The Endocrine Society

The Endocrine Society

Perspective from Megan R. Haymart, MD

Cappola AR. The unhappy thyroid patient: Is there a medical solution? Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).

Disclosures: Cappola reports no relevant financial disclosures.
March 21, 2021
3 min read

The ‘unhappy thyroid patient’: Listen, ask questions, consider medication changes

Perspective from Megan R. Haymart, MD

Cappola AR. The unhappy thyroid patient: Is there a medical solution? Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).

Disclosures: Cappola reports no relevant financial disclosures.
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A subset of patients with hypothyroidism report dissatisfaction with treatment and persistent symptoms, such as fatigue and weight gain, despite medication, but there are steps endocrinologists can take to help, according to a speaker.

Population-based surveys suggest that adults prescribed levothyroxine report substantial impairment in psychological well-being compared with age- and sex-matched controls, even in the setting of a normal thyroid-stimulating hormone level, Anne R. Cappola, MD, ScM, professor of medicine in the division of diabetes, endocrinology and metabolism and director of the Center for Human Phenomic Science at the Perelman School of Medicine at the University of Pennsylvania, said during a virtual presentation at the ENDO annual meeting. In addition, in a study published in 2018 in Thyroid that surveyed more than 11,000 patients treated with levothyroxine, desiccated thyroid extracts or combination levothyroxine and liothyronine therapy, 54% of respondents reported changing physicians more than twice because of dissatisfaction with treatment.

Thyroid ultrasound female 2019
Source: Adobe Stock

“It does look like there is a trend of unhappiness in patients who are hypothyroid and treated with levothyroxine,” Cappola said during the presentation. “But it is important to note that there is a background group in the general population that are also unhappy. What we need to try and focus on is what is this specific component of the unhappiness, if there is one?”

Effects of altering dose

As Healio previously reported, three large professional thyroid organizations recently issued a joint statement calling for new trials of combination therapy to treat hypothyroidism, citing new clinical endpoints and the importance of assessing patient-reported outcomes. The statement noted that endocrinologists are frequently asked to consult on adult patients with hypothyroidism prescribed levothyroxine who are dissatisfied with their therapy; however, use of combination therapy with levothyroxine and liothyronine remains “highly controversial,” in part due to conflicting results from clinical trials.

Anne R. Cappola

Cappola said several factors could explain why a person with hypothyroidism does not feel well when prescribed medication, including other autoimmune diseases; health habits such as sleep, exercise and nutrition; and a levothyroxine dose that is not optimal, leading to an inadequate TSH level.

In a study published in The Journal of Clinical Endocrinology & Metabolism in 2018, researchers assessed whether variations in thyroid function within and near the reference range affect quality of life, mood and cognition for 138 adults with levothyroxine-treated hypothyroidism randomly assigned an unchanged, higher or lower levothyroxine dose in double-blind fashion. Altering the levothyroxine doses did not affect quality of life; however, participants preferred perceived higher levothyroxine doses, despite a lack of objective benefit.

“People who thought they were taking higher doses of levothyroxine felt better, and that is an important effect as well, this idea of placebo control in patient perceptions, that higher doses are going to make them feel better,” Cappola said.

Listen to patients

If a person with hypothyroidism treated with levothyroxine reports continued symptoms, it is important for the clinician not to alienate the patient, Cappola said.

“They are looking for help, and our duty as physicians is to listen first and foremost and be doctors and try to find out what is going on,” Cappola said. “I probe them most deeply on the primary symptom. I also ask about the associated ones, but I try to see, is there something else going on that is not related to the thyroid?”

Cappola said clinicians should ask their patients about life stressors — sleep, diet, exercise — and screen anyone reporting persistent symptoms for depression.

“Depression is common; thyroid disease is common,” Cappola said. “I would hate to miss treating someone for depression because they were focused on their thyroid disease.”

Cappola also recommended educating patients about what thyroid testing means, what synthetic vs. natural thyroid hormone is, and the pros and cons of each.

“They want a discussion, and they appreciate learning what all this means because it is confusing,” Cappola said.

Despite what data show, Cappola said she will tweak doses of thyroid medication for select patients who do not feel well.

“It may well be a placebo effect, but it is a placebo effect that I am comfortable with,” Cappola said. “I will often say let us optimize what is going on with this therapy before we look at alternatives. There are cases where I do add 5 mcg to 10 mcg of [liothyronine], reducing [levothyroxine] by 25 mcg. But I do not do this on the first visit, and I do not do it very often, and if they do not feel better [after], I stop it.

“This is a very challenging patient population, but it is a subset of a larger group of people,” Cappola said. “We need to try and be their doctors, try to help them and not medicalize it as a first resort.”

Editor's note: This article was updated on March 22, 2021, to correct the units of liothyronine and levothyroxine.


Peterson SJ, et al. Thyroid. 2018; doi:10.1089/thy.2017.0681.

Samuels MH, et al. J Clin Endocrinol Metab. 2018; doi:10.1210/jc.2017-02668.