Levothyroxine Dose Tweaks Don't Alter Symptoms in Hypothyroidism

Nancy A Melville

October 25, 2017

VICTORIA, British Columbia — Alterations of thyroid hormone levels through levothyroxine dose adjustments to lower and higher levels within normal reference ranges and even to subclinical hypothyroid levels show no significant effects on quality-of-life, mood, and cognitive-function measures in a double-blind, randomized study.

"Clinicians should set reasonable expectations for hypothyroid patients who request increased levothyroxine doses based on nonspecific quality of life, mood, or cognitive symptoms," senior author Mary H Samuels, MD, of the department of endocrinology, diabetes, and clinical nutrition, Oregon Health & Science University, Portland, told Medscape Medical News.

"These symptoms are unlikely to be related to levothyroxine doses and may not improve when doses are changed," she stressed.

Dr Samuels presented the findings here at the 2017 Annual Meeting of the American Thyroid Association.

Subjective Reporting of Symptoms in Mild Hypothyroidism

Whereas overt hypothyroidism is known to have effects on mood and cognitive function, including attention, memory, and executive function, the neurocognitive effects of variations of thyroid function within the normal range and with subclinical hypothyroidism are less clear, Dr Samuels explained.

The subjective reporting of symptoms in milder hypothyroidism can meanwhile make appropriate treatment a challenge.

"In the absence of conclusive data, many patients with mild hypothyroidism are started on levothyroxine to treat nonspecific quality of life, mood, or cognitive symptoms, and many additional levothyroxine-treated hypothyroid patients request increased…doses due to persistence of these symptoms," she said.

In an effort to more objectively identify the effects of mild variations of thyroid function, Dr Samuels and colleagues enrolled 138 subjects with hypothyroidism treated with levothyroxine to normal thyroid-stimulating hormone (TSH) levels.

Patients had stable levothyroxine doses for at least 3 months prior to the study and were switched to branded levothyroxine if taking a generic formulation to maintain consistency in the study.

The patients, who were 90% female, were randomized to receive their usual levothyroxine dose or a higher or lower dose in a double-blind fashion, targeting one of three TSH levels: low normal (2.5 to 0.34 mU/L; n = 46), high normal (2.51 to 5.6 mU/L; n = 47) or mild hypothyroidism (5.61 to 12.00 mU/L; n = 45), with adjustments every 6 weeks, if needed.

No Significant Differences in Symptoms Between Groups

Surprisingly, assessments after 6 months in a wide variety of measures of mood, quality of life, and cognition showed no significant differences between the three groups, with only a few minor exceptions.

The quality-of-life and mood measures included the SF-36 health survey, the Underactive Thyroid Dependent Quality of Life Questionnaire, and the Profile of Mood States, as well as measures of cognitive function.

The few minor exceptions in differences included the SF-36 bodily pain, which was best in the high-normal TSH group (P = .04), but there were no clinically meaningful effects in any outcomes, the authors reported.

Furthermore, subjects reported preference of levothyroxine doses that they perceived to be higher but were not actually higher (P < .001); meanwhile, preference was not evident when the doses actually were higher.

"Most subjects prefer levothyroxine doses they perceive to be higher, despite lack of objective benefit," Dr Samuels said.

In addition to relatively small sample sizes, limitations of the study included the fact that most of the subjects were women and were relatively young (average ages 48 to 51).

While the subjects were not prescreened for free-triiodothyronine (T3) levels as an inclusion/exclusion criterion, those levels were measured at baseline and at the end of the study in all subjects, Dr Samuels noted.

"We conducted an ancillary analysis of our outcomes using free T3 levels as a continuous variable and did not find any meaningful correlations between free T3 levels and any of the outcomes."

First Placebo-Controlled, Blinded Study Moves the Field Forward

In response to audience suggestions of various other factors that could play a role in symptoms, she agreed, "There's no question there could be a myriad of unmeasured variables.

"Further research in older subjects, men, and subjects with specific symptomatology, low T3 levels, and/or functional polymorphisms would be valuable," she added noting that this new study nevertheless importantly moves the field forward by providing a look at the issue in a randomized group.

"This is the first placebo-controlled, blinded study to show that altering levothyroxine doses in hypothyroid patients does not affect quality of life, mood, or cognitive function using extensive and sensitive measures of these outcomes, which are all common symptoms in treated hypothyroid patients," she stressed.

Catherine A Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, in New Haven, Connecticut, who comoderated the session, agreed that the study sheds important light on responses to levothyroxine doses.

"I think these are interesting data because there is this sense among patients that the levothyroxine dose really affects how they feel," she said.

 "This essentially turns that on its head and [suggests] it's not really clear why patients are potentially not doing well. I think it will be interesting to see more data on this."

The authors and Dr Dinauer had no relevant financial relationships.

2017 Annual Meeting of the American Thyroid Association. October 20, 2017; Vancouver, British Columbia. Abstract 21.

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