Thyroid Biomarkers: TSH

Optimal Takeaways

TSH (thyroid stimulating hormone) is produced in the pituitary gland, but it influences the thyroid by regulating the production of thyroid hormones. Low levels of T4 or T3 stimulate the release of TSH, increasing thyroid hormone production. Low TSH is associated with hyperthyroidism, pituitary hypofunction, and certain medications. An elevated TSH is associated with hypothyroidism, thyroid inflammation, excess iodine, and chronic or severe illness.

Standard Range: 0.40 – 4.50 uU/mL

The ODX Range: 1.00 – 2.00 uU/mL      

Low TSH is associated with hyperthyroidism, pituitary hypofunction, secondary hypothyroidism due to pituitary dysfunction, use of certain drugs (e.g., steroids, aspirin, dopamine, heparin, T3) (Pagana 2021), and post-stroke fatigue following ischemic stroke (Wang 2018). Decreased TSH, even in subclinical hyperthyroidism, is associated with an increased risk of atrial fibrillation and increased CAD mortality (Yeap 2017).

High TSH is associated with primary hypothyroidism due to thyroid dysfunction, thyroiditis, excess iodine, congenital hypothyroidism, thyroid agenesis, TSH-secreting tumor, and chronic or severe illness. Drugs that can increase TSH include potassium iodide, lithium, and antithyroid medication (Pagana 2021).

Elevated TSH, even in subclinical hypothyroidism, is associated with an increased risk of stroke and CAD (Yeap 2017), and in overt hypothyroidism is associated with an increased risk of myocardial ischemia and infarction, arrhythmias (Corona 2021), endothelial dysfunction, atherosclerosis, and altered coagulability (Ning 2017).

A TSH above 2 uU/mL may be related to elevated cortisol (Walter 2012), increased 20-year risk of overt hypothyroidism, increased thyroid autoantibodies, heart disease risk, and hypercholesterolemia (Raymond 2021). Higher TSH may also be observed in breast cancer (Ali 2011).

Overview

Thyroid-stimulating hormone (TSH), also called thyrotropin, is produced by the pituitary when stimulated by thyroid-releasing hormone (TRH) from the hypothalamus. In primary hypothyroidism, low levels of thyroid hormones (T3 and T4) stimulate the production of both TRH and TSH to get the thyroid to produce more hormones, but it is unable to. In secondary hypothyroidism, where the hypothalamus does not produce TRH and the pituitary does not produce TSH, the thyroid is not stimulated to produce more hormones. Ultimately, the thyroid is at fault if T4 is low but TSH is elevated. If T4 and TSH are low, the pituitary is most likely at fault (Pagana 2021).

Thyroid function is essential to macronutrient metabolism, energy expenditure, and vascular integrity (Biondi 2013). Thyroid hormone insufficiency is directly associated with insulin resistance, dyslipidemia, diastolic dysfunction, diastolic hypertension, and endothelial dysfunction (Biondi 2019).

Over time the acceptable range for TSH has tightened, and emerging research suggests that an even narrower range may help identify metabolic issues and thyroid dysfunction early on. A 20-year follow-up study of 2,779 randomly chosen adults found that a TSH above 2 uU/mL (2 mIU/L) increased the likelihood of hypothyroidism. A twofold increase in TSH from 2.5 to 5 uU/mL increased the probability of hypothyroidism from 1 to 4%, a risk that increased if thyroid antibodies were present (Vanderpump 1995).

A more recent 5-year follow-up study of 3,018 individuals also observed that TSH above 2 uU/mL was a risk factor for subclinical hypothyroidism despite subjects having normal thyroid function at baseline. Researchers noted additional risk factors for hypothyroidism, including antithyroid antibodies and excess intake of iodine (Teng 2006).

Approximately 90-95% of healthy individuals maintain a serum TSH below 2.5 uU/mL, with the majority presenting with a TSH of 1.5 uU/mL. Researchers note that a TSH above 2.5 uU/mL is not physiologically optimal, and increased levels may be associated with increased severity of major depression. A study of 13,000 subjects found that a TSH above 2.3 uU/mL doubled the risk of depression in women. Additional research suggests that maintaining TSH below 2.5 uU/mL may be pivotal in controlling symptoms (Cohen 2017).

Additional consequences of a TSH above 2 uU/mL include an increased 20-year risk of overt hypothyroidism and increased thyroid autoantibodies. A TSH above 4 uU/mL can increase heart disease risk, while hypercholesterolemia with a TSH of 2-4 uU/mL responds favorably to thyroid hormone replacement (Raymond 2021).

A higher TSH may be associated with malignant versus benign thyroid nodules. One study of 615 patients with thyroid nodules observed that the risk of malignancy was three times higher in those with a TSH of 2.26 uU/mL or above. Those with benign nodules had a median TSH of 1.25–1.5 uU/mL (Golbert 2017).

A TSH within the conventional range has also been associated with cardiometabolic disorders. In a screening of 24,765 adults, compared to a reference group with a TSH of 0.47-1.48 uU/mL, those with TSH of 2.93 uU/mL and above had significantly increased body fat, central obesity, higher blood pressure, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, and elevated hs-CRP, fibrinogen, uric acid, HbA1C, HOMA-IR, and HOMA-B (Chang 2019).

A U-shaped association between TSH and risk of all-cause mortality was observed upon evaluating data from 9,020 participants in a series of NHANES studies. Researchers found that individuals with subclinical hypothyroidism and ‘high-normal” TSH between 1.96-5.6 mU/L had increased risk of cardiovascular disease and increased all-cause mortality. Unfortunately, the “high-normal” category was not broken down to further differentiate ranges in this evaluation. A “low-normal” TSH of 0.34-1.19 mU/L was also associated with increased risk of all-cause mortality. Those with a “middle-normal” TSH of 1.2-1.95 mU/L had the lowest risk of all-cause mortality (Inoue 2019).

References

Ali, Athar, et al. "Relationship between the levels of serum thyroid hormones and the risk of breast cancer." J Biol Agr Healthc 2 (2011): 56-60.

Biondi, Bernadette. “The normal TSH reference range: what has changed in the last decade?.” The Journal of clinical endocrinology and metabolism vol. 98,9 (2013): 3584-7. doi:10.1210/jc.2013-2760

Biondi, Bernadette, and David S Cooper. “Thyroid hormone therapy for hypothyroidism.” Endocrine vol. 66,1 (2019): 18-26. doi:10.1007/s12020-019-02023-7

Chang, Yi-Cheng et al. “High TSH Level within Normal Range Is Associated with Obesity, Dyslipidemia, Hypertension, Inflammation, Hypercoagulability, and the Metabolic Syndrome: A Novel Cardiometabolic Marker.” Journal of clinical medicine vol. 8,6 817. 7 Jun. 2019, doi:10.3390/jcm8060817

Cohen, Bruce M et al. “Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.” The American journal of psychiatry vol. 175,7 (2018): 598-604. doi:10.1176/appi.ajp.2017.17080949

Corona, G et al. “Thyroid and heart, a clinically relevant relationship.” Journal of endocrinological investigation vol. 44,12 (2021): 2535-2544. doi:10.1007/s40618-021-01590-9

Golbert, Lenara et al. “Serum TSH levels as a predictor of malignancy in thyroid nodules: A prospective study.” PloS one vol. 12,11 e0188123. 16 Nov. 2017, doi:10.1371/journal.pone.0188123

Inoue, Kosuke et al. “Association of Subclinical Hypothyroidism and Cardiovascular Disease With Mortality.” JAMA network open vol. 3,2 e1920745. 5 Feb. 2020, doi:10.1001/jamanetworkopen.2019.20745

Ning, Yu et al. “What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants.” BMC medicine vol. 15,1 21. 2 Feb. 2017, doi:10.1186/s12916-017-0777-9

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Raymond, Janice L., et al. Krause and Mahan's Food & the Nutrition Care Process. Elsevier, 2021.

Sheehan, Michael T. “Biochemical Testing of the Thyroid: TSH is the Best and, Oftentimes, Only Test Needed - A Review for Primary Care.” Clinical medicine & research vol. 14,2 (2016): 83-92. doi:10.3121/cmr.2016.1309

Subekti, Imam et al. “Serum TSH level as predictor of Graves' disease recurrence following antithyroid drug withdrawal: A systematic review.” PloS one vol. 16,1 e0245978. 29 Jan. 2021, doi:10.1371/journal.pone.0245978

Teng, Weiping et al. “Effect of iodine intake on thyroid diseases in China.” The New England journal of medicine vol. 354,26 (2006): 2783-93. doi:10.1056/NEJMoa054022 Vanderpump, M P et al. “The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey.” Clinical endocrinology vol. 43,1 (1995): 55-68. doi:10.1111/j.1365-2265.1995.tb01894.x

Wang, Jinjing et al. “Depressed TSH level as a predictor of poststroke fatigue in patients with acute ischemic stroke.” Neurology vol. 91,21 (2018): e1971-e1978. doi:10.1212/WNL.0000000000006534

Yeap, Bu B et al. “Reference Ranges for Thyroid-Stimulating Hormone and Free Thyroxine in Older Men: Results From the Health In Men Study.” The journals of gerontology. Series A, Biological sciences and medical sciences vol. 72,3 (2017): 444-449. doi:10.1093/gerona/glw132