Thyroid Hormone Homeostasis in Levothyroxine-treated Patients: Findings From ELSA-Brasil
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Context: The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. Objective: This work aimed to assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. Methods: The ELSA-Brasil study follows 15 105 adult Brazilians (aged 35-74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyrotropin (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. Results: Initiation of therapy with LT4 resulted in an 11% to 19% decrease in TSH, an approximately 19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in ∼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and antidiabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least 1 serum FT4 levels above the control reference range (>1.52 ng/dL), 38 participants (15.6%) had at least 1 serum FT3 below the reference range (<0.23 ng/dL). Conclusion: The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.
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Hypothyroidism can exacerbate cardiovascular risk factors (such as dyslipidemia) by increasing cholesterol levels, particularly low-density lipoprotein cholesterol.
“Hypothyroidismcanexacerbatecardiovascularriskfactors(such as dyslipidemia) by increasing cholesterol levels, particularly lowdensity lipoprotein cholesterol, and is associated with diastolic hypertension, increasing the likelihood of cardiovascular disease, particularly in patients with diabetes. 45,46”
From Hypothyroidism: A Review (2025) · cites this paper as [45]
The Discussion reports elevated serum cholesterol in other studies of levothyroxine-treated patients, supporting a link with cholesterol but not the claim about untreated hypothyroidism or LDL specifically. In this study, LDL decreased after treatment (117 to 114 mg/dL), while total cholesterol did not change significantly (Thyroid Hormone Levels Before and After Therapy With Levothyroxine; Table 2). (LLM, conf=0.86)
Experimental — accuracy not yet measuredTreatment with L-T4 that normalizes TSH levels also results in an upshift in the serum free T4 (FT4) levels and a downshift in the serum T3 levels.
“Notably, treatment with L-T4 that normalizes TSH levels also results in an upshift in the serum free T4 (FT4) levels and a downshift in the serum T3 levels.”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [41]
Approximately 47% of patients had at least 1 serum FT4 level above the control reference range (>1.52 ng/dL) and 15.6% had at least 1 serum FT3 below the reference range (<0.23 ng/dL).
“This is so dramatic that approximately 47% of patients had at least 1 serum FT4 levels above the control reference range (>1.52 ng/dL) and 15.6% had at least 1 serum FT3 below the reference range (<0.23 ng/dL) (41).”
From Treatment Preferences in Patients With Hypothyroidism (2025) · cites this paper as [41]
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References 42 · Cited by 16
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- Authors
- Penna, G. C., Bensenor, I. M., Bianco, A. C., & Ettleson, M. D.
- Affiliations
- Universidade Federal de Minas Gerais (BR)
- Center for Clinical and Epidemiological Research, Hospital Universitário, Universidade de São Paulo , São Paulo, 05508-220 , Brazil
- University of Chicago (US)
- Corresponding author
- Ettleson, Matthew D
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2024-03-20
- Volume
- 109
- Issue
- 10
- Pages
- 2504-2512
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC11403308
- OpenAlex
- W4393055243
- Cited by
- 16
- References
- 42
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 2
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK58538, DK65066, DK77148)
- Diabetes Research and Training Center
- University of Chicago (DK020595)
- Brazilian Ministry of Health (01060010.00RS, 01060212.00BA, 01060300.00ES, 01060278.00MG, 01060115.00SP, 01060071.00RJ)
- Brazilian National Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- levothyroxine, thyroid hormone homeostasis, hypothyroidism, free thyroxine, free triiodothyronine, thyroid-stimulating hormone, hyperthyroidism, triglycerides, antidiabetic medication use, ELSA-Brasil
- MeSH terms
- Adult, Aged, Brazil, Female, Homeostasis, Humans, Hypothyroidism, Longitudinal Studies, Male, Middle Aged, Thyroid Function Tests, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine, Hormone Replacement Therapy
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