Axis components
HPT axis: Hypothalamus → Pituitary → Thyroid → Peripheral tissues. The thyroid axis differs from HPG and HPA in having a critical fourth step, peripheral conversion of inactive T4 to active T3.
TRH and TSH
Thyrotropin-releasing hormone (TRH) from hypothalamus stimulates TSH (thyroid-stimulating hormone) release from anterior pituitary. TSH circulates to thyroid and stimulates production of thyroxine (T4) and small amounts of triiodothyronine (T3).
TSH is the most-tested marker because it reflects the pituitary's reading of circulating T4 levels. High TSH = pituitary thinks T4 is low (hypothyroid). Low TSH = pituitary thinks T4 is high (hyperthyroid).
T4 production
The thyroid produces mostly T4 (~80%) and small amounts of T3 (~20%). T4 has 4 iodine atoms; T3 has 3. T3 is roughly 4× more biologically active than T4. T4 is mostly a circulating reservoir that gets converted to T3 in peripheral tissues.
Peripheral conversion
This is the critical step often overlooked. T4 → T3 conversion happens in liver, kidney, muscle, brain, and other tissues. The conversion uses deiodinase enzymes that remove one iodine atom.
Conversion can fail. T4 can be normal, TSH can be normal, but tissue T3 can be inadequate if conversion is impaired.
The deiodinases
Three deiodinase enzymes:
- D1, primarily liver, kidney; T4 → T3
- D2, primarily brain, pituitary, brown fat; T4 → T3 (the major active conversion)
- D3, placenta, brain; T4 → reverse T3 (the inactive form)
The balance between D2 (active conversion) and D3 (inactive conversion) determines tissue T3 availability. Stress, illness, inflammation, and chronic disease shift the balance toward D3, producing reverse T3 instead of active T3.
Reverse T3
Reverse T3 is structurally similar to T3 but biologically inactive. Elevated reverse T3 indicates the body is "putting on the brakes" on thyroid signaling, appropriate in acute illness, problematic in chronic stress.
The free T3 / reverse T3 ratio is sometimes used to assess conversion status. Low ratio suggests poor conversion despite adequate T4.
Why TSH alone misses problems
TSH-only testing misses:
- Patients with central hypothyroidism (pituitary problem; both T4 and TSH low)
- Patients with conversion failure (T4 normal, T3 low, TSH may be normal)
- Patients with elevated reverse T3
- Patients with thyroid antibodies and early autoimmune disease (Hashimoto's) before TSH abnormalities develop
- Patients with low-T3 syndrome from chronic stress or illness
Comprehensive thyroid testing
Full thyroid panel:
- TSH
- Free T4
- Free T3
- Reverse T3
- Thyroid antibodies (TPO, thyroglobulin)
- Iodine status (sometimes)
- Selenium adequacy (cofactor for deiodinases)
OPTML's hormone panels include comprehensive thyroid assessment.
The clinical pearl: Many patients have been told their thyroid is fine because TSH is normal, when full thyroid testing reveals low free T3 or elevated reverse T3 indicating conversion problems. Comprehensive thyroid testing should be standard for patients with thyroid-like symptoms.
Bottom line
The HPT axis includes peripheral T4-to-T3 conversion as a critical fourth step. TSH alone reflects pituitary feedback but misses conversion problems. Comprehensive thyroid testing (TSH + free T4 + free T3 + rT3 + antibodies) reveals patterns invisible to TSH alone.