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Study Reveals Why 1 in 6 Hypothyroid Patients Feels Bad on Levothyroxine Alone

Doctors often treat an underactive thyroid (hypothyroidism) with levothyroxine alone (T4). New research suggests some people also need T3.

What do you think the #3 most prescribed drug in America is? According to the last statistics we have seen, it is a generic drug for thyroid replacement called levothyroxine. Nearly 20 million people take this generic form of synthetic thyroid hormone. That doesn’t take into account the brand name Synthroid. Millions more opt for this brand of levothyroxine. Did you know that one of the most controversial and contentious issues in endocrinology has to do with the best treatment for hypothyroidism? Most doctors insist that standard treatment with levothyroxine alone (LT4, Levothroid, Levoxyl, Synthroid, Tirosint, Unithroid) is the answer to a sluggish or inactive thyroid gland.

They reject natural thyroid or supplementation with T3 (Cytomel or compounded slow-release products) as unnecessary or unreliable. Under pressure from patients and colleagues, however, some are beginning to shift their stance. Others, however, maintain that levothyroxine is vastly overprescribed and that most people taking this hormone don’t actually need it.

When Hyperthyroidism Leads to Hypothyroidism:

This reader went from an overactive thyroid gland to no thyroid gland:

Q. After two years of suffering, I was diagnosed with hyperthyroidism. To control the rapid heart rate and shaking, my doctor prescribed propranolol. I was also put on anti-thyroid medicines to try to get my thyroid hormone level under control.

When I had allergic reactions to those meds, my thyroid was surgically removed. Then I began a long, frustrating process of trying different doses of Synthroid. It turned out I am also allergic to Synthroid.

Finally, my doctor put me on natural thyroid extract. The first prescription was like a difference of night and day. Within a week, I began to feel much better.

Now, after a second dose adjustment, my thyroid hormone is nearly at the right level. My weight is starting to get back to normal, my head is clear, my anxiety is almost gone, my heart rate is nearly normal and my bones do not ache. This compounded medicine has saved my life and my sanity. Why don’t more doctors prescribe it?

A. Most endocrinologists are taught that synthetic levothyroxine (eg, Synthroid) is preferred over natural thyroid hormones. That’s because the dose can be controlled precisely.

But a functional thyroid gland produces two hormones, T4 and T3. Levothyroxine is T4 alone, whereas desiccated thyroid extract contains both T4 and T3. Some people report feeling healthier when they take both hormones. That may be due to a genetic difference in their ability to convert inactive T4 to T3, the active form.

You can learn more about natural thyroid as well as the diagnosis and treatment of both underactive and hyperactive thyroid glands in our eGuide to Thyroid Hormones. You will find this online resource under the Health eGuides tab.

Is TSH Testing Misleading?

A letter to the editor in the journal Clinical Chemistry (March 1, 2023) asserts that 90 percent of levothyroxine prescriptions are inappropriate. The author bases that argument on a study showing that TSH (thyroid-stimulating hormone) is highest in the winter and lower in summer. In effect, he argues that unless TSH levels are significantly elevated to around 10 mIU/L or higher, it makes no sense to treat people as hypothyroid.

We were delighted to see an acknowledgment that TSH can vary seasonally, as we have seen this pattern ourselves. We don’t agree that people with elevated TSH in the wintertime have no business taking levothyroxine, though. Our experience suggests that high TSH may correlate pretty closely with uncomfortable symptoms of hypothyroidism.

Many doctors use TSH as the primary measurement to diagnose and monitor treatment of hypothyroidism. Some endocrinologists are beginning to suspect that TSH alone may not be enough. Some people with TSH levels within the normal range while taking levothyroxine still do not feel good. Keep reading for a fuller explanation of why that may happen. Or listen to our interview with international thyroid expert Antonio Bianco. It is Show 1330: Rethinking Hypothyroidism.

Balancing Thyroid Hormones Was a Big Challenge:

Another surgical story:

Q. I had thyroid surgery to remove a goiter in 2005. Then I spent the next ten years in hell on levothyroxine only.

I was on a thyroid rollercoaster. When my thyroid levels were high, my symptoms included hypertension, anxiety, panic attacks and suicidal thoughts. If the level dropped too low, I had no energy, rapid weight gain, low body temperature, high cholesterol, heavy periods and terrible muscle cramps. The doctor said none of those symptoms had anything to do with my thyroid.

BULL! My body was out of balance from being on T4 only. Why would endocrinologists think we need only one thyroid hormone when our bodies make two? I started taking natural desiccated thyroid gland and I am finally getting my life back.

Why Doctors Prescribe Levothyroxine Alone:

A. Most doctors learned in medical school that the body converts levothyroxine (T4) to the active hormone triiodothyronine (T3). However, in the last several years, scientists have discovered that some people do this less efficiently than others. Their enzymes have a harder time knocking the extra iodine atom off T4 to turn it into T3.

Increasingly, leaders in the field recommend individualized treatment including T3 for people who don’t respond well to levothyroxine alone (Frontiers in Endocrinology, July 9, 2019).  Desiccated thyroid extract from pigs contains both hormones, although not in exactly the same proportions that healthy human thyroid glands produce.

Learn More:

You will find far more information on this research as well as many complementary treatments and considerations in our eGuide to Thyroid Hormones. You may also wish to listen to our interview with Dr. Antonio Bianco, an internationally recognized expert on treating thyroid disease. It is Show 1196: What to Do if Thyroid Treatment Doesn’t Work for You.

Why Levothyroxine Alone Might Not Be Adequate:

Many people with hypothyroidism (estimates range from 12 to 15 percent of patients or higher) complain of symptoms when they are treated with standard levothyroxine. Even when blood tests (TSH & TH) suggest that thyroid function is normalized, these individuals feel like crap. They complain of fatigue, impaired cognition or “foggy brain,” weight gain, and general malaise.

Until now, many endocrinologists and a lot of primary care physicians were inclined to chalk up such complaints as psychosomatic, ie, all in the head. They did not wish to contemplate a problem with the standard treatment regimen. That is starting to change. A splendid article published in one of the most cautious and respected medical journals in the world, the Annals of Internal Medicine, Jan. 5, 2016, offers a nuanced insight into patient management.

The article is titled “The History and Future of Treatment of Hypothyroidism.” You can access the full article for free at this link. The authors point out that 10% to 15% of patients treated with standard levothyroxine “monotherapy” are “dissatisfied as a result of residual symptoms of hypothyroidism, including neurocognitive impairment…” In other words, patients often complained of symptoms such as brain fog, confusion, fatigue or depression even after their lab tests appeared to be normalized.

Here is just one example from a visitor to our website:

“I have been on Synthroid for 40 years. Over the years, my problems have become worse. My TSH blood test comes back within the normal range, so the doctor prescribes my usual .125 mg Synthroid and sends me on my way.

“When I show him my swollen feet and legs and the stasis dermatitis now forming on my lower legs, he says, ‘You have venous insufficiency. Wear compression stockings and elevate your legs as much as possible.’

“When I had two separate incidents of depression and anxiety, I was prescribed the antidepressant Paxil. I took myself off that after one year when my legs swelled up even more than usual.

“I suffer from constipation, lack of energy and lower back pain and have not been able to lose weight for years. My muscles ache all the time and my feet hurt constantly when I walk very far.

“I ‘ll be 66 years old in a few weeks and I feel like I am 80. I read all the articles and am very aware of the foods I should and should not eat. All my doctor cares about is the TSH test, and as long as the result comes back within the normal range he is happy and assumes all is well with my thyroid.” K.H.

How Do We Get from T4 to T3?

To understand the complexity of thyroid supplementation, we need to take a quick detour into some basic biology. Don’t panic! We will do our best to make this understandable.

The thyroid gland makes a few hormones but we are only going to focus on two, T4 (thyroxine) and T3 (triiodothyronine). The numbers T4 and T3 represent the number of iodine atoms ( 4 and 3 respectively) attached to the basic hormone structure.

Thyroxine (T4) is a prohormone and is relatively inactive. It has to be converted to T3 by the body. An enzyme removes one of the iodine atoms to accomplish this. As much as 80% of T4 is converted to T3. T3 is three to five times more potent than T4. So the efficient conversion of T4 to T3 is critical, and levels of circulating “free” T3 are essential to well being.

The Discovery of Genetic Variation in Enzymes:

Okay, before your eyes glaze over, let’s get to the exciting research. A team of investigators led by endocrinologists at Rush University Medical Center (in Chicago, IL) has published studies in the Journal of Clinical Investigation (online, Jan 2, 2015) and the Journal of Clinical Endocrinology & Metabolism (online, Jan. 8, 2015).

Their animal research involved removing rat thyroid glands. When the scientists tried to normalize hormone levels with levothyroxine alone, they were unsuccessful. The animals demonstrated signs of hypothyroidism, especially within the brain, which might account for why some humans complain of cognitive dysfunction on T4 alone. The investigators were able to normalize circulating T3 levels and improve symptoms by supplementing T4 with extra T3.

Their human study uncovered genetic variability in patients suffering from hypothyroidism. They estimate that the mutation exists in 12% to 36% of the population. It makes it harder to convert T4 to T3. The scientists detected negative brain changes in patients that have difficulty making the T4 to T3 conversion. Such patients generally prefer a treatment regimen that involves both levothyroxine together with T3 supplementation (Journal of Clinical Endocrinology and Metabolism (May, 2009).

Old Beliefs Die Hard About Levothyroxine Alone:

A few generations of endocrinologists and primary care physicians learned that the only thing that matters when monitoring thyroid function in hypothyroid patients is TSH levels. And the only treatment needed is levothyroxine alone. Changing such entrenched beliefs is not easy. Although many patients do just fine with such an approach, there appear to be many others who do not. The overview in the Annals of Internal Medicine suggests that a more nuanced, personalized approach may be the wave of the future for people with hypothyroidism. Consensus is building among endocrinologists to support better research on combination therapy (Thyroid, Feb. 2021).

Patient Stories

Pat says:

“I had blood work done a few months ago for thyroid function. My primary care physician states that the test showed that my TSH was normal…12.9.

“I said, ‘what about the test for t3 and t4 levels?’ The doc stated that further testing wouldn’t be required if the TSH levels were in normal range. From what I have been reading, 12.9 seems to be a high normal. Is there some verification on what the normal range is for TSH?

” have been loosing hair, have dry skin, fatigue, and depression, which could also be attributed to the high blood pressure medication that I’ve been using (amlodipine), which I have titrated off of. My blood pressure is still high, (withdrawal symptoms or the rebound effect). My life is continual stress along with all the other work and effort to maintain a healthy lifestyle.”

Neil in the UK shared this:

“I’m a 55 year old man. I was diagnosed with hypothyroidism in 2011 (TSH 98). My doctor prescribed  levothyoxine alone and my hormones tested balanced after 6 months. I was still tired, with foggy thinking, aches and insomnia.

“They tested me yearly and I remained within normal limits. I’ve no idea what my T4 and T3 level are as the Dr. won’t tell me. Last autumn my TSH was 9.5 so they increased my dose of levo from 150 mcg to 175. My TSH fell to 0.05 so they cut me back to 125 mcg. My TSH is now 70.

“For the entire time I have been on  levothroxine I’ve felt bad no matter what my TSH levels are. I don’t know what to do in order to feel better. They don’t offer T3 in the UK.”

Other Patient Stories:

JF wrote about her daughter:

My daughter has had hypothyroidism since she was 12. She is now 28 and took Synthroid up until 2 years ago. She felt lousy and was tired and her hair fell out and she had dry skin, even though they said her levels were fine! Well, she started to take Armour Thyroid two years ago and there was a huge difference!

“She feels better and was also able to lose 60 lbs over the past 2 years. She couldn’t lose any before, as hard as she worked at it. I highly recommend Armour instead of the Synthroid!”

Shasha wishes she could go back to Armour Thyroid as her treatment:

I have struggled with thyroid problems since I was 8. At age 57, I’ve had thyroid cancer twice, 2 surgeries & now high dose radiation/ablation. My last surgery was 18 months ago & I have gained 18 pounds since then.

“I have no energy & struggle to stay awake. My hair & nails are falling off. I’ve been getting weekly iron IV infusions yet my red blood cell & ferritin levels as well as thyroid levels remain low.”

“For years I took Armour Thyroid & was happy & healthy. Now I’m told I MUST take Synthroid even though I feel it’s ruining my life. I’m in my doctor’s waiting room now; I plan to show him these articles & ask for Armour. It’s hard to imagine the damage levothyroxine alone has done to my life unless you have lived it. I urge all people taking Synthroid but feeling poorly to tell their doctor & give Armour a try.”

Diane also prefers Armour Thyroid:

“I have taken Armour Thyroid, Synthroid and Levothroid at various times. The ONLY one of the 3 that did not give me major side effects has been the Armour Thyroid. I have much more energy, no headaches and no fatigue like I have with the synthetic products.”

We are not beating the drum for Armour Thyroid or any particular brand of natural or synthetic thyroid hormone. Some doctors prescribe levothyroxine and supplement it with Cytomel (T3) or with a special timed-release T3 formulation that compounding pharmacists can make. This creates more balanced T4 and T3 levels circulating within the body.

Learn More:

If you are intrigued by this thyroid discussion we think you will find our newly revised extensive eGuide to Thyroid Hormones of great interest. Not only does it go into much greater depth regarding treatment options, it provides information about thyroid testing that you may not find anyplace else.

Thyroid hormones are essential for normal body functioning. Getting the balance adjusted is a little like Goldilocks and the porridge; not too hot, not too cold, not too much and not too little. We want you to get it just right, whether you are using levothyroxine alone or a mix of hormones. Here is a link to our new guide.

Share the Information:

If your physician wants a more authoritative resource, suggest she check out the article in the Annals of Internal Medicine. The authors are endocrinologists. And if you really want to understand this complex story, take some time to listen to our extended interview with one of the authors, Antonio Bianco, MD, PhD. It is free and your doctor may wish to listen as well. Here is a link.

Please share this information with anyone you think would be interested. Comment below in the “Add My Thoughts” section and please vote on this article at the top of the page. We appreciate the feedback. We hope our Guide to Thyroid Hormones will also provide an in-depth understanding of this complex topic.

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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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  • El-Khoury JM, "Seasonal variation and thyroid function testing: Source of misdiagnosis and levothyroxine over-prescription." Clinical Chemistry, March 1, 2023. https://doi.org/10.1093/clinchem/hvad017
  • McAninch EA & Bianco AC, "The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy." Frontiers in Endocrinology, July 9, 2019. DOI: 10.3389/fendo.2019.00446
  • McAninch EA & Bianco AC, "The History and Future of Treatment of Hypothyroidism." Annals of Internal Medicine, Jan. 5, 2016. doi: 10.7326/M15-1799
  • Jonklaas J et al, "Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document." Thyroid, Feb. 2021. DOI: 10.1089/thy.2020.0720
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