This just-out paper in Thyroid shows that use of T3 instead of T4 has no effect on cancer incidence or mortality compared with T4 therapy - its online and can be accessed. More grist to the mill.
Free Access
Liothyronine Use in Hypothyroidism and Its Effects on Cancer and Mortality
Tereza Planck, Fredric Hedberg, Jan Calissendorff, and Anton Nilsson
Published Online:5 Jan 2021doi.org/10.1089/thy.2020.0388
Thanks. Don't have time to read this at the moment but it is probably explained by the fact that there is a receptor for thyroid hormone on the integrin layer that binds to cell membranes. This facilitates the spreading of SOME cancers (and also possibly SARS-CoV-2 infection!). T4 strongly binds to this integrin receptor but T3 binding is very weak. It is T4 binding to the integrin receptor that facilitates the spread of certain cancers. Thus, if serum T4 levels are low - due to hypothyroidism or e.g. replacement by T3 or T3 analogues - the cancer will not spread so easily. This review gives a summary frontiersin.org/articles/10... .
There was also a small prospective L-T3 intervention trial that showed positive results in reducing cancer mortality theoncologist.onlinelibrary... .
Thank-you for posting this fascinating study. It certainly shows that LT3 or combined LT3 / LT4 as practiced in Sweden carries no extra risk over LT4 therapy.
There is a possible flaw in that the LT3 group had a much shorter follow-up time than the LT4 group (2.9 vs 8.0 years). It’s not just a case of working out annual cancer or mortality rates, some cancers may be slow growing and take time to reveal. On the other hand, most of the LT3 group may have been on LT4 monotherapy for some time leading to underestimation of any differences.
The LT3 group we much younger (45.9) than the LT4 group (58.6). Consequently, the numbers in Table 1 are not useful until they have been adjusted for age.
The study mentions Graham Leese’s study scihub.wikicn.top/10.1111/c... which found higher breast cancer rates in patients receiving LT3. Fig 1 appears to show an increased risk of breast cancer, especially in patients on LT3 only. However, this was not statistically significant as only 15 of the LT3 group developed breast cancer. The study was too small.
This latest study assumes LT3 is 3x as potent as LT4 based on a study by Francesco Celi pubmed.ncbi.nlm.nih.gov/204... . On this basis the LT3 group were on higher doses than the LT4 group and there was no difference in cancer or mortality rates between the two groups. In other words, based on current prescribing practice LT3 monotherapy or combined LT3 / LT4 therapy carries the same cancer and mortality risks as LT4 monotherapy. My guess is that we might find combined therapy is safer than LT3 monotherapy, this is speculation.
When the results are ‘fully adjusted’ (including dose) the LT4 group has higher cancer mortality in females and higher all cause mortality in males and females (Table 2). This is also shown in more detail in Fig 1. These results are hypothetical in the sense that in practice the two groups do not receive equivalent doses. I assume this is because those receiving LT3 have more problematic hypothyroidism which requires higher doses.
I think we can draw two conclusions from this study which I will express in tabloid newspaper style!
1. Higher doses of thyroid hormone cause higher cancer and mortality rates (hypothyroidism is thought to be cancer protective).
2. LT4 monotherapy causes cancer in women and higher mortality in men and women.
If we accept that patients receiving LT3 need these higher equivalent doses we can turn our attention to the large group of patients currently receiving LT4 monotherapy, most of whom seem to be doing well. These results suggest that if they were switched to an equivalent dose of combined LT3 / LT4 therapy there would be a significant reduction in cancer and mortality rates. If I’ve got my arithmetic right this would amount to a reduction of about 1,800 cancers and 800 deaths pa in Sweden – population just over 10 million. LT4 monotherapy kills!
Let’s not forget higher doses kill also. My view is that where the T3 comes from is crucial. In healthy people 80% of T3 comes from peripheral deiodinase, mostly type-2 deiodinase (D2) provided hormone levels are not low. D2 controls local T3 levels in tissues such as the brain and skeletal muscle and this locally generated T3 finds its way into the blood as reflected by assays. D2 activity is in part regulated by TSH. If TSH is subnormal there is reduced D2 activity. We can restore normal serum free T3 levels by taking a little LT3 or NDT. However, patients such as myself find this is not enough, I need to take around 50 mcg LT3 which pushes my fT3 above its upper reference limit - a supra-physiological dose. Organs such as the brain prefer to take in T4 and convert it to T3 locally. Thus, as found in this study patients taking LT3 tend to have higher hormone levels.
Our goal should be to correct subnormal TSH secretion. This would enable the use of replacement doses of T3 / T4 that give average fT3, fT4 levels leading to reduced cancer and mortality with improved symptoms. Lower mortality than patients receiving equivalent LT4 monotherapy.
Where the T3 comes from matters. T3 coming from D2 has more effect than T3 from tablets.
What do you mean by subnormal? For a "euthyroid" response on T4 mono therapy, the appropriate TSH range is 0.03-0.5 thereabouts (Ito's paper).. The problem often seen especially with longterm therapy patients is that, at the outset, their TSH was virtually zero. We know that recovery of TSH levels is slow, and for some people indefinitely so. Especially on T4/3 and T3 terapy where I believe the suppression is greater. Every time, we have to abandon generalities, and focus on where the individual finds their best outcome, regardless of the strict numbers.
For example my case. When originally diagnosed my results were: -
TSH 1.0 (0.4-5.5), fT3 4.9(3.5-6.5), fT4 13.3 (9.0-21.0)
I needed high hormone doses for a decade until I discovered my problem (endocrine disruption). A couple of years ago after stopping medication for some time, I had to fall back on 50 mcg levothyroxine with the following results: -
TSH 5.52 (0.27-4.2), fT3 2.9(3.1-6.8), fT4 8.3(12.0-22.0)
As can be expected I was very hypo!
With these very low fT3, fT4 we would expect TSH to be very high. I had given it several months to recover. Clearly my hypothalamic pituitary thyroid axis had been down-regulated by years of TSH suppression by high dose hormone (105 mcg liothyronine). As you say sometimes the TSH recovers, sometimes it doesn't.
The consequences of subnormal TSH secretion are dire, see the examples I give here ibshypo.com/index.php/subno... . In fact I see examples like this every week or so on this forum, patients with low normal fT3 and fT4 and a TSH that is not appropriately elevated. These patients have symptoms much more severe than would be expected with their TSH or fT3 or fT4 viewed in isolation.
Certainly we have to supply sufficient hormone to resolve signs and symptoms regardless of TSH. The point I would like to get across is that the subnormal secretion of TSH in these cases is a major part of the problem due to its effect on type-2 deiodinase.
