Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine

A very disappointing paper. My summary: a bit of T3 seems to help quite a number of people but let us not give it in case it has some risk. I still argue that it is for the patient to choose between say, 30 years of reasonable health and well-being or 40 of suffering. Of course, the question (and answer) is never quite as simple as that. And in evidence-based medicine, surely it should be necessary to show that adding T3 is a worse option and not simply saying that because they don't know for certain, you can't.

If you are interested, these authors have published papers questioning T4 monotherapy over several years.

Best Pract Res Clin Endocrinol Metab. 2015 Jan;29(1):57-75. doi: 10.1016/j.beem.2014.10.004. Epub 2014 Oct 25.

Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine.

Escobar-Morreale HF1, Botella-Carretero JI2, Morreale de Escobar G3.

Author information


At present, the drug of choice for the treatment of hypothyroidism is levothyroxine sodium, even though the thyroid gland secretes both thyroxine and 3',3,5-triiodothyronine; the latter is the more active of the two at the cellular level because of its higher affinity for the nuclear thyroid hormone receptors. To date, combined levothyroxine plus liothyronine treatment for hypothyroidism has been evaluated in 15 clinical trials in humans. In two studies, combined therapy seemed to have beneficial effects on mood, quality of life, and psychometric performance of patients, compared with levothyroxine alone; in some of these studies, the patients preferred levothyroxine plus liothyronine combinations. This preference should be balanced against the possibility of adverse events resulting from the addition of liothyronine to levothyroxine. Until clear advantages of levothyroxine plus liothyronine are demonstrated, the administration of levothyroxine alone should remain the treatment of choice for replacement therapy of hypothyroidism.

Copyright © 2014 Elsevier Ltd. All rights reserved.


combined therapy; hypothyroidism; levothyroxine; liothyronine; replacement



[PubMed - as supplied by publisher]


13 Replies

  • Thanks for this rather disappointing info, Rob.

    I agree it is better to have 30 good years than 40 poor ones. How can we ever move forward using that as an argument ie. we shall just ignore the patient and what they report about preferring a combination therapy and simply stick with a treatment that is less favoured and not always satisfactory for some.

    I'm keeping popping NDT and if I peg it tomorrow at least I'll die happy. No regrets whatsoever, I'd do it all again rather than spend years on Levo feeling half alive. If scientists don't value my opinion given I am experiencing it first hand, that is their problem.

  • Rod, "Drug of choice" implies there are alternatives available. Levothyroxine is the only drug the majority are offered. I don't know of any other chronic health condition where there is only one treatment available. It's usually accepted that patients may have less than optimal reactions or adverse reactions to one drug but may do well on alternative drugs.

    I don't understand why so many research studies state that some patients prefer, or some do better on T4+T3, but then go on to say 'but further research is needed'. Why not do the necessary research instead of repeating other studies and adding this caveat?

  • As I understand it, they never give the trial participants enough T3, so don't get the results we know happen when you're on sufficient medication. A tactic many GPs try too, it seems, as part of a ruse to persuade you that having T3 won't make any difference.

  • J, I think you are pretty much spot on there...... it is a tactic used by drug companies in clinical trials. They use less or more of a competitor drug to 'tweak' their end points and achieve their PLANNED outcome. When did we all become so cynical...............:-)

  • They are studying people who do fine on levothyroxine alone. If they studied people like my sister for example, then yes she might prefer some T3 to thyroxine alone, but she is fine on the thyroxine if she does not have any T3. So yes they prefer it (just like one would say someone prefers coffee to tea). They obviously didn't study people like myself who cannot function at all without it. For me it is not a preference it is a necessity.

  • This paper does not consider what now is becoming important; namely the efficiency of peripheral T4-T3 conversion vis a vis direct thyroid T3 output. The trouble is with all these papers is that they usually study a "mixed bag" of subjects with varying degrees of residual thyroid activity confounded with various degrees of peripheral T4-T3 conversion efficiency or thyroid direct contribution of T3. Any perceived benefit of T3 in such a group is diluted by the failure to stratify patients into thyroid residue groups (amount of thyroid left) and peripheral conversion efficiency groups. We're planning a new trial to use carcinoma athyreotic patients only, stratify them into good and poor peripheral converters, and then test T4 mono therapy v dual therapy (blinded trial). In this way, you get rid of the confounding presence of residual thyroid activity in a trial. It's still a glint in our eyes, but we're preparing some kind of protocol. This should also help those who've lost their thyroids entirely by autoimmune destruction.

  • It sounds an excellent study.

  • Diogenes, that will be quite interesting if you can get that study done. To my knowledge yours would be the first study to use that approach. PR

  • I think it's going to happen. Everybody involved is highly motivated. A protocol is being assembled as I write. We just need to argue amongst ourselves as to how to do it best with the optimum outcome (one way or the other).

  • This is from Thyroidscience (aka Dr Lowe) who read and analysed (I assume the same research documents) and an extract of his response:

    In reporting this specific result of the studies—that neither type of replacement therapy effectively relieved patients’ symptoms or abnormal neuropsychological test results—three groups of people have is represented, perhaps inadvertently, the outcome: the endocrinology researchers who conducted the studies, the endocrinologists who commented on them, and the journalists who reported them. Rather than reporting the specific study result, these groups reported a false general conclusion: that no approach to T4/T3 therapy (replacement is the only one they tested) was more effective than T4 alone. This false general conclusion violates a rule of quality scientific reporting—that we precisely formulate our statements to accurately convey conclusions that

    we can validly deduce from the studies we report.

    Oddly, based on the negative outcome of these studies, some endocrinologists advise that T4 replacement should remain the treatment of choice for hypothyroid patients. Their advice, however, disregards two humanitarian imperative"

    Excerpt and I believe 'replacement' is just keeping the TSH in normal range:-

    T4 replacement therapy increases the incidence of potentially fatal diseases and boosts chronic drug use to control the patients’ hypothyroid symptoms.

    and those of the other diseases.

  • Think it's a cost issue - the most common adverse event is the impact on GP budgets and the interference of CCGs. I'm very fortunate in having both an Endo and a GP who give me both. GP says he's not worried about the cost but CCG may chip in. Think if they do he'll give them a run for their money. It's taken me a lot of time and effort to get to this stage. The myth that mono therapy suits everyone is just so convenient. Throw in a few frighteners like crumbling bones and heart problems and you manage to con most of the people most of the time.

    Let's not forget either that, pre 1970 and the birth of the Thyroid Function Tests, people with symptoms were dosed with natural thyroid therapies (contain T3 and T4) until they felt well. Oh for the good old days.

    I'm aware that many obese people eat too much of the wrong food and don't exercise enough. I do wonder. though, how many of these folks are either undiagnosed hypothyroid or incorrectly treated hypothroids.

    A bit of joined up thinking could have such a positive effect on the nation's health and, not least, the cost to the NHS. So many symptoms being presented at Primary Care are potentially thyroid based. How much obesity, depression etc was diagnosed before 1970? I've has Breast Cancer as well as Thyroid Cancer. My Oncologist for the BC tells me that when a patient presents with depression, the first thing they test for is thyroid function.

  • Whatever happened to this man's research of June 1996??? This formed part of the references for the above article and appears to contradict his current findings completely. However, were he to do some research with patients who have been on this combined therapy for some time (in my own case 4+ years) he would find his original conclusion more than borne out... I would be more than happy to take part in such a survey!

    Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.

    We have recently shown that it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone. The present study was undertaken to determine whether this is achieved when T3 is added to the continuous sc infusion of T4. Thyroidectomized rats were infused with placebo or T4 (0.80 and 0.90 microgram/100 g, alone or in combination with T3 (0.10, 0.15, or 0.20 microgram/100 g Placebo-infused intact rats served as euthyroid controls. Plasma and 12 tissues were obtained after 12 days of infusion. Plasma TSH and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine deiodinase activities were assayed using cerebral cortex, pituitary, brown adipose tissue, liver, and lung. Circulating and tissue T4 levels were normal in all the groups infused with thyroid hormones. On the contrary, T3 in plasma and most tissues and plasma TSH only reached normal levels when T3 was added to the T4 infusion. The combination of 0.9 microgram T4 and 0.15 microgram T3/100 g resulted in normal T4 and T3 concentrations in plasma and all tissues as well as normal circulating TSH and normal or near-normal 5'-deiodinase activities. Combined replacement therapy with T4 and T3 (in proportions similar to those secreted by the normal rat thyroid) completely restored euthyroidism in thyroidectomized rats at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.

  • That was 1996 and this brand new one is saying pretty much the same, with added science!

    They've been banging on about not knowing enough about safety of T3 for decades too, even though it was deemed good enough for President JFK in the sixties. I think Dr Malcolm Kendrick has it spot on. Scientists are invested in their pet theory, they struggle to be parted from their bias.

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