Though I sent this paper to TUK to archive, posters may not have seen its contents. So I've recorded the conclusion here. There seems to be little difference between the three dosage possibilities (NB most would be T4-tolerant anyway and would have no preference) as to effects on patients and Hashimoto patients preferred the alterantives to T4 only. Also the well known D2 mutation didn't make a difference either. This does NOT specifically address those who would benefit on alternatives to T4 but it does not indicate any possible problems with combination therapy of whatever kind. The next step is obvious: to address those specifically unable to use T4 alone. At least there seem to be no drawbacks.
RESULT
There was no significant difference between the 3 arms on the thyroid symptom questionnaire (p=.32), and the secondary outcomes showed no between group differences. Auditory memory index (p=.008), and visual working memory index (p=.02) were higher in the Hashimoto’s than non-Hashimoto’s group. There was no significant primary or secondary outcome difference among various genotypes of deiodinase 2. There was no relationship between Hashimoto’s vs. non-Hashimoto’s based on genotypes or likelihood of carrying Thr92AlaD2 polymorphism. Though there was no statistically significant preference for any treatment, numerically more patients with Hashimoto’s preferred DTE and LT4/T3 combination than LT4-monotherapy.
Conclusions: There was no significant difference between hypothyroid patients taking DTE vs. LT4/T3 combination vs. LT4 monotherapy. Numerically, Hashimoto’s patients tended to prefer DTE and LT4/T3 combination. Also, there was no observed relationship between Hashimoto’s and polymorphism. Further studies with more patients may be needed.
If more preferred combination. therapy (and I have seen this stated before), why is it impossible to get any measure demonstrating statistical significance? Is it down to small sample size, methodology or,...god forbid...it really is the case? May be it’s only a few that prefer it (over most that have no preference) and they are over represented on this forum.
Thanks for the info.
The other thing I have found odd is that close members of my family have done really well on Levothyroxine but I did not. I know I have the DIO2 ‘poor conversion’ (not sure what else to call it heterogeneous perhaps?) combination but I have no idea of those relatives’ DIO2 status. I had atropic autoimmune thyroiditis but they had primary NHL of the thyroid One had chemo one had total thyroidectomy. I just assumed my DIO2 status explained the difference (ie Levothyroxine never restoring me to health but getting excellent results on NDT ). Could the type of disorder have a bearing on it? There must be a reason for the difference in response, all three of us had no thyroid function. They never tried combination therapy to see if they found it better than t4 alone. Maybe there are other genes involved as yet unelucidated. It’s all very interesting.
I am surprised that patients didn't prefer either NDT, or combination therapy, especially those with the polymorphism DIO2. Was it because patients were considered optimised by TSH rather than level of T3, or are some other polymorphisms to blame such as DIO1 or DIO3?
In one of the only studies comparing desiccated thyroid extract to levothyroxine, doctors from Walter Reed National Military Medical Center in Bethesda, MD, compared the results when 70 people with hypothyroidism took each medication for 16 weeks. Afterward, 49% said they preferred the extract, 18% preferred levothyroxine and 33% had no preference. “Patients who preferred DTE [desiccated thyroid extract] lost approximately 4 pounds …compared with L-T4 treatment. In addition, their general well-being and thyroid symptoms were significantly better,” the researchers report.
And in a 2014 study in the Journal of Endocrinology, Diabetes & Obesity of 154 women and men who didn’t feel better while taking levothyroxine, 78% who switched to a thyroid extract said they preferred it. Side effects were minor.
. “The discovery of thyroid replacement therapy. Part 1: In the beginning.” Slater S. Journal of the Royal Society of Medicine, 2011: 104: 15–18. URL: ncbi.nlm.nih.gov/pmc/articl...
Also some research suggesting adding T3 for the DIO2 gene:-
The Deiodinase 2 (DIO2) gene was researched in 2009 and the results were published in a paper titled Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine plus Triiodothyronine Therapy in Hypothyroid Patients. Panicker V, Saravanan P, Vaidya B, et al. Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patients. The Journal of Clinical Endocrinology & Metabolism . Published online May 1, 2009:1623-1629. doi:10.1210/jc.2008-1301
The patients on this study were given levothyroxine (T4) only for a set period and then combination treatment of both levothyroxine and liothyronine (synthetic T3). The patients who had normal genes did not feel any different on T4/T3 combination treatment. However, those who had one variant gene (inherited from one of their parents) felt better on the combination treatment and those with two variant genes (inherited from both parents) felt better still.
This means that there is a possibility that patients who are on levothyroxine alone, still have symptoms and have the variant Deiodinase 2 gene may improve with the addition of liothyronine.
What the Endocrine Society of AAAS (American Association for the Advancement of Science) thought of the article (here in full)
Treatment of hypothyroidism, which results from an underactive thyroid gland, should be individualized and consideration should be given to alternatives to the first-line therapy, including desiccated thyroid extract and combination therapy to replace the body's two main thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Results of their new randomized clinical study are being presented at ENDO 2021, the Endocrine Society's annual meeting.
Combination therapy has been shown to be equally as effective as the standard treatment with levothyroxine alone, researchers say.
"There are now proven good treatment options for the more than one in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain and other symptoms despite taking levothyroxine," said the study's principal investigator, Thanh D. Hoang, D.O., a staff endocrinologist at Walter Reed National Military Medical Center in Bethesda, Md.
For some of these patients, Hoang said he has observed dramatic improvement--"a night and day difference"--in thyroid symptoms after they switch to desiccated thyroid extract (DTE), one of the drugs tested in the new study.
Also known as thyroid USP, DTE was the original treatment of hypothyroidism established almost 100 years ago. Unlike levothyroxine, which contains only one form of the thyroid hormone (thyroxine, T4), DTE comes from animal thyroids and contains both of the main thyroid hormones in the body, T4 and triiodothyronine (T3), Hoang said.
Past research from Hoang's group found that DTE safely led to modest weight loss and possible improvement in mental health over levothyroxine.
In their new study, Hoang and colleagues investigated the effectiveness of DTE in reducing thyroid symptoms as well as another combination therapy, levothyroxine plus liothyronine, the pharmaceutical grade version of T4 and T3. Although a few studies have shown that this combination works better than levothyroxine monotherapy in some patients, other studies failed to show superiority. As a result, doctors do not always consider it when patients respond poorly to levothyroxine, Hoang said.
The investigators randomly assigned 75 adults with hypothyroidism to three months' treatment, with one of three drugs: DTE, levothyroxine-liothyronine combination, or levothyroxine alone. At the end of three months, the patients then randomly received a different treatment for three months, and finally took the third drug regimen for the last three months. Neither the patients nor the investigators were aware of which drug the patients were taking. After each treatment arm, patients completed a questionnaire of their thyroid symptoms.
The researchers found no significant difference between any of the three treatments in symptom relief. However, most patients reported a preference for combination therapy over levothyroxine alone, according to Hoang. Among the study participants, 45 percent reportedly preferred DTE over the other two treatments, 32 percent preferred the levothyroxine-liothyronine combination, and 23 percent preferred levothyroxine alone. Patients were more likely to prefer combination therapy if they had Hashimoto's disease, an autoimmune disease that is the most common cause of hypothyroidism in the U.S.
Because Hoang said it would be helpful for doctors to select which patients would initially respond better to a combination treatment than to levothyroxine alone, the researchers are further studying their data to find potential predictors of treatment response.
As the majority of patients preferred a combination treatment, only one in four preferring levothyroxine monotherapy, is there not an argument that the standard treatment should be a combination?
(Especially as those who preferred levothyroxine monotherapy might, eventually, have found a combination treatment that they preferred – if they had been given the opportunity to try a wide range of combination including, possibly, desiccated thyroid with some extra levothyroxine.)
A hyper-simplistic view:
You have a patient in front of you and there is a 75% chance they will prefer A to B. And 25% that they would prefer B to A. Do you try A and switch to B after a period of time not doing very well on A? Or try B and switch to A after a period of time not doing very well on B?
If it took one year to make the decision whether to switch, and you have 100 patients:
A then B would imply 25 patient years on the less preferred treatment.
B then A would imply 75 patient years on the less preferred treatment.
Further, the preference for A sometimes gives rise to a “night and day difference”. Any preference for B is not distinguished by such an eloquent description.
I think it boils down to: look at, talk with, diagnose the patient as a candidate for thyroid function testing: When treating the patient, do whatever combination is necessary to alleviate their symptoms - perhaps try T4 only first , then if insufficient improvement move flexibly onto T4/T3 combination or DTE or any suitable mixture containing T3. Measure FT4 and FT3, TSH if you must (but it should be secondary rather a primary test). Patient experience held above all other considerations.
Many thanks Diogenes! In a nutshell, I think you have distilled the most ideal treatment protocol to patients and symptom management and control! So frustrating that the NICE Guidelines are based on other criteria and archaic evidence based on “pharmaceutical”tests and promotion of monodosing! Who is the real customer I wonder and where is the Duty of Care?
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High out of range ft4 & ft3 (high) on NDT but huge TSH too..?
Dropped down to 2 grains of NDT from 3, FT3 above the range, FT4 nearly below?
Advice for Optimal FT3/FT4
optimal ft3 and ft4? 
TSH, FT3 & FT4 results
