{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:15:37Z","timestamp":1783012537647,"version":"3.54.6"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Objective: Thyroid hormone treatment is the standard therapy for hypothyroidism, particularly in women. Concerns have been raised that exogenous thyroid hormone use may increase breast cancer risk, but evidence remains inconclusive. This study aimed to systematically review and synthesize observational evidence on the association between thyroid hormone treatment and breast cancer risk in women. Design: We conducted a systematic review and meta-analysis of observational studies. Methods: MEDLINE, EMBASE, and Web of Science were searched from January 1976 to February 2025. Eligible studies assessed breast cancer incidence in adult women receiving thyroid hormone treatment versus non-users. Pooled ORs were calculated. Findings from cohort studies reporting hazard ratios were synthesized qualitatively. Heterogeneity, publication bias, and certainty of evidence were assessed. PROSPERO ID: CRD42022348966. Results: Four case\u2013control studies including 221,254 women receiving thyroid hormone treatment and 4,385,666 controls were included in the prespecified primary OR-based meta-analysis. In the primary random-effects meta-analysis, thyroid hormone treatment showed a possible epidemiological signal with breast cancer risk (OR 1.43, 95% CI: 0.90\u20132.28; I2 = 94.3%), although the confidence interval crossed unity and heterogeneity was substantial. Formal assessment of publication bias was performed but should be interpreted cautiously given the small number of included studies. The certainty of evidence was rated as low due to heterogeneity, serious inconsistency and imprecision. Conclusions: Thyroid hormone treatment was associated with a possible epidemiological signal for breast cancer in observational studies; however, the primary pooled estimate was not statistically significant and should be interpreted as hypothesis-generating because of substantial heterogeneity and residual confounding. Further well-designed prospective studies are required before causal or clinical inferences can be made.<\/jats:p>","DOI":"10.3390\/metabo16070465","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:51:25Z","timestamp":1783003885000},"page":"465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thyroid Hormone Treatment and Breast Cancer Risk in Women: A Systematic Review and Meta-Analysis of Observational Studies"],"prefix":"10.3390","volume":"16","author":[{"given":"Stylianos","family":"Kopanos","sequence":"first","affiliation":[{"name":"Academic Department of General Internal Medicine, Endocrinology, Diabetes and Infectiology, Medical School and University Medical Center East Westphalia-Lippe, Bielefeld University, 33604 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9242-1959","authenticated-orcid":false,"given":"Jasper David","family":"Feldkamp","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology, and Cancer Immunology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2062-031X","authenticated-orcid":false,"given":"Johanna","family":"Tyssen","sequence":"additional","affiliation":[{"name":"Academic Department of General Internal Medicine, Endocrinology, Diabetes and Infectiology, Medical School and University Medical Center East Westphalia-Lippe, Bielefeld University, 33604 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5559-4657","authenticated-orcid":false,"given":"Xinjun","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research, Lund University, 202 13 Malm\u00f6, Sweden"},{"name":"Department Family Medicine and Clinical Epidemiology, University Clinic Primary Care, Sk\u00e5ne University Hospital, 205 02 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8031-279X","authenticated-orcid":false,"given":"Kristina","family":"Sundquist","sequence":"additional","affiliation":[{"name":"Center for Primary Health Care Research, Lund University, 202 13 Malm\u00f6, Sweden"},{"name":"Department Family Medicine and Clinical Epidemiology, University Clinic Primary Care, Sk\u00e5ne University Hospital, 205 02 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1032-8953","authenticated-orcid":false,"given":"Carolina","family":"Pape-K\u00f6hler","sequence":"additional","affiliation":[{"name":"Klinikum Bielefeld\u2014Rosenh\u00f6he, Bariatric Clinic, 33647 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Binneb\u00f6sel","sequence":"additional","affiliation":[{"name":"Academic Department of Surgery, Klinikum Bielefeld, Medical School and University Medical Centre East Westphalia-Lippe, Bielefeld University, 33604 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0241-9951","authenticated-orcid":false,"given":"Annika","family":"Hoyer","sequence":"additional","affiliation":[{"name":"Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, 33501 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5169-2965","authenticated-orcid":false,"given":"Per","family":"W\u00e4ndell","sequence":"additional","affiliation":[{"name":"Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 141 57 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5216-3851","authenticated-orcid":false,"given":"Joachim","family":"Feldkamp","sequence":"additional","affiliation":[{"name":"Academic Department of General Internal Medicine, Endocrinology, Diabetes and Infectiology, Medical School and University Medical Center East Westphalia-Lippe, Bielefeld University, 33604 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, B., Lu, Z., Huang, Y., Li, R., and Lin, T. (2020). Does hypothyroidism increase the risk of breast cancer: Evidence from a meta-analysis. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07230-4"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Voutsadakis, I.A. (2022). The TSH\/Thyroid Hormones Axis and Breast Cancer. J. Clin. Med., 11.","DOI":"10.3390\/jcm11030687"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.5306\/wjco.v5.i3.503","article-title":"Triiodothyronine and breast cancer","volume":"5","author":"Sibio","year":"2014","journal-title":"World J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13058-018-1017-8","article-title":"Thyroid hormones and breast cancer association according to menopausal status and body mass index","volume":"20","author":"Ziv","year":"2018","journal-title":"Breast Cancer Res. BCR"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1111\/cas.14908","article-title":"Risk of cancer in long-term levothyroxine users: Retrospective population-based study","volume":"112","author":"Wu","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nappi, A., D\u2019Esposito, V., Miro, C., Parascandolo, A., Cicatiello, A.G., Sagliocchi, S., Acampora, L., Torabinejad, S., Restolfer, F., and Raia, M. (2025). Thyroid Hormone Activation Regulates the Crosstalk between Breast Cancer and Mesenchymal Stem Cells. Front. Biosci. Landmark, 30.","DOI":"10.31083\/FBL26113"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1002\/j.2040-4603.2016.tb00712.x","article-title":"Thyroid Hormone, Cancer, and Apoptosis","volume":"6","author":"Lin","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"309","DOI":"10.5603\/EP.a2022.0020","article-title":"Free triiodothyronine and free thyroxine hormone levels in relation to breast cancer risk: A meta-analysis","volume":"73","author":"Lei","year":"2022","journal-title":"Endokrynol. Pol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111454","DOI":"10.1016\/j.mce.2021.111454","article-title":"Effects of thyroxine on apoptosis and proliferation of mammary tumors: Thyroxine effects on mammary carcinogenesis","volume":"538","author":"Zyla","year":"2021","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1097\/MED.0000000000000877","article-title":"Epidemiologic changes in thyroid disease","volume":"31","author":"Acosta","year":"2024","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_11","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1001\/jama.1977.03270410046018","article-title":"Thyroid supplementation for hypothyroidism. An latrogenic cause of breast cancer?","volume":"237","author":"Mustacchi","year":"1977","journal-title":"J. Am. Med. Assoc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1001\/jama.1976.03270110022020","article-title":"Breast Cancer: Relationship to Thyroid Supplements for Hypothyroidism","volume":"236","author":"Kapdi","year":"1976","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Harrison, H., Griffin, S.J., Kuhn, I., and Usher-Smith, J.A. (2020). Software tools to support title and abstract screening for systematic reviews in healthcare: An evaluation. BMC Med. Res. Methodol., 20.","DOI":"10.1186\/s12874-020-0897-3"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101707","DOI":"10.1016\/j.canep.2020.101707","article-title":"Levothyroxine treatment is associated with an increased relative risk of overall and organ specific incident cancers\u2014A cohort study of the Swedish population","volume":"66","author":"Carlsson","year":"2020","journal-title":"Cancer Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1001\/jama.1980.03310150021021","article-title":"Use of thyroid supplements in relation to the risk of breast cancer","volume":"244","author":"Shapiro","year":"1980","journal-title":"J. Am. Med. Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00404-018-4837-y","article-title":"Levothyroxine use and the risk of breast cancer: A nation-wide population-based case-control study","volume":"298","author":"Wu","year":"2018","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1089\/thy.2020.0388","article-title":"Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality","volume":"31","author":"Planck","year":"2021","journal-title":"Thyroid. Off. J. Am. Thyroid. Assoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/jrsm.1164","article-title":"Methods to estimate the between-study variance and its uncertainty in meta-analysis","volume":"7","author":"Veroniki","year":"2016","journal-title":"Res. Synth. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Inthout, J., Ioannidis, J.P., and Borm, G.F. (2014). The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-25"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"DerSimonian","year":"1986","journal-title":"Control. Clin. Trials"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12961-018-0320-2","article-title":"The GRADE Evidence to Decision (EtD) framework for health system and public health decisions","volume":"16","author":"Moberg","year":"2018","journal-title":"Health Res. Policy Syst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106011","DOI":"10.1016\/j.ebiom.2025.106011","article-title":"Prospective evaluation of circulating plasma thyroid hormones concentrations and breast cancer risk in the EPIC cohort","volume":"121","author":"His","year":"2025","journal-title":"eBioMedicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5030","DOI":"10.1210\/jc.2016-2104","article-title":"Thyroid Function and Cancer Risk: The Rotterdam Study","volume":"101","author":"Khan","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Dekkers, O.M., Vandenbroucke, J.P., Cevallos, M., Renehan, A.G., Altman, D.G., and Egger, M. (2019). COSMOS-E: Guidance on conducting systematic reviews and meta-analyses of observational studies of etiology. PLoS Med., 16.","DOI":"10.1371\/journal.pmed.1002742"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1002\/sim.3246","article-title":"On effect-measure modification: Relationships among changes in the relative risk, odds ratio, and risk difference","volume":"27","author":"Brumback","year":"2008","journal-title":"Stat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Calissendorff, J., and Falhammar, H. (2020). To Treat or Not to Treat Subclinical Hypothyroidism, What Is the Evidence?. Medicina, 56.","DOI":"10.3390\/medicina56010040"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26710","DOI":"10.1038\/s41598-024-77896-4","article-title":"Trends in the use of thyroid diagnostics and treatments between 2008 and 2019 in Germany","volume":"14","author":"Thiyagarajan","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1056\/NEJMoa1603825","article-title":"Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism","volume":"376","author":"Stott","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1159\/000356507","article-title":"2013 ETA Guideline: Management of Subclinical Hypothyroidism","volume":"2","author":"Pearce","year":"2014","journal-title":"Eur. Thyroid. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"988","DOI":"10.4158\/EP12280.GL","article-title":"Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association","volume":"18","author":"Garber","year":"2012","journal-title":"Endocr. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"317398","DOI":"10.1155\/2014\/317398","article-title":"Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples in menopausal women","volume":"2014","author":"Conde","year":"2014","journal-title":"ISRN Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1002\/ijc.31156","article-title":"Thyroid-associated genetic polymorphisms in relation to breast cancer risk in the Malm\u00f6 Diet and Cancer Study","volume":"142","author":"Brandt","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1590\/2359-3997000000191","article-title":"Is there an association between thyroid function abnormalities and breast cancer?","volume":"61","author":"Angelousi","year":"2017","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"bqac075","DOI":"10.1210\/endocr\/bqac075","article-title":"Hormonal Crosstalk Between Thyroid and Breast Cancer","volume":"163","author":"Halada","year":"2022","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s12672-018-0326-9","article-title":"Thyroid hormone in the clinic and breast cancer","volume":"9","author":"Hercbergs","year":"2018","journal-title":"Horm. Cancer"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:17:00Z","timestamp":1783009020000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["metabo16070465"],"URL":"https:\/\/doi.org\/10.3390\/metabo16070465","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}