How do you test when alternate day dosing?

Many members do not take the same dose of levothyroxine every day.

A typical example is alternating 50 and 75 micrograms in order to average 67.5. Or 75 and 100 to get 87.5. Or 100 and 125 to get 112.5. Or even 50 and 100 to get 75.

We also see some patterns such as a higher (or lower) dose on Saturdays and Sundays, or three or four days a week. I consider all these regimes questionable. They often seem to have been chosen to make the life of the prescriber easier. Or because the prescriber thinks we are unable to cope with more even patterns or tablets splitting.

In particular, three or four days a week on a higher dose seem odd to me. You inevitably end up with two consecutive days on the lower, or higher, dose. It would probably make more sense to dose alternate day for 7 days in each fortnight - with hardly any difference in total dose.

Personally, having alternate day dosed for some considerable time, I realised it didn’t suit me. I used to split the 25 microgram tablets so as to take 112.5 every day. And would do so again, if needed, to end up taking the same dose every day.

To get to the point of this blog! The trouble I want to discuss is testing. Taking a simple 50/75 alternate day dosing regime as the example, do you get your blood tested on a day you took 50? Or 75?

And precisely what effect does that decision have on TSH, Free T4 and Free T3? The answers are not immediately obvious - though we can expect the Free T4 to be a bit higher if the last dose was a higher dose. Effects on TSH and Free T3 levels are somewhat more subtly affected by levothyroxine dosing.

And can you achieve that consistently into the future?

Of course, there are the usual issues of how many hours after your dose to do the blood draw, but if you are alternating, you now ALSO have to consider whether that dose was a low or high dose!

I don’t think there is a satisfactory answer to this conundrum.

Either ensure you take an even dose every day. (At least for several days before testing.) Or accept that the effects on your results could be somewhat unpredictable.

Advancing drug safety and mitigating health concerns: High-resolution mass spectrometry in the levothyroxine case study

This paper is a fascinating study which performed detailed chemical analysis on levothyroxine products in order to identify degradation products and unexpected substances. This was partly the result of the reformulation of Merck levothyroxine from lactose to mannitol - and the consequences in several countries - especially France which was the first to receive the new formulation.

The paper is extremely heavy going in parts with highly technical language. Nonetheless, it is actually quite easy to skip most of that and read the explanatory parts which are much easier. We don't need to know how to perform the analyses! Only what they found.

Next time a doctor, a nurse, a pharmacist or anyone else tells you all levothyroxine products are the same, offer a copy of this study... 

Advancing drug safety and mitigating health concerns: High-resolution mass spectrometry in the levothyroxine case study

 

Abstract

Levothyroxine is a drug with a narrow therapeutic index. Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability, which can result in major health problems. However, the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed. In this study, we used a non-targeted analytical approach to examine the various levothyroxine formulations in detail and to reveal possible chemical changes. Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry (UHPLC-DIA-HRMS) was employed. UHPLC-DIA-HRMS allowed not only the detection of levothyroxine degradation products, but also the presence of non-expected components in the formulations. Among these, we identified compounds resulting from reactions between mannitol and other excipients, such as citric acid, stearate, and palmitate, or from reactions between an excipient and an active pharmaceutical ingredient, such as levothyroxine-lactose adduct. In addition to these compounds, undeclared phospholipids were also found in three formulations. This non-targeted approach is not common in pharmaceutical quality control analysis. Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.

And the first sentence of the conclusion:

This work was designed as an independent study with the aim to comprehensively investigate levothyroxine formulations and thus contribute to their quality and safety in response to previous significant health crises.

Full paper including PDF version are open access at link below.

https://www.sciencedirect.com/science/article/pii/S2095177924000674

And

https://europepmc.org/article/MED/39350965 

Fecal glucocorticoid metabolite and T3 profiles of orphaned elephants differ from non-orphaned elephants in Zambia

Many times, members have mentioned issues in their early lives. In this paper, these are referred to as early-life adverse events (ELAEs).

I note that diogenes several times referred to issues such as stress in early life as being causative, or at least contributory, to thyroid issues.

It is, in my view, entirely reasonable to look for links between elephants and humans. We have a lot in common. 

Fecal glucocorticoid metabolite and T3 profiles of orphaned elephants differ from non-orphaned elephants in Zambia

Daniella E Chusyd  1 , Janine L Brown  2 , Steve Paris  2 , Nicole Boisseau  2 , Webster Mwaanga  3 , Moses Kasongo  3 , Lisa Olivier  3 , Stephanie L Dickinson  4 , Bailey Ortyl  4 , Tessa Steiniche  1 , Steven N Austad  5   6 , David B Allison  4   5 , Michael D Wasserman  7

    PMID: 40196305 PMCID: PMC11974515 DOI: 10.7717/peerj.19122

Abstract

Background: 

Elephants provide valuable insight into how early-life adverse events (ELAEs) associate with animal health and welfare because they can live to advanced ages, display extensive cognitive and memory capabilities, and rely heavily on social bonds. Although it is known that African savanna elephants that experienced ELAEs, such as being orphaned due to human activities, have altered behavioral outcomes, little is known regarding the physiological consequences associated with those stressors.

Methods: 

We compared fecal glucocorticoid (fGCM) and thyroid (fT3) metabolites as well as body condition scores (BCS) in rescued and rehabilitated orphaned (early-dry season: n = 20; late-dry season: n = 21 elephants) African savanna elephants in Kafue National Park, Zambia to age- and sex-matched wild non-orphaned controls groups (early-dry season: n = 57; late-dry season: n = 22 elephants) during the early- (May/June) and late- (September/October) dry seasons, respectively. Age and sex were known for orphans. For non-orphan controls, age was estimated based on dung diameter, and sex was determined based on external genitalia. Hormone concentrations were compared between groups by age class to account for developmental and nutritional transitions experienced in early life. Given that environmental stressors (e.g., availability of food and water sources) change over the course of the dry season, early- and late-dry seasons were separated in the analyses.

Results: 

fGCM concentrations were higher in orphans at younger ages than non-orphaned controls of any age. This may be due to the younger orphans being temporally closer to the traumatic event and thus not having had sufficient time to establish meaningful social bonds that could buffer the negative outcomes associated with ELAEs. Alternatively, orphans could have acclimated to living under human care, resulting in fGCM concentrations that were not different from wild controls at older ages. Orphans also had significantly higher mean fT3 concentrations than non-orphans, suggesting increased caloric intake during rehabilitation. There was no difference in BCS between orphan and non-orphan elephants at any age or time period, possibly reflecting the limitations associated with BCS assessments in younger elephants.

Conclusions: 

Together, these results provide insight into possible physiological responses underlying ELAEs and/or living under human care, including alterations in fGCM and fT3 concentrations, particularly in younger orphans. While these hormonal changes suggest a physiological response to trauma, the support of social bonds and acclimation to human care may mitigate long-term stress effects, highlighting the critical role of social integration in elephant rehabilitation and conservation efforts.

Keywords: African savanna elephants; Early life adversity; Stress; Thyroid hormone. 

https://pubmed.ncbi.nlm.nih.gov/40196305/

Open access here:

https://pmc.ncbi.nlm.nih.gov/articles/PMC11974515/

What happens to T3?

If you are familiar with thyroid hormones, you will probably be aware that the interaction of the T3 hormone (tri-iodo-thyronine) with the T3 receptor is how it has its effects on cells.

We need enough T3 - much of which will be transported into our cells from the bloodstream. (Some might be formed by de-iodinating T4 within cells. But I'm desperately trying to simplify this to the extreme!)

The diagram below illustrates T3 (whether supplied to the cell as T3 or converted within the cell) to the T3 receptors in the nucleus. 

We often see descriptions of T3 (and many other substances) reaching their receptors as if a key is being put into a lock. And that makes it very clear that only the specific substance can actually properly activate the receptor. Other substances could potentially block a receptor, or act rather like the the proper substance - but often with less (or more) stimulation of the receptor.

For example:

• Blocking TSH-receptor antibodies prevent the usual TSH stimulating the thyroid gland to produce and release thyroid hormone.
• Stimulating TSH-receptor antibodies act more powerfully than the usual TSH thus stimulating the thyroid gland to produce and release excess thyroid hormone. Which is the fundamental issue in Graves disease.

But what is almost never discussed is what happens to the T3 when it has locked into the receptor. How long does it remain there? What eventually makes the receptor releasee it? Why doesn't that T3 molecule immediately re-attach to that same receptor? Or, if that receptor has become exhausted, why does it not attach to another T3 receptor?

Or does the T3 attach to several T3 receptors in succession?

I find it difficult to see how to combine the processes that would appear obvious with the extremely tight requirement for T3.

If one T3 molecule can attach to multiple receptors, what controls the total number?

Does the T3 molecule released by the T3 receptor get expelled from the cell?

Does the T3 molecule get degraded in some way? Or converted into T2? In which case we need to go through the same questions regarding T2 and T2 receptors!