Thyroid Stimulating Hormone (TSH)

Thyroid stimulating hormone is a glycoprotein secreted by the anterior pituitary under the control of thyrotropin releasing hormone and negative feedback from free T4 and T3. Because the log of TSH changes inversely with free T4, a small change in thyroid hormone causes a large change in TSH, and it is the most sensitive first line test of thyroid function.

It is measured by third generation immunometric assays with functional sensitivity under 0.01 mIU/L. A single TSH is the screening and monitoring test in most primary thyroid disease, and free T4 (and sometimes free T3) is added when TSH is abnormal or when pituitary disease is suspected.

Overt hypothyroidism affects 0.3 to 1% of adults, and subclinical hypothyroidism 4 to 10%, rising to over 20% in women older than 60 years. Hyperthyroidism affects 0.5 to 2% of adults (more in iodine deficient regions), and subclinical hyperthyroidism 0.5 to 2%. Thyroid disease is 5 to 10 times more frequent in women. TSH is also used in pregnancy, infant screening, thyroid cancer suppression therapy and amiodarone monitoring.

Indications. Suspected hypothyroidism or hyperthyroidism (fatigue, weight change, palpitations, heat or cold intolerance, goitre, menstrual disturbance, constipation, atrial fibrillation, hypercholesterolaemia, depression, subfertility). Screening in high risk groups (autoimmune disease, family history, goitre, previous thyroid surgery or radioiodine, amiodarone, lithium, immune checkpoint inhibitors). Monitoring levothyroxine therapy and antithyroid drug therapy. Pregnancy and planning pregnancy. Newborn screening. Follow up of thyroid cancer.

Specimen. Serum 1 mL (or plasma), no fasting. Stable for several days at 2 to 8 °C. TSH has a circadian rhythm with a night time peak (about 50% higher between 22:00 and 04:00) and a nadir in the afternoon, so for monitoring, samples are taken at a consistent time. In patients on levothyroxine, a sample before the morning dose is advised, although timing makes a small difference.

Reference interval (adults, assay dependent). 0.4 to 4.0 mIU/L (some laboratories 0.27 to 4.2). The upper limit rises with age (up to 6 to 7 mIU/L in people over 80 years). Pregnancy: first trimester 0.1 to 2.5 mIU/L, second 0.2 to 3.0, third 0.3 to 3.0 (trimester specific local ranges are preferred). Neonates: peak 25 to 60 mIU/L at birth, falling to under 10 mIU/L by day 5.

Interpretation with free T4 (and free T3).

Thresholds.

• TSH over 10 mIU/L: significant hypothyroidism in most, with levothyroxine given.
• TSH 4 to 10 mIU/L with a normal free T4 (subclinical): repeat in 6 to 12 weeks, treatment considered with symptoms, positive anti-thyroid peroxidase antibodies, goitre, pregnancy or planned pregnancy, infertility, hyperlipidaemia, heart failure or age under 70 years. Many cases normalise on repeat testing.
• TSH under 0.1 mIU/L with normal free T4 and T3: subclinical hyperthyroidism with higher risk of atrial fibrillation, osteoporosis and cardiovascular events, so treatment is considered especially over 65 years. TSH 0.1 to 0.4 mIU/L has less risk, and is observed.
• Levothyroxine monitoring: target TSH within the reference range, usually 0.5 to 2.5 mIU/L. After dose change, TSH is rechecked at 6 to 8 weeks.
• Antithyroid drug therapy: TSH lags behind free T4 recovery by 4 to 6 weeks (or months), so free T4 and T3 are used to adjust dosing in the early phase.
• Thyroid cancer follow up: TSH suppressed (under 0.1 mIU/L in high risk disease, 0.1 to 0.5 mIU/L in lower risk) with levothyroxine, and TSH stimulation before radioiodine or thyroglobulin testing.

Pregnancy. Overt hypothyroidism is treated. Subclinical hypothyroidism with positive anti-thyroid peroxidase antibodies or TSH over 4 (or the upper limit of local trimester specific range) is treated to reduce miscarriage and preterm birth risk. Levothyroxine dose is typically increased by 25 to 30% on confirmation of pregnancy.

Critical values and findings needing immediate action.

• TSH over 50 mIU/L with low free T4 and hypothermia, bradycardia, hypotension, hyponatraemia or reduced consciousness: myxoedema coma, a medical emergency needing intravenous levothyroxine and hydrocortisone.
• TSH under 0.01 mIU/L with fever, tachycardia over 140/min, agitation, delirium or heart failure: thyroid storm, needing urgent treatment with beta blockade, antithyroid drugs, iodine and steroids.
• Newborn TSH over the screening cut off (usually over 20 to 40 mIU/L on a blood spot): congenital hypothyroidism, with confirmatory serum tests and treatment started within 2 weeks of birth to protect development.
• Pregnant woman with TSH over 10 mIU/L: immediate treatment.
• Atrial fibrillation with suppressed TSH: assessment for hyperthyroidism and anticoagulation.

Interferences and pitfalls.

• Non-thyroidal illness: TSH may fall transiently in severe illness and rise to 5 to 20 mIU/L during recovery, so thyroid function is deferred until the patient is well unless thyroid disease is strongly suspected.
• Drugs: glucocorticoids, dopamine, dobutamine, octreotide and bexarotene suppress TSH. Amiodarone, lithium, iodine, immune checkpoint inhibitors and interferon alter it. Metoclopramide and domperidone raise it.
• Biotin supplements (over 5 mg a day) interfere with streptavidin biotin immunoassays, causing falsely low TSH and falsely high free T4 (mimicking hyperthyroidism), and should be stopped for 2 days before testing.
• Heterophile antibodies and macro-TSH cause falsely high TSH.
• Central hypothyroidism: TSH is low, normal or mildly raised with low free T4, and TSH alone misses it. Free T4 is the test when pituitary disease is suspected.
• TSH-secreting adenoma and thyroid hormone resistance give inappropriately normal or high TSH with high free T4.
• Recovery from hyperthyroidism or thyroiditis: TSH may remain suppressed for weeks to months after free T4 normalises.
• Levothyroxine absorption is reduced by calcium, iron, proton pump inhibitors and coffee, and adherence and timing are checked when TSH is high on treatment.
• Assay differences: reference intervals are method dependent.

Special groups.

• Pregnancy: trimester specific ranges, since human chorionic gonadotrophin lowers TSH in the first trimester.
• Neonates and children: age specific ranges, with TSH falling over childhood to the adult range by adolescence.
• Older adults: higher TSH is normal for age, and treatment of mild elevation (under 10 mIU/L) is usually not indicated over 70 to 80 years.
• Women with infertility or recurrent miscarriage: TSH target under 2.5 mIU/L is used by many units.
• Regions: iodine deficiency causes high TSH and goitre, and iodine excess or amiodarone use alters function.

Follow up tests. Free T4 and free T3, anti-thyroid peroxidase and anti-thyroglobulin antibodies, TSH receptor antibodies, thyroid ultrasound, radioiodine uptake scan, thyroglobulin, lipid profile, creatine kinase, full blood count, other pituitary hormones (cortisol, prolactin) when central disease is suspected, and pituitary MRI.