What do you think the # 1 most prescribed drug in America is? No, it’s not a statin. According to the last statistics we have seen it is a drug for thyroid replacement called levothyroxine. Over 120 million prescriptions were dispensed annually. 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 (L-T4, 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.

Why Levothyroxine Alone Might Not Be Adequate

Many people with hypothyroidism (estimates range from 12 to 15% 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 insights 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. I definitely have problems that have grown over the years. I go for my TSH blood test and it 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 New Discovery

Okay, before your eyes glaze over, let’s get to the new and 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 just levothyroxine (L-T4) 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

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. 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.

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). I was tarted on levothyoxine and ended up balanced after 6 months. I was still tired with foggy thinking, aches and insomnia.

“They the 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:

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!” J.F.


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 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.” Shasha


“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.” Diane


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.

If you are intrigued by this thyroid discussion we think you will find our newly revised 25-page Guide 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. Here is a link to our new guide.

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.

Revised: 1/12/17

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  1. Sheila Turri
    SC/USA
    Reply

    Due to Graves disease i had a thyroidectomy when I was 20.
    I am now soon to be 53. I have felt like total crap for 33 years.
    My primary always did my bloodwork and prescribed synthroid about 5 yrs ago that changed to levothyroxine. It got worse after starting levethyroxine but I never realized that was why..I figured it couldn’t be my thyroid since I was taking the med. Gained 40 lbs and was so tired it hurt I to walk. Then I heard about T3 and cytomel. Went to Endo a year ago she started my on cytomel and made adjustments to Levo. 3 months later no change.
    Ive been taking intirosint for 3 mnths..TSH is now 6.5. and no change. Not one pound lost and every joint and muscle hurt so bad. my quality of life sucks. so tired I can cry..But cant get good sleep. Been diagnosed with fibromyalgia, depression, anxiety, chronic fatigue and add.
    At 55, retired and 2 grandsons I so want to enjoy the rest of my life!
    I go back to Endo in 3 days.
    Anyone with thyroidectomy do better with Armour and another?
    Please share because enough is enough 33 years of no energy for life is enough. I’m afraid of waiting another 3 months on another waisted prescription.
    Reading all the comments … At least we are not alone.

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