Hypothyroidism Symptoms Linger Despite Medication and Normal Test Results

The ideal therapeutic goal in hypothyroidism would be to restore clinical and biochemical euthyroidism via physiologic thyroid hormone replacement.

For the last four decades, the standard approach for thyroid hormone replacement in hypothyroidism has been administration of levothyroxine (LT4) at doses that normalize the serum thyroid-stimulating hormone (TSH). The dogma in clinical thyroidology is that LT4 monotherapy at doses that normalize serum TSH is sufficient to restore euthyroidism.


Scientists at the Rush University Medical Center (Chicago, IL, USA) identified 469 adults who were taking levothyroxine monotherapy and compared them to 469 individuals who were not on levothyroxine. Both groups were matched for age, sex, race, and serum TSH levels. Peripheral tissues produce most of the circulating active form of thyroid hormone, triiodothyronine (T3), via conversion from thyroxine (T4). The eligible population was restricted to individuals18 years of age or older who had serum TSH, free T3, total T3, freeT4 and total T4 measured during the study period.

Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to ~15–20% lower serum T3:T4 ratios in LT4 treatment. In comparison to matched controls, LT4-treated participants: had higher body mass index (BMI) despite report of consuming less calories/day/kg; were more likely to be taking beta-blockers, statins, and anti-depressants; and reported lower total metabolic equivalents.

A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum high-density lipoproteins (HDL) and lower serum lower- density lipoproteins (LDL), triglycerides, and C-reactive protein (CRP). Age was associated with serum free T3: free T4 ratio in all participants; caloric intake was associated in LT4-treated individuals.

Sarah Peterson, PhD, the first author of the study, said, “We looked to see how 52 clinical measures differed between the two groups. Individuals taking levothyroxine weighed significantly more and moved less, they were also more likely to take antidepressants than those who were in the control group.” The study was published on October 4, 2016, in the Journal of Clinical Endocrinology and Metabolism.

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Rush University Medical Center