Breakthrough Discovery in Thyroid Hormone Therapy: Part 2

Treatment of hypothyroidism (low thyroid function) is accomplished by administering thyroid hormone by mouth in sufficient amounts to restore levels back to normal. At first glance this might seem like a simple goal to achieve. The truth is hormone replacement therapy is complex because there exists two very different thyroid hormones and because levels of thyroid hormone in the blood do not always reflect the amount of thyroid hormone within the cells where the hormone exerts its effects. In Part One of this blog I began to discuss how genetic differences among individuals could explain why some people need a complex mix of thyroid hormones to adequately treat hypothyroidism. In Part 2, I want to explain the nature of the differences between individuals and how it determines what sort of thyroid hormone therapy may be needed.

In May 2009 a group of researchers (Panicker, V. et al) in the UK published the WATTS study, the largest and most comprehensive study to date, of hypothyroid patients treated with combination t4 and t3. The goal of the study was to discover whether genetic differences in the population of hypothyroid patients accounts for some individuals needing t3 in addition to traditional t4 therapy. The researchers looked at 697 hypothyroid individuals and analyzed their DNA for differences in the portions controlling crucial enzymes which process thyroid hormones known as deiodinases. These enzymes are found widely distributed in the body including the thyroid, brain, muscle, liver, kidney and pituitary gland. As explained above, deiodinases convert t4 to the much stronger form of thyroid hormone, t3. At the same time the researchers measured patients’ mood and sense of well being on t4 alone and when t3 was added to the therapy.

Key findings of the WATTS study are that there is a substantial difference among individuals in the genes that make the deiodinases. In other words, due to genetic differences (mutations), there are differences in the way individuals make t3 out of t4. In a group of people, mutations in the genes that make a particular protein (in this case, the deiodinase), are called polymorphisms. The researchers discovered that a certain mutation in the deiodinase gene is associated with a poor sense of well being on t4 only therapy, and in the presence of this mutation a significantly better response to adding t3 can be found compared to those without this mutation. Of the group of hypothyroid patients studied in the UK about 16% possessed the faulty deiodinase gene. In other groups in other countries the percentage of people with this mutation could be higher or lower.

The traditional treatment of hypothyroidism is to administer t4 (Synthroid, Levothyroxine, Levoxyl etc.). It is the conventional wisdom that inactive t4 is converted in the body to the active thyroid hormone t3 by “peripheral conversion” in sufficient amounts to restore normal thyroid balance. The recent breakthrough discoveries described in the WATTS study reveal for the first time that individuals differ in how their bodies process (metabolize) thyroid hormone. While some may convert enough t4 to t3 in the cells of the body to restore normal function, due to genetic differences some individuals will not be able to make enough t3 leaving them with persistent hypothyroid symptoms. Since the problem is a deficiency of t3 within the cells of the body, measuring thyroid hormone levels in the blood cannot adequately reveal the problem. T4 replacement treatment alone can result in thyroid levels that appear normal on blood tests so doctors conclude that persistent hypothyroid symptoms are not related to the hormone therapy.

Based on my personal experience and the documented experience of many of the members of it is clear that endocrinologists and other physicians are often reluctant to consider combination therapy for hypothyroidism, either by using Armour thyroid or adding t3 (Cytomel, liothyronine) to t4 only therapy. With this new research in hand, hypothyroid individuals and their advocates can finally state with confidence that: Yes! There is a firm scientific foundation for combination t4/t3 therapy and; No! We are not just chronic complainers or kooks. If I had hypothyroidism and was going to request a change in my thyroid treatment I would say something like, “Due to polymorphism of the deiodinase gene I probably possess a defective D2 deiodinase and therefore my peripheral conversion of t4 to t3 is impaired. I need t3 added to t4 to compensate for reduced intracellular t3 levels which cannot be detected on blood tests. Without t3 I continue to suffer with cellular hypothyroidism which is the likely cause of my persistent symptoms.”

If you try this approach and your doctor looks bewildered hand them a copy of the study by Panicker et al in the Journal of Clinical Endocrinology and Metabolism, 2009, 94(5): 1623-1629.

Gary Pepper, M.D.


Notice: This article is for informational purposes only and does not substitute for the advice or treatment of your own physician. The disclaimer for all blogs at, applies.

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  • Nancy

    Dear Dr. Pepper,

    I read your post with interest and hope that you might be able to provide me with added advice.

    I was diagnosed with hypothyroidism in 1990 and at that point began taking a relatively low dose of synthroid. Later, in 1997, I was diagnosed with fibromyalgia. I mention the latter only because a recent physician that I have been seeing told me that for people with both ailments, cytomel is better than synthroid.

    I am now taking 50 mcg. of cytomel daily, after taking synthroid for 19 years, having worked up to a daily dose of .175 mg. The problem is that previous to developing hypothyroidism, I was slim and had a good amount of energy. Since then, however, I have had a considerable weight problem and suffer from severe fatigue on a daily basis — whether I am taking synthroid or cytomel.

    Additionally, based on my last blood work, both my T3 and T4 are in the average range — neither too little or too much.

    Do you have any ideas about the above. I would greatly appreciate any advice you can share.

    Many thanks,


  • Dr. G. Pepper

    Hi Nancy

    Your story is not that uncommon. Many of the members here at share similar experiences.

    As you know I cannot offer medical advice in this blog. But I can share some educational thoughts with you.

    As I understand it, you are on 50 mcg of Cytomel daily and off Synthroid. Cytomel is relatively short acting and needs to be divided into two if not more doses daily, for best results. Personally I have had better results with combination t4 (eg Synthroid) plus Cytomel as the Synthroid supplies a background of thyroid hormone while the Cytomel supplies the “booster” effect.

    If it weren’t for the Armour crisis, I would usually advise people in your situation to try dessicated thyroid since of all the choices it has offered the best clinical response at the best price. If you are interested you might ask you doctor if Armour or similar is a possible choice for you, then you will have to join everyone else in the struggle to obtain it.

    Good luck and keep us posted.

    Gary Pepper, M.D. , editor-in-chief,

  • Angel

    Dr. Pepper,
    I read your blog with interest. When I was 18 I was diagnosed with hypothryoidism, due to change in insurance I had to switch doctors and subsequently (more than 20 years) tested normal instead of hypothyroid until 2 years ago. I went to a physician who ran a free t3, free t4, etc test and my t3 was at 307. He encouraged me to take RAI which I did as he said that my thyroid would end up burning out and I would be sicker than I was at the time. Since that time I have struggled to get within the normal range of 200-250 for t3. I am currently taking Synthroid @ 200 mcg. Given the fact that I do not have a thyroid, is it reasonable that the combination of t3 and t4 may work better than just the Synthroid alone? Is it possible that the fact that I don’t have a thyroid may be affecting the gene you spoke about? Or is that only for individuals who still have a thyroid?

    • Dr. G. Pepper

      Hi Angel

      You may have noticed a few articles at describing how many people with hypothyroidism taking replacement therapy feel best when receiving extra amounts of t3, either as combination Cytomel and levothyroxine (Synthroid, Levoxyl etc), or in the natural product dessicated thyroid (Armour etc).

      We are all born with a certain set of genes which determine everything about our physical selves. Our genes are constant throughout our lives. You may have the genetic makeup which requires t3 replacement but only by doing a genetic analysis would you be able to know that. An easier way is to ask your doctor if it is reasonable to try adding t3 to your Synthroid. Reducing your Synthroid dose may be necessary to accommodate the addition of the t3. After that you can see if the combination is better than Synthroid alone. Due to the acute shortage of Armour it is hard to recommend trying that, as you see on all the turmoil people are going through to get it.

      As you know, only you and your doctor can decide what is appropriate therapy for you. My comments are for educational purposes only.

      Keep us posted and good luck.

  • Laura

    Dr. Pepper,

    Hi, I am a mother of two, my oldest daughter Peyton(3yrs) , was put on synthroid 75, the bloodwork they take from the hospital when she was born came back high, so we took her back a week later for more bloodwork, it came back good, and over the years her bloodwork has came back good. But now, my daughter Dana’s(23 days old) bloodwork from the hospital came back high, so she’s on the synthroid now. they’re doctor wants to take Peyton off and test her to see if she can be taken off, if so, she thinks Dana does not need it either. They’re doctor said something, like I have something that is blocking their thyroid, because it’s just their first bloodwork that comes back high. Can I just have your point of view?

  • prosanta

    Iamsuffering from Diabetes type2.recently on routine Blood test—
    FT3(ECLIA) 2.33pg/ml
    FT4 1.07ng/ml
    TSH 9.32microIU/ml
    AntiThyroid Peroxidase 37.02IU/ml

    Do I need to take only Levothyroxine

  • Dr. G. Pepper

    Hi Prosanta

    You know I can’t recommend medical therapy in this forum. I can make some general comments, however.

    There is debate among endocrinologists about what level of TSH indicates a clinical degree of thyroid deficiency, but there is no doubt that a TSH of 9 is abnormally high. Since elevated TSH amost always indicates that the pituitary gland is releasing excessive TSH in response to thyroid hormone deficiency, unless there is a pituitary tumor (exceedingly rare), replacement therapy with thyroid hormone is indicated.

    Thyroid hormone replacement therapy in the U.S. usually consists of taking a pure t4 product such as Synthroid or levothyroxine (generic t4). On this website you will notice extensive posting about treating hypothyroidism with alternative forms of thyroid hormone replacement, particularly desiccated thyroid products such as Armour Thyroid. An appropriate concern in a situation like yours is whether to take t4 only or to use desiccated thyroid or t4 plus t3 therapy.

    If you are like most people in this country being treated with t4, you will wonder why someone might need alternative forms of thyroid hormone replacement. In the past year or so researchers have discovered that a portion of the population lacks the ability to normally metabolize t4 into the highly biologically active t3. This means that affected individuals may continue to experience symptoms of thyroid hormone deficiency when treated with conventional t4 therapy [ ]. How does a person know if they won’t respond to t4? The simpliest approach is to try t4 and see how you feel. Then you and your doctor can decide whether you are a t4 responder or not.

    You may be aware that Armour Thyroid and similar products are in very short supply in the U.S. Even if some advocates of desiccated thyroid therapy for hypothyroidism argue that only desiccated thyroid can result in a full return to normal, in my opinion the present shortage makes t4 therapy the clear initial choice. If symptoms of hypothyroidism persist even after a full course of t4 has been tried, then you may be forced to join the ranks of those struggling with the pharma industry to get desiccated thyroid products.

    Please discuss these ideas with your own physician.

    Let us know how you do.

    The disclaimer and terms of service of applies to all my posts on this website.

  • lscallion

    I have a Hyper Thyroid and am tatally confused on the weight gain, what can I do or take for the weight gain?

  • Kimba116

    Hi Dr. Pepper,

    Great article and so true! I am a testiment to augmenting T4 with T3. However I have a question. I think I remember you telling me once that T4 can block T3 absorption and/or efficacy. Am I remembering that correctly? And if so, to what degree?

    I’m still constantly tweaking my Armour and Cytomel ratio for the best balance and often wonder if I should ease up on the Armour and instead take more Cytomel to more effectively address my low T3 count. What do you think?

    Thanks and thanks for being my doctor!!!

    Kimberly Bain

  • Dr. G. Pepper

    Hey Kim

    I think I was trying to convey the idea that in order to achieve higher t3 levels by increasing t3 doses, sometimes we need to reduce sources of t4 such as levothyroxine and even Armour (which contains both t4 and t3). I agree with your idea that if you want to see how you feel by upping your t3 levels by increasing your Cytomel I would advise reducing the Armour dose. Please let me know if you need further instruction or how the change works out for you.


    Dr. P.

  • mary

    Dr Pepper, thank you so much for this article. I love the last part of where you give us the perfect phrases to say to our doctor. I have been suffering with hypothyroidism for 14 years now (10 years undiagnosed, 4 years insufficiently treated). Over these years I have come to know quite a bit about my condition and can speak with my doctor using the correct terminology most of the time, but not always (I have to get through the brain fog). Your phrases are just what I need to say to my doctor since I believe I have a conversion problem. I will enjoy presenting the study to him an talking to him about polymorphism and deiodinase! 🙂 Some people tell me I should have changes doctors along time ago. My doctor may have given up on me but I will not give up on him. I am determined to educate him. He did recently admit to me that he doesn’t know much about the thyroid. I fail to understand why the vast majority of General Practitioners don’t get up to speed on this subject since so many of their patients are suffering from thyroid problems. My doctor has wasted time and money giving me anti-depressants and appetite suppressants (Reductil) and sending me to a counsellor. Thanks again for helping.

  • Marie

    I’m living in the UK and have been diagnosed hypo for 2 1/2 years. For the last 12 months I have been on 100mcg. I do not feel any better at all since starting treatment. If anything my symptoms have got worse -cold, fatigue, memory loss, dry skin, weight gain despite low appetite etc etc..
    Last week I went to see my GP about T3. I had only just read online that there was an alternative treatment to just Levothyroxine. He was not happy at all! He said my recent bloods (he used the word bio chemistry!) is showing that everything is fine. He suggested that the problem is something else and asked why I was getting upset. I felt he thought I was depressed and was looking for something else to blame. I am a busy mum to four gorgeous children and I do have a busy life but I’m exhausted in a way I never used to me. I had to practically beg him to help me as he didn’t want to do anything. He has agreed to write to an endocrinologist and refer me but that will take some time. He also said he would be very interested to see what I had read in favour of combination therapy as to his knowledge it wasn’t known to make a blind bit of difference. I certainly will be taking in the information about the polymorphism and deiodinase -I’ll try and get my head round it first though. Can you point me in the direction of the most recent studys done on t3? I am desperate for support with this, I feel like my doctor thinks I am neurotic.
    One last thing, it has really made me smile reading how people on here have helped each other. I daren’t get my hopes up that one day I might be free from these symptoms but I am so pleased many of you now are due to the support you have given each other.
    Kindest regards from England.

  • mlsw kosicki

    I have had thyoid/weight gain problems since I was 16….have battled weight gain eating a minimum of nutrtious food and exercising . I will NOT do a colonic cleanse! Not for me!! BUT I need help with something other than what the usual endocrinologists prescribe for me in thyroid medication. I would like to see an endocrinologist in my area ( Baltimore, MD-Baltimore County) who thinks outside the box……I am currently taking 120 mg Armour Thryoid medication. I am 5 ft 3 inches and weigh 140. Small frame. My best weight has been 122-125. I feel awful with rolls around my waist and thighs rubbing together. I need to get back to size 8-10. What help can you be? m lsw kosickl (86 yr old female)

  • mlsw kosicki

    I just left the comments above. I will add that my hair is dry, thin and my eye brows and lashes are disappearing fast. My skin is dry and flaking off. I need an interior temperature of 73 degrees F. in order not to be chilly. I also have osteopenia. I need 10 hrs of sleep at night- and still can fall asleep sitting up during the day. I have also fought constipation- now live on CHia seeds daily. I used to have enormous energy- but not of late.
    I will add that I was on Cymbalta for 2.5 yrs for depression and feel that iot affected
    my metabolism. Just quite three months ago.
    My mother was very heavy at one point in her life- and fought fat constantly. My father was what you might call “heavy” although not “fat”. However he died at 49 yrs of age.

  • Hi… you hadn’t mentioned whether or not you have been tested for hypothyroid function but it sounds like you have a number of related symptoms. Hopefully you can get a baseline (if you haven’t had one yet) for Free T3, TSH, reverse T3 and thyroid antibodies. A full comprehensive metabolic assessment would be useful in pinpointing possible nutrient deficiencies as well.

    Chia seeds are a great source or antioxidants, fiber and omega-3’s so they help to decrease inflammation as long as you are converting the plant based source to the EPA/DHA and subsequent eicosanoids needed to control inflammation, blood pressure, blood clotting, etc. etc. You can’t live on Chia alone though!

    A balanced diet, developed to address your carbohydrate, protein and fat requirements would help you to get on track with healthy weight maintenance. Even if someone has the genetic propensity to be overweight/overfat, you can still control your “environment” as far as intake and exercise and modify that gene expression!

    Consider having an individualized consultation!

    Beth Ellen DiLuglio, MS, RD, CNSD, CCN, LD/N
    In regards to this reply please read the our terms of service at:

  • Hi again MLSW….
    I’m sorry, I didn’t see all 3 sets of your comments… I see you are on 120 mg Armour.. .and sounds like you still have hypothyroid symptoms. You didn’t mention excess stress but if your adrenals are out of balance, it becomes nearly impossible to straighten out the thyroid! As far as returning to 122-125#, our total energy needs decrease as we get older so it is especially important for you to try and build some lean body mass/muscle that will work for you as far as burning Calories and increase your exercise/walking to tolerance. You’ll need to burn an extra 250 Calories per day as well as decrease Calorie intake by 250 Calories per day in order to lose 1 pound of fat per week. Slow and steady!

  • nbarnard

    Hello Dr. Pepper,

    I just found your blog and decided to join. I admire you for helping so many people this way. As with many people on this board, I have hypothyroidism. They removed my thyroid due to Hashimoto’s Thyroiditis a few years ago. It took a very long time before I started to feel better after taking the generic T4 meds. I was much heavier than I am now, since having started a special diet program where I lost 100+lbs. During my weight loss experience, I felt my best ever when I was down 60-80lbs. At that time, I was taking 250mcg Levothyroxine daily, with 25mcg every other day. (also taking maxzide 25mg, levonorgestre, and calcitriol – due to the parathyroid glands malfunctioning). Now I am down 100lbs and feel like I did before they removed my thyroid and I cannot lose any more weight. I am on a program where I should be losing everyday and nothing. My current dose is 200mcg per day. The doctor did blood work and they stated the levels were too high, so she lowered my thyroid medication. At the same time, I had to lower my blood pressure meds. My concern is that as the days go by, I feel worse and worse. My hypothyroid symptoms are so bad, that I cannot function. I am tired, cannot concentrate, dizzy, depressed, and on and on. I live in Texas and need a heater by my desk because I am so cold. I talked to the doctor about this and we did another blood test. She said the level dropped from 20 to 16 and that is an indication the med change is working. In the past when my numbers were too high, the doctor raised my medication. I am very concerned that this might be wrong dosage direction. I have appointments to see her, but cannot get in for a few months. In the mean, time, I am researching what can be done to help my situation. Any help would be appreciated.

  • Peggy

    I’m from Chicago and I have been hypothyroid since I was 12 years old. I almost died from synthroid, Lavoxol, levothyroxine and Armour. I had a fever of almost 105%, was incoherent and burning up and when my husband carried me to the car drove me to the doctors office and she didn’t know what was wrong with me. I stopped taking the meds each time it happened and I had to wait till it wore off and not take anymore and I was fine. In the book Thyroid Power 10 steps to total health by Richard L.M.D. & Karilee Halo R.N. Ph.D Shames. They say that many people are toxic to medications for thyroid. About 6 years ago I went on Cytomel once a day and about 3 years ago my thyroid went crazy and I gained 60 pounds in 6 months and lost 80% of my hair. My diet was no different, I bake, broil or pressure cook all my foods, seldom fry anything and I don’t eat sweets or even grave them. Doctor didn’t even know what to do. I have a new doctor now and she said that Cytomel only works for 8 hours and you need to take it twice a day. I have very bad water retention and the new blood pressue med I’m on is making it worse. I’m feeling better, but not up to par, but because of the weight gain I now have high colestrol and blood pressure. Which those meds make me ill! and I have fibromalgia so that adds to pain and sleepless nights. Lightheaded, dizzy, nausia alot of! I asked my doctor if I need Cytomel 3 times a day and she said no. I think I do! What do you think? I have been dieting for a long time, I mean years and can’t lose unless I eat under 25 carbs a day and 600 to 800 calories. It’s had to do that when you just turned 64. The body can’t handle it like it did when I was younger. The arthris in my knees and right foot won’t let me excersie and walk like I use too. I do some but not alot. Any suggestions? P.S. Everyone should read Thyroid Power and avoid all the foods that can cause a goiter in the thyroid

  • katherine walker

    Dr. Pepper – General Question: How does one determine the “RIGHT” Ratio of T3 to T4? I have been on 100mcg of Synthroid for a year. I want to add some T3. My old-school trained Dr. said to just add 5 mg Cytomel to the 100mcg., but I see dangers in doing this, and possible side-effects. I want to reduce my Synthroid, when I add the Cytomel. How do I determine the correct ratio?? Also, do you recommend dissolving the T3 Cytomel under your tounge? What are the pros/cons to that? Also, is is always necessary to take T3 2x per day because the half-life isn’t so great, OR can you only take it once and be OK…? Thanks! 🙂

    • Dr. G. Pepper

      What is the correct ration of T4 to T3 is a question I have been asked a lot. t is very difficult to say what the correct ratio of t4 to t3 is for any individuals. The often quoted “correct” ratio of T4 to T3 in humans is approximately 14:1 but that is merely an average. It’s like saying the shoe size of humans is 7 because if you take the average shoe size of 1000 people that is what you get. How many people out of that 1000 actually wear a size 7 shoe? Not many. Likewise the t4 to t3 ratio is highly variable between people and what you are asking is what should yours be. I don’t know but I can tell you that you and your doctor can come close to finding your ideal set point with some effort and willingness to be flexible with different dosing trials. As long as you and your doctor don’t go to extreme doses outside of normal physiology it is likely you will find a healthy and comfortable solution to this problem.

      I don’t see any major benefit to dissolving T3 under the tongue. It is absorbed very well from the stomach if the stomach is empty. Some people can’t wait enough time between their thyroid med and eating so maybe in that case under the tongue may be better.

      T3 action is short, particular compared to T4. I find most people do better on twice daily. But my goal is to have a happy, comfortable patient so if taking T3 twice daily is impractical because of schedule, hectic lifestyle may be worthwhile to see if acceptable results can be obtained with once daily. Not much downside to trying. Please ask you own doc if they agree in your case however. Each individual responds differently to medication changes.

      Good luck.

      Dr. G. Pepper

  • zeesanyoura

    I had irregular period for 3 months actually from last December untill today I was getting my period every 15 days then the doctor noticed that is because I have hyper active thyroid I did my blood test and it was abnormal TSH 0,05 and T4 17,7 now I am under medication synthroid 0.088 but my question is: do this means that I am under a risk or I could be okay, I am too late cause it is been 3 month cause really I am scared of infertility please can you help by answering my questions thank you in advance

  • Ive had under active thyroid since i was 6, im now 49, ive been on 125mg thyroixine for as many years as remember, just recentley my blood results came back as borderline, high, t4 22.6, tsh level 0.43, doc says dont need to do anything, but been consipated, bloated, foggy brain, tired, etc etc. ive been reading your comments, and it appears i might be having problem converting my t4 to t3, does this sound likely. im a little bit confused to say the least.

    • Gary Pepper M.D.


      As you probably read on this site, there is growing scientific evidence that a percentage of people with hypothyroidism treated with T4 (levothyroxine, Synthroid etc) do not achieve the proper balance of T4 and T3 inside of their cells due to genetic factors. Clinical practice shows that for those being treated for hypothyroidism with T4 who have persistent “hypo” symptoms that addition of T3 either as synthetic Cytomel/liothyronine or within extract of pig thyroid (Armour Thyroid), relief of these symptoms is possible. Hopefully you can find a physician who is willing to follow this line of reasoning so you can have the benefit of trying something along these lines.

      You can read more about this in my book, available on this website, “” in the section on thyroid treatment. For a limited time if you input the code Pbdes (capitalize “P”) at checkout you can get the “e” version of the book at a 30% discount;

      Keep us posted and good luck.

      Dr. P.