note to Gimel

[telus2]

Note to Gimel

First let me commend you and your co-authors for your effort in your paper The Diagnosis and Treatment of Hypothyroidism: A Patient’s Perspective.

Re your questions and comments from AUGUST 14:

Daily thyroid hormone production
• a natural healthy thyroid gland secretes about 100 mcg of T4 and 6 mcg of T3 daily. Reference: "2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism".
• a further 24 mcg of T3 daily is produced by conversion of T4 into T3 in peripheral tissues. Thus total T3 production is about 30 mcg daily, of which 20% (6/30) is secreted by the thyroid gland and 80% (24/30) by conversion of T4 into T3 in peripheral tissues.
• Total production of 30 mcg of T3 and 100 mcg of T4 is equal to 46 and 129 nmols respectively (which compares to the 50 and 110 nmols from the paper that you cite).
• I have seen a blog claiming that some T3 (4 mcg?) is produced in the thyroid gland by conversion of T4 to T3; however I have not yet been able to confirm that, or whether that would be additional to the 6 mcg secreted.
• IMHO these basic numbers should be kept firmly in mind when determining doses in thyroid hormone replacement.

Circadian rhythm
• the reference that you cite showed the circadian rhythm of TSH and FT3, but not FT4. Other hormones such as cortisol and testosterone also show circadian rhythm.
• I have seen at least two papers comparing night versus morning consumption for T4-only therapy. There were no apparent ill effects for night time; absorption was just as good or better.
• the fellow who wrote the books "Recovering with T3" and "The CT3M Handbook" is very adamant that timing and dose are very important: He says, "The standard methods of providing T4/T3, T3 or natural thyroid do not mimic this natural physiological circadian process, as the T3 content of these medications is nearly always provided during the awaking hours. Far from being a strange concept, the Circadian T3 Method (CT3M) is actually far closer to a physiological replacement of T3 in these medications than any other method of dosing thyroid hormone has ever managed to achieve until now." I am going to research this method further because I was under the impression it was for T3-only therapy; but he is saying on his blog that it works with T3 only, T3-T4 combos and also NDT.
• re sleep problems with night doses - I think that a lot of the problems could be happening due to taking too much thyroid hormone, and/or caused by issues other than thyroid. The CT3M guy says that sleep improves when you get it right.
• in any event I don't see any downside in taking thyroid meds at night and I find it more convenient.

Slow Release
T3, T4, and natural desiccated porcine thyroid can all be compounded in slow release capsules; they can be compounded in any proportions. The compounded products are USP Liothyronine, USP Levothyroxine and USP Thyroid respectively. There is not much written about using slow release meds. An ND from Oregon wrote a good paper describing how he is successfully prescribing it. However I do not agree with his mathematics for calculating amounts of T4 and T3. The paper is "Hypothyroidism: Optimizing Medication with Slow-Release Compounded Thyroid Replacement".

The Ultimate Goal of thyroid hormone replacement
I agree with you that the ultimate goal is the "relief of thyroid symptoms", but I think we should qualify it to say "long term relief of thyroid symptoms", and we should also add "and the avoidance of any other future side effects". I see two major issues that have to kept in mind when using symptoms to guide thyroid hormone dose: (1) new thyroid patients are typically younger and their bodies are very adaptive. Thus they can achieve relief from symptoms with less than ideal thyroid meds, but in the longer term problems will arise. For example many people seem to be fine on T4-only therapy for many years but then problems start to occur. (2) Trying to achieve relief of symptoms for long term thyroid patients is made more complex because many have developed problems beyond the original thyroid problem. But these patients have a tendency to believe that all symptoms are thyroid symptoms and separating thyroid symptoms from non- thyroid symptoms becomes a problem in reaching appropriate thyroid med doses.

The road to the Goal
I advocate setting an initial target for thyroid meds of getting all thyroid test to near the mid-point, this includes TT4, FT4, TT3, FT3 and RT3 (and TSH around 1.0). Followed by an adequate wait period to see if relief of symptoms occurs. Also during this period, all of the other variables you mention (e.g. iron, cortisol, Vitamin D, etc, etc) need to be checked and rectified if necessary. Then after these steps have been taken, adjust thyroid meds if symptoms of hypo or hyperthyroidism clearly remain. I recognize that defining an appropriate mid-point is an issue because of the problems with the data that goes into setting the reference ranges. For myself, I adjusted my meds to get my labs near the mid-points. I also use the ratio of FT3 to FT4. Unfortunately I still have atrial fibrillation; I am convinced that there is a connection because the amount of AF that I have seems to change with the thyroid meds.

Best.

[gimel]

Glad you clarified about slow release T3 as an alternative.  No problem with that.  

Peak and blood draw.  

So SRT3 is not absorbed in a uniform manner over the whole 8-12 hours.  As shown in the paper you mentioned, SRT3 just does not peak at quite as high a level as plain T3.  

Regarding the cost of SRT3

That is always possible; however, the AACE and ATA are so erroneously adamant about T4 being the only thyroid med required that it would take a lot to get that changed so that pharmaceutical companies might become interested.  

Perhaps a significant benefit from SRT3 might be that the lower peak level would have less effect on TSH levels.  Doctors are generally unaware that suppression is a common occurrence for many hypo patients and does not mean hyperthyroidism unless there are hyper symptoms due to excessive levels of Free T4 and Free T3.  So anything that minimizes the possibility of an erroneous diagnosis of hyperthyroidism based only on TSH, with attendant reduction of thyroid med,  would be helpful for those patients.

[gimel]

Thanks for your comment on the paper.  We tried very hard to give patients concise information that could be easily utilized in discussions with doctors, and also provide enough analysis and scientific evidence that would hopefully convince doctors to make changes in their testing, diagnosis and treatment of hypothyroid patients.  One thing I have always firmly believed is that everyone is entitled to their own opinion, but not their own facts.  So we wanted to make sure we presented plenty of scientific evidence.  

Daily Hormone Production
Thanks for helping clear up the quoted info.  I also knew that the ratio of T4 to T3 from the thyroid gland is approximately 13 to 1.  The numbers in the quote I previously used was obviously not production but the product of production plus conversion.  I have no problem with using that knowledge to develop target doses, from which to adjust as needed to relieve symptoms.   We discuss that in article 11 on p. 13 of the paper.  However, the amount of thyroid medication required daily to relieve hypo symptoms has to take into consideration that each person may have different thyroid hormone levels that meet his needs, the variation in conversion rate of T4 to T3, and also that their may be different absorption rates of the med.  Also, serum thyroid levels may not accurately reflect tissue thyroid levels, plus there are numerous variables affecting tissue thyroid effects.  So in the words of an excellent thyroid doctor,  medication dosage should be adjusted as needed to eliminate signs/symptoms of hypothyroidism without creating signs/symptoms of hyperthyroidism.  


Circadian Rhythm
I have no problem with taking thyroid med at night or whenever it works best for the patient overall.

Slow Release
I was fully aware of the compounding of slow release thyroid meds.  I am not fully confident that results from the process, as practiced by so many different compounding pharmacies, is consistently effective.  I have seen one scientific study where the researchers showed the value of using a slow release form they had compounded that was reportedly effective and they planned to push forward with the concept.  I have seen nothing further.   If someone comes up with such a product, in the right T4/T3 portions, I would be all for it.  But even then I can envision that individuals might get different results from variability in conversion, and other confounding variables, and might require a separate dose of T3.

The Ultimate Goal of thyroid hormone replacement
I am not convinced that we need to add "long term" to the goal of "relief of thyroid symptoms".  I am not sure that new thyroid patients are typically younger and more adaptive.   Many young hypo patients are not adequately tested and diagnosed for some time.  In addition, many people, especially women seem to develop hypothyroidism later in life.  Also I don't expect initially successful thyroid hormone therapy to last a lifetime.  As shown in Fig. 1 in our paper there are many variables that can affect tissue thyroid effects.  These variables are not static throughout our lifetime.  For that reason hypo patients may find that conditions changed and they have become hypo and in need of followup testing and med/supplement adjustment.   True that some symptoms are non-specific in nature, but there are a number that occur much more frequently in hypothyroid patients than in other patients.  So those are the key ones to assess along with levels of Free T4, Free T3, Reverse T3, cortisol, Vitamin D, B12, ferritin, etc.  

The road to the Goal
On this subject I refer you to article 11, p. 13 of the paper.  "The aim of dose determination for a patient should be to get the patient on the required or optimum dose as quickly as possible.  ....Some sets of rules have been proposed which may serve as an initial crude estimate to predict the final dose, which would equal the starting dose in unproblematic situations.  Dose adequacy should then be assessed and adjusted as needed, with relief of symptoms being the main concern."  

With that goal in mind that is why we suggest the tests on p.2 of the paper should be done up front.  There is no advantage to delaying testing for  cortisol, Vitamin D, iron, etc.  That will identify and start supplementation quicker for any identified deficiencies.  

No question about value of the ratio of Free T3 to Free T4.  It is also mentioned in the paper.  There are some people who are more susceptible to AF than others.  If raising your thyroid hormone causes AF, then it is best to reduce the dose.  From what I have read, there are also other variables that can cause reactions when raising thyroid med dosage, including low ferritin and low cortisol.  Have you been tested for those, and if so, are they adequate?  Also, if no other option available some people have used beta blockers to control the AF, in order to get the needed thyroid med dosage.

Thanks for your comments and your participation on the Forum.

[telus2]

I reproduce your recent comment here and then I follow below with my comment.
Just to be clear I am totally on board with the concept of using a slow release T3 thyroid med; however, they are more costly than regular med and I have not seen scientific evidence that anyone has a compounding method that guarantees slow, even release over a 12 hour period.  Further, when I read a site written by the doctor you mention,  I found this.  

"The amount of slow-release T3 prescribed, whether formulated
in combination with T4 or taken separately from T4 , should be
about 25% more than the mathematical equivalencies would suggest.
This is because T4 blunts the utilization of T 3 to some extent.
The compounded slow-release form seems to allow for less total
drug absorption. This can vary considerably from patient to patient.
The best approach is to monitor serum levels of free T4 , free
T3 , and TSH in patients taking T4 and slow-release T3 replacement
6 to 8 weeks after every dose adjustment. Further dose adjustments
can then be made if necessary. Since T 3 has a short
half-life and serum levels tend to peak 3 to 4 hours after dosing of
compounded slow-release T3 , we instruct patients to not take their
morning slow-release medication until after their blood draw."

So two things there.  One is that slow release versions are more expensive and the doctor suggests using 25% more to assure similar absorption, which will add more cost.  Two is that if it truly is slow release over an extended period up to 12 hours, then why the need to mention that it peaks 3-4 hours after dosing and that the morning dose should be deferred until after blood draw?   I don't understand that.

[telus2]

I'd like to make clear that I am not saying that taking slow release T3 (SRT3) is better than taking cytomel. I'm suggesting that SRT3 may be an alternative here if the Doctor is adamant that he will not increase the cytomel dose because of the suppressed TSH. From my experience, TSH stays in 'normal' kind of range when using T4 plus SRT3.

Absorption:
The author states, "The compounded slow-release form seems to allow for less total drug absorption." As he is using the words "seems to", he likely does not have any hard data on this. I can only surmise that because the amount of T3 that he is prescribing (e.g. 30 mcg SRT3 in his example) is much larger than the approx 6 mcg secreted from a normal thyroid, he is concluding that there is an absorption issue. However he does note that there is considerable variation.

Peaks & blood draw:
In this paper - "Thyroxine Plus Low-Dose, Slow-Release Triiodothyronine Replacement in Hypothyroidism: Proof of Principle" they took serial blood samples over a 9 hour period following taking 125 mcg T4 plus 6 mcg SRT3 in one undivided dose. Both TT4 and TT3 reached maximums in 2 - 5 hours from taking the dose and then slowly decreased. Again, I can only surmise that Milner is aware of this and does not want to obtain blood draws near the maximums but rather wants to "capture their lowest level of circulating  T3 in the 24-hour period".

12 hour slow release period?
The data in the paper that I cite above shows that TT3 was still above the baseline at the end of their 9 hour testing period for the 125 mcg T4 plus 6 mcg SRT3 dose . I have not seen any data for longer test periods.

Regarding the cost of SRT3:
Perhaps if demand was high enough, some drug company would mass produce SRT3 capsules in units of 2.5, 5 and 10 mcg. This would probably work for 99% of cases and bring the cost down.