAGIC group, GRADE): strong recommendation against thyroid hormones for adults with subclinical hypothyroidism (raised TSH, normal free T4). Not applicable to women trying to become pregnant or to TSH above 20 mIU/l; may not apply to severe symptoms or adults aged 30 or under. Based on a systematic review of 21 trials with 2192 participants: no clinically relevant benefit for quality of life or thyroid-related symptoms (moderate to high quality evidence). Deaths at 2 years 14 against 27 per 1000 without and with thyroid hormones (95% CI 5 fewer to 62 more per 1000; low quality, one trial). The evidence addresses starting treatment and only indirectly informs stopping it.
Независимое
Larsen C, Winther KH, Cramon PK, Rasmussen ÅK, Feldt-Rasmusssen U, Knudsen NJ, et al. Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism European Thyroid Journal, 2024.
doi:10.1530/ETJ-23-0175 PubMed 38215286
Финансирование и результат
Участники
412
Наблюдение
12 months of intervention, assessed to 18 months
Финансирование
The study received funding from The Danish Council for Strategic Research, the Region of Southern Denmark, University of Southern Denmark, The Nissenske Family Foundation, and the Danish Thyroid Patient Federation. UFR's research salary was sponsored by a grant from Kirsten and Freddy Johansen's Fund. Analytical work in the lab of LS was supported by the German Research Foundation.
Поддержка в натуральной форме
Selenium-enriched yeast tablets and placebo provided by Pharma Nord ApS, Vejle, Denmark.
Результат
Selenium 200 µg daily as selenium-enriched yeast or placebo, added to levothyroxine, for 12 months. Quality of life improved in both groups without difference in any ThyPRO-39 scale; composite score 28.8 (95% CI 24.5 to 33.6) against 28.0 (24.5 to 33.1), P = 0.602; at 12 months the hypothyroid symptoms scale favoured placebo (P = 0.016). TPO antibodies were lower with selenium (1995 against 2344 kIU/l) without effect on levothyroxine dose or the free T3 to free T4 ratio. The trial stopped before its target of 472 participants.
Финансирование не установлено
Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism Lancet, 2017.
doi:10.1016/S0140-6736(17)30703-1 PubMed 28336049
Финансирование и результат
Финансирование
not stated
Результат
Review. Most long-term consequences of hypothyroidism have been studied in subclinical hypothyroidism, because overt hypothyroidism is generally treated; few studies have examined hypothyroidism and all-cause mortality. Myxoedema coma, the outcome of long-standing untreated severe hypothyroidism, has a mortality of 40% despite treatment. An estimated 35% to 60% of levothyroxine-treated patients do not reach the target TSH range; overtreatment can cause atrial fibrillation and osteoporosis, and the review lists osteoporotic fracture among features of hypothyroidism as most probably caused by overtreatment. A substantial proportion of patients have persistent complaints despite biochemical targets.
Независимое
Xu Y, Hysaj O, Qi X, Feller M, Pingitore A, Brown SJ, et al. Natural history of thyroid function in ageing: an individual participant data analysis of 137 488 participants from 31 prospective cohort studies Lancet Diabetes and Endocrinology, 2026.
doi:10.1016/S2213-8587(26)00009-4 PubMed 42061390
Финансирование и результат
Регистрация
PROSPERO CRD42023408086
Участники
137 488
Финансирование
There was no funding source for this study.
Результат
Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and lower TSH in iodine-insufficient regions; longitudinally TSH rose with age regardless of iodine status. From age 18 to 100 years TSH rose by 0.61 mIU/l in women and 0.99 mIU/l in men from iodine-sufficient regions, with greater variability from age 65. Against stable thyroid function, rising TSH with stable or falling free T4 carried a mortality hazard ratio of 1.80 (95% CI 1.57 to 2.06), and falling TSH with stable or rising free T4 1.94 (1.68 to 2.24).
Независимое
Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study JAMA Internal Medicine, 2014.
doi:10.1001/jamainternmed.2013.11312 PubMed 24100714
Финансирование и результат
Участники
52 298
Наблюдение
TSH up to 5 years after initiation
Финансирование
Access to the GPRD was funded through the Medical Research Council's license agreement with the UK Medicines and Healthcare Products Regulatory Agency. The UK Medicines and Healthcare Products Regulatory Agency had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Результат
Median TSH at initiation fell from 8.7 mIU/l in 2001 to 7.9 mIU/l in 2009. Adjusted odds of starting levothyroxine at TSH 10.0 mIU/l or less in 2009 against 2001: 1.30 (95% CI 1.19 to 1.42); older people and people with cardiac risk factors had higher odds of starting at such values. At 5 years after initiation 5.8% had TSH below 0.1 mIU/l; depression or tiredness at baseline increased the odds of a suppressed TSH, whereas cardiac risk factors did not.
Независимое
Brito JP, Ross JS, El Kawkgi OM, Maraka S, Deng Y, Shah ND, et al. Levothyroxine use in the United States, 2008-2018 JAMA Internal Medicine, 2021.
doi:10.1001/jamainternmed.2021.2686 PubMed 34152370
Финансирование и результат
Участники
110 842
Финансирование
This work was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Результат
Median TSH at initiation was 5.8 mIU/l in 2008 and 5.3 in 2018 (P = .79). Among 58,706 starters with TSH and free or total T4 available, levothyroxine was started for overt hypothyroidism in 4948 (8.4%), subclinical hypothyroidism in 35,814 (61.0%) and normal thyroid function in 17,944 (30.5%), without significant change over the decade except a rise in overt (7.6% to 8.4%) and a fall in severe subclinical hypothyroidism (2.5% to 1.3%).
Консенсус
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management JAMA, 2004.
doi:10.1001/jama.291.2.228 PubMed 14722150
Финансирование и результат
Финансирование
not stated in the publisher page text. Representatives of the American Thyroid Association and the American Association of Clinical Endocrinologists formed the planning committee, with the Endocrine Society; continuing medical education credit was provided through the Endocrine Society; nonendocrinologist panelists received an honorarium.
Результат
The panel did not recommend routine levothyroxine for TSH between 4.5 and 10 mIU/l, finding insufficient evidence of therapeutic benefit and a small likelihood of symptom improvement. It judged levothyroxine reasonable for TSH above 10 mIU/l, while stating that evidence that treatment lowers cholesterol and improves symptoms is inconclusive.
Консенсус
National Institute for Health and Care Excellence. Thyroid disease: assessment and management National Institute for Health and Care Excellence, NICE guideline NG145, published 20 November 2019, last updated 12 October 2023, 2019.
https://www.nice.org.uk/guidance/ng145
Финансирование и результат
Финансирование
not stated
Результат
Offer levothyroxine first-line for primary hypothyroidism; do not routinely offer liothyronine alone or with levothyroxine, because there is not enough evidence of benefit over monotherapy and its long-term adverse effects are uncertain; do not offer natural thyroid extract. Start 1.6 µg/kg/day under 65 without cardiovascular disease, 25 to 50 µg/day with titration at 65 or over or with cardiovascular disease; aim for TSH within the reference range and avoid doses causing TSH suppression or thyrotoxicosis. In subclinical hypothyroidism consider levothyroxine when TSH is 10 mIU/l or higher on 2 occasions 3 months apart, and a 6-month trial for adults under 65 with TSH above the reference range but below 10 on 2 occasions and symptoms, stopping if symptoms persist once TSH is in range. The rationale states that there was little evidence on treating subclinical hypothyroidism, mostly in older adults; that TSH 5 to 10 mIU/l may return to the reference range without treatment in about half of people; that for TSH below 10 the committee judged, based on its experience, the balance most favourable under 65; and that over 65 improvement is less likely and harms from TSH suppression, such as atrial fibrillation, greater. Evidence from 7 trials suggested no important benefit of levothyroxine with liothyronine.
Консенсус
Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: management of subclinical hypothyroidism European Thyroid Journal, 2013.
doi:10.1159/000356507 PubMed 24783053
Финансирование и результат
Финансирование
The Task Force had no commercial support.
Результат
Recommends levothyroxine for younger patients (below 65 to 70 years) with TSH above 10 mU/l even without symptoms, and a trial in younger patients with TSH below 10 and symptoms, stopped if symptoms do not improve. Age-specific TSH reference ranges should be considered in older people; the oldest old (above 80 to 85 years) with TSH of 10 mU/l or less should be followed with a wait-and-see strategy. Treatment target for most adults a TSH in the lower half of the reference range (0.4 to 2.5 mU/l), and 1.0 to 5.0 mU/l above 70 years. The guideline notes that no large controlled trials had evaluated levothyroxine for cardiovascular events or mortality and cites an observational UK database analysis in which younger treated patients had fewer coronary events; it states that 40% to 60% of treated patients in population studies are under- or over-replaced.
Независимое
Burgos N, Toloza FJK, Singh Ospina NM, Brito JP, Salloum RG, Hassett LC, et al. Clinical outcomes after discontinuation of thyroid hormone replacement: a systematic review and meta-analysis Thyroid, 2021.
doi:10.1089/thy.2020.0679 PubMed 33161885
Финансирование и результат
Участники
1 103
Финансирование
Dr. Maraka receives support from the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000. Dr. Singh Ospina was supported by the National Cancer Institute of the National Institutes of Health under Award Number K08CA248972.
Результат
Studies were at moderate to high risk of bias. 37.2% (95% CI 24.2% to 50.1%, I2 97.5%) remained euthyroid after discontinuation: 11.8% (0.4% to 23.2%) of those first diagnosed with overt hypothyroidism and 35.6% (8.2% to 62.9%) of those diagnosed with subclinical hypothyroidism. No study followed a framework for systematic deprescribing.
Независимое
Ravensberg J, Gussekloo J, Le Cessie S, Dekkers OM, Mooijaart SP, Poortvliet RKE. Discontinuation of levothyroxine in adults aged 60 years or older JAMA, 2026.
doi:10.1001/jama.2026.2864 PubMed 41941226
Финансирование и результат
Участники
370
Наблюдение
1 year (mean 12.9 months)
Финансирование
The RELEASE trial was supported by research grant 839110026 from ZonMw for the Primary Care and Elderly Care program. ZonMw had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Результат
Open-label, single-group, stepwise dose reduction with thyroid tests at least 6 weeks after each step. At 1 year 95 of 370 (25.7%, 95% CI 21.5% to 30.4%) had stopped levothyroxine with TSH below 10 mIU/l (median 5.0) and free T4 within the reference range; 46 of these 95 had TSH below 4.8 mIU/l. 56 of 88 (63.6%) taking 50 µg/d or less and 79 of 176 (44.9%) taking 75 µg/d or less stopped successfully; odds ratio for success 0.95 (95% CI 0.94 to 0.96) per 1-µg higher baseline dose. Of the 271 who did not stop, 142 halted dose reduction because TSH reached 10 mIU/l or more. Changes in thyroid-related quality of life stayed below minimal clinically important differences; 21 participants reported a clinically important rise in hypothyroid symptoms at the end of dose reduction. 17 serious adverse events in 16 participants, including 2 deaths, none judged related. Indication for treatment and thyroid antibodies were not recorded, and the design had no control group.

Обновлено 2026-10-22