Objective: To determine whether subclinical hypothyroidism causes decrements in health status, mood, and/or cognitive function.

Design: Double-blinded, randomized, cross-over study of usual dose L-thyroxine (L-T4) (euthyroid arm) vs. lower dose L-T4 (subclinical hypothyroid arm) in hypothyroid subjects.

Patients: Nineteen subjects on L-T4 therapy for primary hypothyroidism.

Measurements: Subjects underwent measurements of health status, mood, and cognition using validated instruments: Short Form 36 (SF-36), Profile of Mood States (POMS), and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, Digit Span Backwards), and motor learning (Pursuit Rotor). The same measures were repeated after 12 weeks on each of the study arms.

Results: Mean TSH levels increased to17 mU/L on the subclinical hypothyroid arm (p < .0001). Mean free T4 and free T3 levels remained within the normal range. The POMS fatigue subscale and SF-36 general health subscale were slightly worse during the subclinical hypothyroid arm. Measures of working memory (N-Back, Subject Ordered Pointing) were worse during the subclinical hypothyroid arm. These differences did not depend on mood or health status, but were related to changes in free T4 or free T3 levels. There were no decrements in declarative memory or motor learning.

Conclusions: We found mild decrements in health status and mood in L-T4 treated hypothyroid subjects when subclinical hypothyroidism was induced in a blinded, randomized fashion. More importantly, there were independent decrements in working memory, which suggests that subclinical hypothyroidism specifically impacts brain areas responsible for working memory.