Looking at Past, Questioning Present; need for studies of hypothyroidism treatments


By Maggie Van Dyke

Jan. 11, 2016

Looking back in time can reveal missed connections and unanswered questions that are worthy of re-examination today. That’s what endocrinologist Elizabeth A. McAninch, MD, learned when she started digging through old medical textbooks to detail the history of hypothyroidism — that is, an underactive thyroid.

McAninch assumed that she’d find evidence supporting the current treatment for hypothyroidism — which has been the standard of care for about four decades — as being superior to other therapies. Instead, she discovered a major gap in scientific research, as described in an article published in the Jan. 5 issue of the Annals of Internal Medicine. An assistant professor in the Division of Endocrinology and Metabolism at Rush, McAninch co-authored the article with Antonio C. Bianco, MD, PhD, president of Rush University Medical Group and vice dean of clinical affairs at Rush Medical College.

Hypothyroidism is a condition caused when the thyroid gland in the front of the neck doesn’t produce sufficient quantities of thyroid hormones, which are important in many processes in the body, including growth, development, metabolism and cognition. About 10 million people in the U.S. have this condition, according to McAninch, and it is especially common in women. In the very early stages it may not cause symptoms, but over time, untreated hypothyroidism can cause significant health problems, such as cognitive dysfunction, infertility, cardiac disease and slowed metabolism.

“What we all learn in medical school today is that hypothyroidism treatment is straightforward,” McAninch says. “Patients are treated with levothyroxine, a synthetic thyroid hormone, and the majority of patients do really well on this therapy.”

Even after taking levothyroxine, however, about 15 percent of patients still suffer troubling symptoms, including fatigue and forgetfulness. This quandary led McAninch and Bianco to wonder how the medical community came to agree that levothyroxine by itself (i.e., levothyroxine monotherapy) should be the first line treatment.

Before that protocol became commonplace in the 1970s, patients with hypothyroidism typically were given a desiccated (or dried) form of thyroid gland harvested from animals. Because the thyroid gland contains both types of thyroid hormones, triiodothyronine (T3) and thyroxine (T4), patients treated with desiccated thyroid received a combination therapy, in contrast to patients receiving levothyroxine monotherapy, which only contains only T4.

McAninch’s historical research surprised her. “I had assumed that levothyroxine monotherapy had been shown to be superior than other therapies, that it was either more efficacious or safer. I had assumed that appropriate comparative clinical trials had been done with modern techniques and measures,” she says. “But the bottom line is these studies have not been done — and still need to be.”

What led us here?

To identify the major historical turning points in hypothyroidism treatment, McAninch and Bianco decided to go back 120 years. “PubMed (a search engine for online medical research) and the Internet didn’t exist back then, plus a lot of medical science was not published in journals at that time,” McAninch says.

“So we scoured bookstores for old books on thyroid disorders and collected a library of endocrinology textbooks across the decades. Then I went through every single book — easily over 50 books — and wrote down the hypothyroidism medication that was recommended, along with the dose, during each time period.”

After putting all this information into a timeline, McAninch pinpointed when treatment recommendations changed to support levothyroxine monotherapy, and why. She learned that the majority of patients did relatively well on desiccated thyroid, but the capsules themselves were a problem.

“They would crumble or lose their efficacy when stored in humid conditions. So people were upset about the inconsistency of those tablets,” she explains. “Also, overdose was commonplace in the early 20th century. because doctors did not have access to the type of blood tests available today that can measure the amount of thyroid hormones in the blood and ensure safe levels.?

Then, in the early 1970s, scientists discovered that the body converts the T4 hormone to T3. “So scientists and clinicians both suggested, ‘If the human body can produce its own T3, then taking T4 must be enough to replace thyroid hormone.”

As a result, it became more popular to give patients synthetic levothyroxine monotherapy —which, remember, is T4 alone. The pills could be produced consistently without any storage issues, and patients would make their own T3 by taking the T4.

The rest, as they say, is history. Since the majority of patients with hypothyroidism do well on levothyroxine monotherapy, which is also a very safe medication, there has been limited interest in conducting time-consuming and expensive clinical trials comparing treatment options to address the minority of patients with residual symptomatology.

Where do we go now?

However, recent discoveries suggest that the human body may not be as efficient at turning T4 into T3 as previously believed. For one, patients who are treated with levothyroxine monotherapy tend to have relatively low or lower-than-normal T3 levels. This difference may help explain the minority of patients who remain symptomatic.

Animal studies by Bianco, McAninch and other scientists provide further support for this theory. When animals with hypothyroidism were treated with levothyroxine, blood tests suggested they had normal thyroid hormone levels. However, researchers found that their brain and other tissues were still exhibiting markers suggestive of hypothyroidism.

McAninch hopes that her paper in addition, to their other research findings, prompt expanded, clinical trials soon that compare the efficacy and safety of combination T3/T4 therapy to levothyroxine monotherapy. Until that happens, physicians can continue to follow the recommendations of the American and European Thyroid Associations, which now support trials of combination T3/T4 therapy in patients who do not respond adequately to levothyroxine monotherapy.

Given the contemporary emphasis on evidence-based medicine, McAninch also sees tremendous value in researching the historical precedence behind many of today’s well-accepted treatment regimens.

“I think the historical methodology I used for hypothyroidism could be applied to other diseases and illnesses,” she says. “We really need to make sure that the current standard of care we are applying in the clinic and teaching our medical students has been shown to be the safest and most efficacious approach.”


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21 Replies

  • dmf240,

    Much of great sense there.

    We often see suggestion of a golden era of hypothyroid treatment. Whilst I am more than happy to criticise where we are, things like capsules (or was it tablets? a bit of inconsistency there) crumbling and inconsistency were problems.

    It is ironic that the valid criticism of at least some desiccated thyroid products, plus current day analytical techniques, have resulted in what are probably the most consistent desiccated thyroid products ever. Against a background of levothyroxine dominance in which we might have expected desiccated thyroid to have almost disappeared, there have been numerous consistency problems with levothyroxine (and possibly liothyronine) rather than desiccated thyroid. [ Am currently ignoring to somewhat confusing issues surrounding Erfa and Armour in recent years. ]

    They also rather miss the advertising and marketing budgets of the makers of Synthroid. Which are quite possibly the most significant single factor.

  • Thank you very much for posting, Dmf240, very interesting article.

    Bianchi and McAninch (and others) have been questioning the efficacy of T4 monotherapy for some time. Usual response from endocrinologists is that rigorous evidence based clinical trials into T4+T3 combination is required before benefits and dangers can be evaluated. Happily several papers published in the past couple of years demonstrate that a significant subset of patients don't convert sufficient T3 from T4 only and that they may benefit from combination T4+T3 therapy.

    Levothyroxine therapy replaced NDT once it was able to be produced much more cheaply than NDT. The aggressive marketing by the makers of Levothyroxine and their sponsorship of medical schools is undoubtedly another reason why Levothyroxine has gained such sway over alternative therapies.

    This 20-year safety review of liothyronine was published in 2015 and didn't find increased incidences of atrial fibrillation and osteoporosis patients are often warned about.


  • dmf240, a wonderful find, and very interesting. I don't know how much impact it will have though. If evidence comes up that contradicts what doctors firmly believe in they will most likely ignore it. However, I sincerely hope I'm wrong, and that some doctors at least will think "Hang on, that's interesting... "

  • Pleased to read this. I hope the recent research begins to filter through sufficiently to 'change minds' in the medical profession at large.

  • At last a scientist has looked back dispassionately at how the present beliefs in optimal thyroid treatment came about. I'm extremely surprised at the clear finding that the logic behind T4 mono therapy is so flawed and lacking in scientific rigour of proof, though one suspected as much. I'm even more confident that our ongoing work and discoveries about the complexity of thyroid function and treatment continues to be worthwhile. We're now tackling a more basic problem - the use and diagnostic power of different ways of using the TSH, FT4 and FT3 tests for diagnosis. We've just submitted a paper in which we show that combining statistically the three measurements rather than treating each separately shows that a significant number of patients who were thought to be sub clinically hypo or hyperthyroid (TSH out of range, but FT4/3 normal in range) aren't out of range at all. This may better distinguish patients who truly are ill from those who are not. Again a controversial idea, and I expect the usual deep thinking from reviewers (not).

  • We've just submitted a paper in which we show that combining statistically the three measurements rather than treating each separately shows that a significant number of patients who were thought to be sub clinically hypo or hyperthyroid (TSH out of range, but FT4/3 normal in range) aren't out of range at all.

    I think this comment may be like a red rag to a bull on this forum, diogenes. We have people who come here with a mid-range TSH, with hypo symptoms galore, and doctors simply ignore them or go chasing after evidence of "something else".

    If you produce evidence that being a bit over the range doesn't make us hypo, you are just stabbing us in the back and making our lives even harder than it already is.

  • I think you have the wrong idea here. What we're looking at are those people who show no signs whatever of thyroid problems but give slightly over the range results which have to be followed up simply because of that, with no clinical outcome. We're trying to clean up screening so that unnecessary work hasn't to be done on people without the disease. Symptomatic people we hope will be better discriminated from this group. There never will be a clean separation, but at least we might be able to make it cleaner than it is using TSH only as a discriminator.

  • Thanks for the explanation, diogenes.

    I now worry that a lot of doctors might jump to the same conclusion I just did!

  • Scientific research is not all its cracked up to be. The pharmaceutical industry will only find what they want to find, they decide on results before they do tests.

  • Well said Glynisrose. Don't forget who finances the tests and studies that the American Thyroid Association (ATA) does. Whooo, Big Pharma! So guess what the ATA recommends, that which BPh makes, synthetic monotherepy via Levothyroxine. And, of course, that which is making them billions of dollars.

  • I found this article extremely interesting but not at all surprising. I think it goes to show that not much has changed since the 1970s and probably earlier. Treatment for thyroid patients seems to be governed by cost. With the fact that the majority of patients do well on the treatment being used to confirm that the treatment is correct. I have read various figures for the suffering minority of between 10 and 20%. Even if only 10 % of thyroid suffers are not being treated properly and still suffering life affecting symptoms, surely that is too many? It seems to me that doctors are told not to look at symptoms and consultants very often ignore symptoms.

    I think what is becoming more clear is that researchers and consultants have probably known the reason for many of us suffering for years but are either unable or unwilling to offer the correct treatment due either to financial restraints or NHS rules.

    This simply does not work and serves only to waste larger amounts of money.

    In my own case, I have been prescribed huge numbers of drugs that were never going to help my thyroid symptoms and in fact made me more ill.

    For example I was given 9 different HRT tablets and 2 different HRT patches to treat my premature menopause - all made me feel very sick. I didn't go through the menopause for another 18 years!! I also took up a valuable place each month at a menopause clinic for almost 2 years - my female gp did not believe in the simple blood test that would have shown no menopause. May be I'm being cynical but if she had, she would have had to find another cause for my thyroid symptoms!!

    I think the big change is the arrival of the internet and sites like this one. We are no longer individuals struggling with our illness. We know that we are not alone.

  • Thanks for posting this extremely interesting article! It's utterly amazing how little 'science' there is in medicine. How naive I was before I got sick!

    Yesterday I was listening to a podcast where I thought they had quoted a figure for the percentage of patients who were taking medication that had not been passed through the 'gold standard' clinical trial. As T4 is one of the most prescribed medicines, and so are anti-depressants, which have a very similar chequered history, the figure must be high. Yet we are always being bamboozled with arguments that these drugs are based on high quality evidence!

  • Just jumped through to read the original abstract, and it emphasises there even more than in this summary that patients of the past were 'overdosed', as the newly invented TSH test labelled them as such. It's an interesting twist on something we often hear reported by Dr P or in this forum, that people were on higher doses and that was a good thing, because they needed those doses.

    So even though this paper is taking a historical approach, it's going in with very much the present day assumptions that the current diagnostic framework is superior. Which ends up with quite a circular argument - whoever made the judgement that TSH is supposed to be at any particular level?

  • Just a word of warning.

    So far as I have bee able to tell, the UK desiccated thyroid (Thyroid BP) was approximately half as potent as USA products. So if you read a UK report of some patient taking 6 grains - that would more nearly equate to 3 grains of current-day product such as Nature-Throid or Armour.

    (The approximateness is because both were assayed by iodine content - which is not a good way of measuring potency.)

  • Dmf240 thank you for posting this very interesting and helpful article. Hopefully it will give Doctors some food for thought and I will be showing 2 Doctors this in the next week. About a couple of years ago there was a very interesting timeline posted from about the late 1800's. Is there a link to this?

  • Hi j_bee. Is this the one you meant?


    If it doesn't work, it's the one posted by PR4NOW 2 years ago under his post

    "American Thyroid Association Thyroid History Timeline"

  • That is a fabulous link, crabapple, I'd never seen it before. I hadn't realised how long people had been trying to fix thyroid problems in any kind of serious or systematic way. I found it ironic that it said, in 1981, "G.R. Murray introduces the use of thyroid extract to treat myxedema", when apparently the Chinese first did this in 1475.

  • Hi Crabapple, Thank you for giving me the link. This is the one I was thinking of. We need to keep Doctors abreast of this information so they can go on learning.

  • I think absolutely everyone on this forum needs to print that article off and present it to their GPs and Endos

  • I couldn't get this to load through this link. Was I just not waiting long enough?

    Like SilverAvocado I went looking for the original by McAninch. Some very interesting stuff on the Bianco Lab site.


  • dmf240, thanks for the article. If you would like to read the full PDF here is the link.

    At the bottom of the abstract and further down on the right side under "Review Articles" are links for the PDF.


    Using the TSH to titrate the dose based on reaching the 'normal range' is a fools errand if there ever was one. Many of us on NDT have an almost, or completely, suppressed TSH and yet absolutely no "hyper" symptoms. There is still very little understanding of the control system for each individuals 'set point' and how it changes under various conditions. Although doctors are taught in medical school to treat the patient and not the lab test, reality is just the opposite. No one has really touched on children that have been abused or suffered a great terror or fright or bullying and how that affects the endocrine system. So much yet to be explored. PR

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