Hypothyroidism Often Unrelieved by Levothyroxine and Normal TSH


levothyroxine treatment for hypothyroidism may not resolve all symptoms

For more than 40 years, the conventional way to treat hypothyroidism has been to provide the thyroid hormone replacement drug levothyroxine (i.e., Synthroid, Levoxyl); with the goal of ensuring that the TSH level falls within the reference range. This has been considered full treatment for the condition.

The theory behind this conventional treatment approach is that treatment with levothyroxine—a synthetic form of the thyroxine (T4) hormone produced by the thyroid gland—will provide enough T4, restore one to normal thyroid function—known as euthyroidism—and resolve all thyroid-related symptoms.

Many leading practitioners, including prominent endocrinologist Dr. Anthony Weetman, have even stated that patients who have “normal thyroid function tests” but insist they should be treated for multiple thyroid symptoms or who have continuing symptoms actually have “somatoform disorders.” (Somatoform disorders are defined in medical dictionaries as “psychological disorders marked by physical complaints, for which no organic or physiological explanation is found and for which there is a strong likelihood that psychological factors are involved.”)

A normal thyroid gland produces several key hormones, including the storage hormone thyroxine (T4) and the active hormone triiodothyronine (T3). The majority of hormone produced by the gland is T4, but T4 must be converted in the body into the active T3 hormone in order for it to have an impact on your body.  The strong and prevailing dogma is that hypothyroidism should be treated only with levothyroxine–sometimes referred to as LT4 monotherapy or levothyroxine monotherapy–at doses that result in your being euthyroid, with your TSH levels falling within the reference range.

This dogma claims when there is enough T4, the body will always make enough T3.

Despite the predominance of this belief in conventional medicine, for several decades some thyroid patients have become increasingly vocal about levothyroxine’s limitations in resolving their symptoms. Researchers conservatively estimate that 15% of patients continue to experience troublesome hypothyroidism symptoms despite levothyroxine treatment.

Surveys of thyroid patients suggest that the number is much higher.

The Research Findings

To explore whether restoring the TSH level to the reference range using levothyroxine was effective, researchers at Rush University Medical Center in Chicago did a study comparing a control group of people who were healthy, with no evidence of thyroid disease, versus a group of people who were being treated with levothyroxine for hypothyroidism. The results were reported on in the October 2016 issue of the Journal of Clinical Endocrinology and Metabolism.

The results were quite surprising. The research found that:

  • The levothyroxine-treated group had 20 percent higher TSH levels, 10 percent lower free T3 levels, and 15% lower total T3 levels when compared to the control group.
  • The levothyroxine-treated group had a higher body mass index, even though they reported eating fewer calories per day. They weighed about 10 pounds more, despite ingesting slightly fewer calories per day.
  • The levothyroxine-treated group was 1.6 times more likely to be taking beta-blockers, which are most often used to treat elevated blood pressure.
  • The levothyroxine-treated group was 1.5 times more likely to be taking statin drugs, used to treat elevated cholesterol.
  • The levothyroxine-treated group was 1.46 times more likely to be taking antidepressants.
  • The levothyroxine-treated group reported being far less active physically than the control group.
  • The levothyroxine-treated group self-reported more days in the previous month where they felt their physical and mental health were “not good.”

The Theories

The researchers said that they have two theories as to why–despite being euthyroid with TSH levels in the reference range—the levothyroxine-treated group was not as healthy as measured by a number of parameters, and why the levothyroxine themselves reported that they didn’t feel well far more often than the control group.

  • One theory is that despite a normal TSH level, the levels of T3–the active hormone–might not be fully normalized, because T4 is not sufficiently converting into T3.
  • A second theory suggests that the levels of T3 that actually reach the cells may not be reflected by the TSH or T4 blood test levels, due to the actions of deiodinases, which play a role in the T4-to-T3 conversion process.

The researchers concluded the journal article with the following quote:

The concept that establishing a normal serum TSH renders individuals on (levothyroxine) monotherapy clinically euthyroid should be revisited and quality of life measures should be more highly prioritized in hypothyroidism research and professional guidelines.

Additional Insight From Study Author Antonio Bianco, MD

One of the study’s authors, Antonio Bianco, MD, immediate past president of the American Thyroid Association, and a professor at Rush University, gave an interview to MedicalResearch.com. In that interview, he explained the study further:

At face value the present study indicates that the normalization of TSH levels in hypothyroid patients might not be as useful as once thought to monitor treatment. Despite normal TSH levels, patients are at a significant higher risk of developing depression and a metabolic dysfunction characterized by increased body weight and high cholesterol levels…We have been saying that by normalizing blood levels of TSH all symptoms associated with hypothyroidism should go away. This probably needs to change.

In a press release about the study, issued by Rush University Medical Center where the research was conducted, Dr. Bianco also said:

While the therapeutic goal is to make patients feel better, symptoms alone are not utilized for judging adequacy of treatment. Blood TSH levels are. In other words, the dose of levothyroxine is adjusted based on the TSH levels and not whether or not the patient feels better…The important thing to understand is that T4 is not the active hormone. T4 must be converted to T3 by our bodies with an enzyme called deiodinase.

Patients complain of being depressed, slow and having a foggy mind. They have difficulty losing weight. They complain of feeling sluggish and have less energy. Yet we doctors keep telling them, “I’m giving you the right amount of medication and your TSH is normal. You should feel fine.”

These findings correlate with what patients have been telling us. This study documents for the first time, in an unbiased fashion, that patients on levothyroxine feel worse and are much less active than controls, exhibiting objective cardiometabolic abnormalities despite having normal TSH levels.

Dr. Bianco is one of the leaders in the movement to research whether genetic defects in some patients may impair the function of deiodinase and impair T4-to-T3 conversion, as well as whether the addition of T3 to levothyroxine monotherapy may result in better resolution of symptoms, patient quality of life, and improved health parameters for some people being treated for hypothyroidism.

Dr. Bianco has publicly stated that he believes that better medications are needed to treat hypothyroidism. In the meantime, he recommends that physicians depart from the traditional, “easy to treat, take this pill and you’ll be fine” approach to treatment, and instead, take a different approach when counseling patients about hypothyroidism treatment. According to Dr. Bianco:

Doctors should be telling their patients, “I’m going to normalize your TSH, but you’re going to be at a higher risk for gaining weight, experiencing depression and fatigue. It is also more likely that your cholesterol will go up.” That’s what we should be telling patients, based on our study.

What This Research Means for You

For two decades, patient advocates and some practitioners have been saying that levothyroxine monotherapy should not be the only option. While it works for some people with hypothyroidism, a significant subset of patients still do not feel well, despite being treated with levothyroxine, and being deemed euthyroid with “normal” TSH levels, according to blood tests.

Dr. Bianco’s commitment to researching and developing evidence regarding the potential need for T4/T3 combination therapy in a subset of hypothyroid patients is both promising and notable.  And yes, as Dr. Bianco has said, better medications are needed to treat hypothyroidism.

In the meantime, however, there is an option for patients that Dr. Bianco is not publicly advocating. You can have your Free T3 tested, and if it is low or not optimal, you can work with a practitioner who will either add a T3 drug—​such as Cytomel (liothyronine), or a compounded, prescription, time-released T3 drug–to your treatment, or who will prescribe a natural desiccated thyroid drug such as Nature-throid or Armour Thyroid for you.


Interview with Antonio Bianco, MD. MedicalResearch.com. October, 14, 2016.

Rush University Medical Center. Press Release: Hypothyroidism symptoms linger despite medication use, normal blood tests. October 12, 2016. Science Daily.

Sarah J. Peterson, Elizabeth A. McAninch, Antonio C. Bianco. Is a Normal TSH Synonymous with “Euthyroidism” in Levothyroxine Monotherapy? The Journal of Clinical Endocrinology & Metabolism, 2016; jc.2016-2660