Levothyroxine

Serious harms

Levothyroxine is prescribed when the thyroid gland makes too little hormone, and in thyroid cancer to suppress thyrotropin (TSH), the pituitary hormone that stimulates the gland ¹².

Condition	How often	Who is at risk	Source
Atrial fibrillation and other dysrhythmias	367 events in 17,684 users over a median 4.5 years; hazard ratio (HR) 1.6 at TSH 0.03 mU/l or less	Older people	³⁴
Cardiovascular events and death	2144 events in the same users, HR 1.37 at that TSH; 75,963 cardiovascular deaths in 705,307 veterans over a median 4 years, HR 1.39 at TSH below 0.1 mIU/l	Also undertreatment: HR 2.67 at TSH above 20	³⁵
Stroke	41,931 of 663,809 veterans over a median 59 months; odds ratio 1.33 at TSH below 0.1 mIU/l	Also TSH above 5.5	⁶
Angina, heart failure, myocardial infarction, cardiac arrest	Not quantified	Elderly people; cardiovascular disease	⁴
Osteoporotic fracture	562 in the same users, HR 2.02 at that TSH; 10.4% of 213,511 users aged 70 or more over a mean 3.8 years	Higher doses; women after the menopause	³⁷⁴
Cognitive impairment or dementia	By age 75, 11.0% after low TSH against 6.4% without, of 65,931	Aged 65 or more; HR 1.34 when treatment lowered TSH	⁸
Death	HR 1.18 at TSH below 0.1 and 2.21 above 10 mIU/l, against 2 to 2.5, in 160,439 over a median 6 years	Over- and undertreatment	⁹
Acute adrenal crisis	Not quantified	Uncorrected adrenal insufficiency	⁴
Cerebral embolism, shock, coma, death	Reported in overdose	Overdose, including use for weight loss	⁴
Craniosynostosis, early growth-plate closure, pseudotumour cerebri, slipped capital femoral epiphysis	Not quantified	Infants and children	⁴
Seizures; angio-oedema and serum sickness	Rare; not quantified	Start of therapy; sensitivity to inactive ingredients	⁴

Most adverse reactions are those of excess hormone, which may raise heart rate, cardiac wall thickness and contractility ⁴. Excess is common: 41.0% of 339 users aged 65 or more had TSH below 0.45 mU/l ¹⁰. In people, hyperthyroidism shifts bone remodelling towards resorption, with a net loss of about 10% per cycle ¹¹. A dose change may take 4 to 6 weeks to act fully ¹.

Other pathways it affects

Thyroid hormone acts through two receptors, TRα and TRβ, whose amounts differ between tissues ¹³.

Tissue	Mechanism	Known in people
Bone	In mice, T3 is anabolic in the growing and catabolic in the adult skeleton, mainly through TRα1 ¹¹	Over-replacement may raise resorption and lower density ⁴
Liver	T3 stimulates transcription of the LDL receptor and HMG-CoA reductase; many such mechanisms come from rodents ¹³	No significant change in LDL cholesterol at 12 months in 286 older adults, post hoc ¹⁴
Muscle and fat	T3 stimulates SERCA, which hydrolyses ATP ¹³	Resting energy expenditure tracked thyroid status in 138 treated adults; weight did not differ ¹⁵
Brain	DIO2 activates T4 in the hypothalamus ¹³	Doses reaching mean TSH of 1.85 to 9.49 mU/l left mood and memory unchanged ¹⁶
Glucose and cortisol	Increases glucocorticoid clearance ⁴	May worsen glycaemic control in diabetes ⁴

What it is for and how it works

Levothyroxine is synthetic thyroxine (T4), the main hormone the thyroid releases ¹¹⁸. In subclinical hypothyroidism TSH is raised and free T4 normal ¹⁹.

Thyroid peroxidase iodinates thyroglobulin and couples its iodotyrosines into T4; DIO1 and DIO2 convert T4 to active T3, and DIO3 inactivates both ²⁰¹⁸. Pituitary DIO2 forms the T3 through which T4 suppresses TSH, so TSH guides the dose in primary hypothyroidism ¹⁸¹.

Thyroid hormone synthesis and activationThyroid follicle, then target tissues

Iodide in plasma
Sodium–iodide symporter (SLC5A5)2 Na+PerchlorateThyrotropin (TSH) up-regulates the symporter
Iodide in the thyroid follicle
Thyroid peroxidase (TPO)Haem b, H2O2 from dual oxidase 2 (DUOX2)Mono- and diiodotyrosyl residues form in the follicle lumen
Iodotyrosyl residues of thyroglobulin
Thyroid peroxidase (TPO)H2O2Two diiodotyrosyls couple and leave dehydroalanine; some T3 also forms
Thyroxine residues of thyroglobulin
Cathepsins B, K and LThyroglobulin proteolysis in the lumen and after endocytosis
Thyroxine (T4)
Iodothyronine deiodinases 1 and 2 (DIO1, DIO2)Outer-ring deiodination; in humans DIO2 supplies most circulating T3
Triiodothyronine (T3)
Iodothyronine deiodinase 3 (DIO3)Inner-ring deiodination inactivates T3; DIO3 also forms reverse T3 from T4
3,3′-Diiodothyronine

In the body

Levothyroxine is absorbed best from an empty stomach and is cleared slowly, with a half-life of 6 to 7 days ¹.

Proton pump inhibitors, antacids, calcium carbonate, ferrous sulfate, bile acid sequestrants and dietary fibre may reduce absorption ⁴. With tricyclic antidepressants levothyroxine may increase arrhythmia risk, and with sympathomimetics the risk of coronary insufficiency in coronary artery disease ⁴. The EMA judged biotin interference with thyroid tests causal, with significant potential for mismanagement ²¹.

Genetic variation

Rare mutations show which tissues depend on each thyroid hormone receptor ²³.

A child with a dominant-negative THRA mutation had growth retardation, constipation and bradycardia despite near-normal thyroid tests; thyroxine suppressed TSH but improved growth, heart rate and gut function little ²³. DIO2 Thr92Ala was associated with lower enzyme velocity in human thyroid and muscle ¹⁸.

Benefit against harm

In 21 trials with 2192 adults with mildly raised TSH, thyroid hormone brought the test into range without improving quality of life over 3 to 18 months ²⁴.

Group	Benefit	Serious harm
Aged 65 or more, TSH 4.60 to 19.99 mIU/l (737)	Symptom and tiredness scores at 1 year differed by 0.0 and 0.4 points; minimum important difference 9 ¹⁹	Deaths 10 of 368 (2.7%) against 5 of 369 (1.4%); HR 1.91 (0.65 to 5.60) ¹⁹
Aged 65 or more, two trials, median 17 months (842)	Cardiovascular events HR 0.74 (0.41 to 1.35) ²⁵	Deaths HR 1.28 (0.54 to 3.03) ²⁵
Euthyroid women with TPO antibodies and miscarriage or infertility (952)	Live births at 34 weeks or more, 37.4% against 37.9% ²⁶	Serious adverse events 5.9% against 3.8% ²⁶

TRUST was underpowered for cardiovascular events and mortality, its authors state ¹⁹.

Without the medicine

Selenium tablets did not improve well-being: in 412 Danish adults with autoimmune hypothyroidism on levothyroxine, 12-month quality-of-life scores were 28.8 against 28.0 on placebo ²⁸.

How the recommendations were set

TSH rises with age in people without thyroid disease ³⁰.

Among 52,298 UK adults, median TSH at initiation fell from 8.7 to 7.9 mIU/l between 2001 and 2009 ³¹. Of 58,706 US starters in 2008 to 2018, 30.5% had normal thyroid function ³².

Stopping

Some people stay in the normal range after stopping, more often after a mildly raised TSH than after overt hypothyroidism ³⁶.

In 17 observational studies with 1103 patients, at moderate to high risk of bias, 35.6% first treated for subclinical and 11.8% for overt hypothyroidism stayed euthyroid ³⁶. In 370 Dutch adults aged 60 or more, open-label stepwise reduction left 95 (25.7%) off treatment at 1 year; 142 halted when TSH reached 10 mIU/l or more ³⁷.

A prescription is changed together with the prescriber.

References

Regulator
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
Funding and finding
Funding
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.
Finding
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.
Independent research
Brent GA. Mechanisms of thyroid hormone action Journal of Clinical Investigation, 2012.
doi:10.1172/JCI60047 PubMed 22945636
Funding and finding
Funding
This work was supported by Veterans Affairs Merit Review Funds and NIH grant R01 CA89364.
Finding
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.
Independent research
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
Funding and finding
Participants
17,684
Follow-up
median 4.5 years; 78,518 person-years
Funding
We thank Chest Heart Stroke Scotland and the Anonymous Trust, University of Dundee, for providing grants to support this work.
Finding
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.
Regulator
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
Funding and finding
Funding
not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, AbbVie Inc.
Finding
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.
Independent research
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
Funding and finding
Participants
705,307
Follow-up
median 4 years (IQR 2 to 9)
Funding
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).
Finding
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.
Independent research
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
Funding and finding
Participants
733,208
Follow-up
median 59 months
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
213,511
Follow-up
mean 3.8 years
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
65,931
Follow-up
primary care records from 1 January 2014 to 6 May 2023
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
160,439
Follow-up
median 6 years
Funding
Funding: None.
Finding
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.
Independent research
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
Funding and finding
Participants
339
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Funding
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.
Finding
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.
Funding unknown
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
Funding and finding
Participants
8,573,313
Follow-up
2009 to 2015
Funding
Funding statement not read: the publisher's full text returned a captcha to automated access. The PubMed record gives the competing interest statement only.
Finding
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.
Independent research
Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism Physiological Reviews, 2014.
doi:10.1152/physrev.00030.2013 PubMed 24692351
Funding and finding
Funding
This work was supported by Veterans Affairs Merit Review Funds and National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1 DK98576.
Finding
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.
Independent research
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
Funding and finding
Participants
286
Follow-up
12 months
Funding
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.
In-kind support
Levothyroxine and matching placebo supplied free of charge by the healthcare business of Merck KGaA, acknowledged as nonfinancial support.
Finding
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.
Independent research
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
Funding and finding
Registration
NCT00565864
Participants
138
Follow-up
6 months
Funding
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).
Finding
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.
Independent research
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
Funding and finding
Participants
138
Follow-up
6 months
Funding
This work was supported by National Institutes of Health Grants R01 DK075496 (to M.H.S.) and UL1 RR024120 (to OHSU).
Finding
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.
Independent research
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
Funding and finding
Participants
5,686
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Registration
NCT01660126
Participants
737
Follow-up
primary outcomes at 12 months; median follow-up 18.0 months with levothyroxine and 17.3 months with placebo
Funding
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.
In-kind support
Merck (Darmstadt, Germany) provided levothyroxine and matching placebo free of charge.
Finding
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.
Textbook or database
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
Funding and finding
Funding
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].
Finding
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.
Regulator
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
Funding and finding
Funding
European Medicines Agency
Finding
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.
Expert consensus
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
Funding and finding
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
1
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
2,192
Follow-up
3 to 18 months
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
842
Funding
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.
In-kind support
Levothyroxine and matching placebo donated by Merck KGaA, which did not receive or provide financial contributions.
Finding
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.
Independent research
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
Funding and finding
Registration
ISRCTN15948785
Participants
952
Follow-up
from before conception to the end of pregnancy
Funding
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.
Finding
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).
Expert consensus
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
Funding and finding
Funding
This guideline was not funded.
Finding
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.
Independent research
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
Funding and finding
Participants
412
Follow-up
12 months of intervention, assessed to 18 months
Funding
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.
In-kind support
Selenium-enriched yeast tablets and placebo provided by Pharma Nord ApS, Vejle, Denmark.
Finding
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.
Funding unknown
Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism Lancet, 2017.
doi:10.1016/S0140-6736(17)30703-1 PubMed 28336049
Funding and finding
Funding
not stated
Finding
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.
Independent research
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
Funding and finding
Registration
PROSPERO CRD42023408086
Participants
137,488
Funding
There was no funding source for this study.
Finding
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).
Independent research
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
Funding and finding
Participants
52,298
Follow-up
TSH up to 5 years after initiation
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
110,842
Funding
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.
Finding
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%).
Expert consensus
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
Funding and finding
Funding
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.
Finding
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.
Expert consensus
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
Funding and finding
Funding
not stated
Finding
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.
Expert consensus
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
Funding and finding
Funding
The Task Force had no commercial support.
Finding
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.
Independent research
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
Funding and finding
Participants
1,103
Funding
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.
Finding
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.
Independent research
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
Funding and finding
Participants
370
Follow-up
1 year (mean 12.9 months)
Funding
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.
Finding
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.

Updated 2026-10-22