New Study Shows the Variability of TSH and T4 Data

TSH test measures Thyroxine levels, among other things

A new study published in the Journal of Thyroid Research explores the difference between the theory of T4 (thyroxine) and TSH (thyroid stimulating hormone) interactions and the actual data found in populations.

The conclusion of researchers is that “The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4.”

In other words, TSH responds to T4 therapy, but there is greater variation between individuals’ response to how TSH affects T4 levels than to how TSH is affected by T4 (More T4 is supposed to make TSH levels go down).

This is a really important finding and something I have written about on several occasions.

This matters because so many doctors determine everything they do on lab results and the most common lab tests, by far, that are ordered are TSH and T4.

And what this study tells us is that this is not always the best way to practice because everyone is not the same and everyone does not respond the same way to T4 only treatment.

Let me explain how this all works in your body.


TSH is thyroid stimulating hormone. This is released by the pituitary gland to stimulate the thyroid so that more thyroid peroxidase (an enzyme) is made.

This enzyme combines with iodine to make thyroid hormone, T4 and T3. About 97% is T4 and 3% is T3.

The body can’t really use T4, so it has to convert this into T3 which is the form that the cells of the body can use to do stuff. 60% of T4 is converted by cells in the liver, another 20% by cells in the gut and the remaining 20 or so % is converted by cells in the peripheral tissues of the body (muscles, fat, etc.)

And this is the basic premise of thyroid replacement hormones like Synthroid. It’s synthetic T4. The theory is that you just give it to the patient and tell them to call you in 6 months. An everything should be hunky dory.

(Only in real life, it sometimes isn’t. Here’s a detailed post I wrote on this.)


And the reason it doesn’t work is that thyroid hormone must be converted from T4 into T3 in order for the body to utilize it. This conversion happens differently in different parts of the body.

The problem with TSH only testing to determine thyroid hormone levels in the entire body is that the pituitary, which releases TSH, converts thyroid hormone differently than the rest of the body.

This is why you often see normal TSH with lots of hypothyroid symptoms.

Many doctors, somehow, are ignorant of this fact and instead of truly understanding what is happening physiologically, blame the patient for having symptoms when their lab tests say that they should be fine.

Another thing that this study points out is “The pituitary, though ultimately responsive to T3, is more responsive to T3 generated in the pituitary from circulating T4 by type 2 deiodinase than to circulating T3, and TSH levels are more consistently related to levels of T4 than T3. There are physiological advantages of this preference.”

Another very important observation. Here’s how this happens.

How Does T4 get Converted to T3?

There is an enzyme that is largely responsible for thyroid hormone conversion. It is called 5′ deodinase. And it actually comes in 3 forms: deodinase type I (D1), deodinase type II (D2)and deodinase type III (D3).

D1 and D2 Don’t Behave the Same Way

D1 converts inactive T4 to active T3 throughout the body. In the pituitary, D2 controls this conversion. These two forms behave very differently and are affected by different things.

D1 is suppressed and down-regulated (which means it decreases T4 to T3 conversion and increases reverse T3 levels) in response to stress (both  physiologic and emotional),  depression, dieting, weight gain and leptin resistance, insulin resistance, obesity and diabetes, inflammation from autoimmune disease or systemic illness, chronic fatigue syndrome and fibromyalgia, chronic pain, and exposure to toxins and plastics.

What did we just describe? Your average Hashimoto’s patient living in the modern world!

Most people with Hashimoto’s have the majority of conditions mentioned above.

In addition,  D1 activity is also lower in females, making women more prone to tissue or functional hypothyroidism.

Sound familiar? Normal lab results but hypothyroidism at the cellular level.

And when you have these conditions, there are reduced tissue levels of active thyroid hormone in all tissues except the pituitary because D2 does not behave like this, at all.

D2 is 1,000 times more efficient at converting T4 to T3 than D1 in the rest of the body. And it isn’t suppressed and down regulated by any of the things we mentioned.

So TSH is within normal range because the pituitary is getting plenty of thyroid hormone, but the rest of the body is hurtin’ for certain.


T4 has a long half life, so pituitary responses to it must be slow or you’d have very little TSH signaling.

A large portion of thyroxine (T4) binds reversibly to plasma proteins. Only a small free fraction (0.02% to 0.03%) is available for conversion to T3 and transport to cytoplasm.

T3 is formed from T4 by 5 deiodination at the outer ring by type 1 deiodinase predominantly in liver, kidney, and thyroid.

Type 2 deiodinase mediates intracellular deiodination in glial cells, pituitary, brown adipose tissue, skeletal muscle, and placenta. 

These higher levels of Type 2 deiodinase in the pituitary help keep the body balance and help keep feedback loops working.

In theory.

But real life is not theory and it is very common to have normal test results and still not feel normal, or even feel really lousy. The reason for this is that there is so much variability in how T4 behaves in the body.


There a few simple things that you can do.

#1. Understand that how you feel is diagnostically important and clinically relevant. If you have normal test results, but you feel like crap, something is not working.

Don’t just accept that this is how things are going to be. They don’t have to be, but you will have to look elsewhere for solutions.

#2. Get your doctor to order other tests: free T3, free T4 and reverse T3 all provide meaningful information on how well thyroid hormone is being utilized in your body.

#3. Do everything you can to improve thyroid hormone conversion. There’s a lot you can do. Begin by reading this post where I explain how to improve conversion in depth.

#4. Make reducing inflammation your top priority. Inflammation is the root of all evil. It is a primary reason why thyroid hormone doesn’t work in your body.

Take natural anti-inflammatories and understand that stress is very inflammatory. You need to take it very seriously.

#5. Keep circadian rhythms. TSH is released in a pulse with your body’s natural circadian rhythm. (I’ll be exploring how to do this in an upcoming post.)

#6 Consider treatments that involve adding T3. Natural desiccated hormone therapy like Naturethroid or Armour contains more T3 and there are synthetic T3 treatments like Cytomel. Check out this post for a detailed discussion on thyroid replacement hormone.


About the Author Marc Ryan

So now, not only is it my profession, it’s my passion, and it’s personal. I’ve been joking with people lately saying it’s a blessing and a curse. A blessing because I really get it, and a curse because I really got it! ?

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