Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects

Thyroid. 2016 Sep;26(9):1173-84. doi: 10.1089/thy.2016.0141. Epub 2016 Jul 25.


Background: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function.

Methods: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions.

Results: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels.

Conclusions: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.

Trial registration: ClinicalTrials.gov NCT00565864.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Affect / physiology*
  • Cognition / physiology*
  • Cross-Sectional Studies
  • Executive Function / physiology
  • Female
  • Health Status
  • Hormone Replacement Therapy
  • Humans
  • Hypothyroidism / blood
  • Hypothyroidism / drug therapy
  • Hypothyroidism / psychology*
  • Male
  • Memory / physiology
  • Neuropsychological Tests
  • Reference Values
  • Thyroid Function Tests
  • Thyroid Gland / physiopathology*
  • Thyrotropin / blood
  • Thyroxine / blood
  • Thyroxine / therapeutic use*
  • Triiodothyronine / blood


  • Triiodothyronine
  • Thyrotropin
  • Thyroxine

Associated data

  • ClinicalTrials.gov/NCT00565864