[wolverine]

@DrMariano 1483 wrote:

Free T4 of 0.8 to 0.9 is fairly low from a behavioral point of view. My criterion for suboptimal Free T4 is a Free T4 < 1.2 Based on clinical observation, I suspect behavioral hypothyroidism when one of these criteria is met:

• Free T3 < 3.3 (or 330 depending on the units)
• Free T4 < 1.2
• TSH > 2.0

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There isn’t a way to assess brain levels of thyroid hormones because we don’t have a window into which we can see – outside of a lumbar puncture. For norepinephrine, we can see an approximation of brain levels from a Fractionated Plasma Catecholamine test – so long as the sympathetic nervous system to adrenal medulla circuit is not disconnected (i.e. the serotonin signal at the junction is intact). Diabetes is one example where this circuit is disconnected. But for thyroid hormone, we have no clear direct access.

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Perhaps one way to do so is actually TSH – since TSH is the brain’s opinion of how much thyroid hormone it needs. Unfortunately, if the brain is not functioning well – as in mental illness or other metabolic-nutritional problem – then TSH may not be produced in sufficient quantities for a given thyroid hormone level. Another confounding variable is that TRH is made by numerous cells outside the hypothalamus – e.g. by the testes, the spine, etc. Thus, TSH may be a response to extra-hypothalamic signaling.

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At this time, I think the best way to encourage good brain levels of T4 is to optimize Total T4. To an Armour Thyroid treatment, this means adding T4 to Armour Thyroid. It isn’t tricky to do so. If T3 goes too high, reduce the Armour dose. Since the half-life of T3 is much shorter than T4, it is far easier to adjust T3 (which stabilizes after 5 or fewer days) than T4 (which stabilizes after 6 weeks). I would watch for early signs of excessive T3 such as facial skin dryness, chapped lips or palpitations (a sensation of the heart bouncing uncomfortably in the chest).

Is it unusual, Dr. Mariano, to have a Total T4 of 4.0 on 3 gr Armour (even before the new formulation)? Particularly when Free T4 (.8-.9), Total T3 (167) Free T3 (445), and Reverse T3 (17) are relatively normal?
Also, if T4 is added to the 3 gr Armour regimen, would you expect to need to decrease the Armour dose?
Thanks.

[wolverine]

@DrMariano 1397 wrote:

T3 and T4 are bound to three proteins in the blood:

• Thyroid Binding Globulin (also called Thyroxine-Binding Globulin, TBG)
• Transthyretin
• Albumin

The distribution of thyroid hormones and binding proteins are approximately:
T4: 68% to TBG, 11 % to Transthyretin, 20 % to Albumin
T3: 80 % to TBG, 9 % to Transthyretin, 11 % to Albumin

T4 has a stronger bond to TBG.
T3 has a stronger bond to Transthyretin
Both T3 and T4 have a much weaker bond (approximately 100 to 1000 x less) to Albumin.

The thyroid hormones dynamically change between the free state and the bound state. Since the bond to Albumin is weaker, much of what is bound to Albumin may be free at any given moment, but won’t be registered as Free T3 or Free T4. Some portion of T3 and T4 is also free at any given moment but may not be registered as Free T3 or Free T4.

Free T3 and Free T4 give you only a snapshot – one moment in time – of the state. But this state varies from moment to moment.

This is why it is useful to take Total T3 and Total T4 into account to help determine total thyroid function.

This is analogous to Testosterone. Some use “bioavailable” testosterone as a measure of testosterone signaling activity. This would represent testosterone that is free and testosterone that is loosely bound to albumin. However, even tightly bound testosterone to sex-hormone binding globulin (SHBG) has signaling functions via induced conformational changes in the SHBG molecule then binding of testosterone-bound SHBG to SHBG receptors.

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Thyroid hormone does not directly diffuse into cells.

Thyroid hormone is transported across cell membranes by various transporter molecules. In the brain and in the blood brain barrier (BBB), two known transporter molecules are Thyroid Hormone Transporter Molecule MCT8 and Organic Anion Transporting Polypeptide OATP1C1. MCT8 is also produced in heart, kidney, liver, and skeletal muscle.

There are two blood brain barriers: The Blood Brain Barrier Endothelial cells that line the blood vessels of the brain and are connected to astrocytes of the brain, and the Blood Cerebral Spinal Fluid Barrier Choroid Plexus Epithelial Cells that connect the blood to the Cerebopinal Fluid. The Choroid Plexus filters blood in order to produce Cerebrospinal Fluid.

From blood, T3 and T4 enter the brain via two paths:

1. T3 and T4 are transported into a BBB Endothelium Cell (via OATP). T3 and T4 are then transferred into an attached Astrocyte. In the Astrocyte, Deiodinase D2 coverts T4 to T3. T3 then exits the Astrocyte via MCT8. T3 then enters neurons via MCT8 transporters.

2. T3 and T4 are transported into Blood Cerebral Spinal Fluid Barrier Choroid Plexus Epithelial Cells (via MCT8). They they exit the choroid plexus (via OATP) and enter the Cerebrospinal Fluid (CSF). From the CSF, T3 and T4 are taken up by Tanycytes or Astrocytes. These cells have D2 Diodinase, which convert T4 to T3. Upon exiting these cells, T3 enters neurons.

Notably, neurons have Diodinase D3 enzyme which converts T4 to reverse T3 and T3 to T2.

The presence of thyroid hormone can reduce production of OATP as part of a negative feedback loop control.

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Within brain cells, there are variations nuclear membrane thyroid transporters. Usually, 90 % of the intracellular T3 is located in the cytosol and 10 % is in the nucleus. In the pituitary gland’s cells, however, 50 % of T3 is in the nucleus.

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Adding to the complexity of how thyroid hormone works, there is an Intracellular T3 Binding Protein (CTPB) which is produced in high amounts in the brain and heart, though is also widespread in production in the body.

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Serum measurements of thyroid hormone can’t be used to infer CSF concentrations. Only a spinal tap will be able to tell what the CSF concentrations are.

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Brain thyroid hormone levels and T3 to T4 ratios are going to be determined at several levels.

For example, the number and types and location of thyroid transporters determines what amount of thyroid hormone gets through.

Variations in the genes for the thyroid transporter molecules will determine how effective they are and how selective they are for T3 or T4 transport – creating a difference between Blood and Brain concentrations of Thyroid hormones.

Variations in Astrocyte and Tanycyte Diodinase D2 production will determine T3 to T4 conversions in the brain, which may be different from the blood.

etc.

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From my point of view, given the differences that can arise in blood versus brain levels of thyroid hormone and thyroid hormone conversion, it is important to consider in some patients to not only optimize T3 but to also optimize T4 levels.

This is important, for example, in mood disorders. Here, the difference between T3 and T4 treatment becomes apparent.

In major depressive disorder, historically, T3 is a more effective treatment than T4 in reducing depressive symptoms. Spectulating: perhaps T4 to T3 conversion in the brain’s astrocytes and tanycytes is impaired by lack of D2 Diodinase production, among other possible problems in brain thyroid hormone metabolism.

In bipolar disorder, historically, T4 is much more effective than T3 in stabilizing mood. T4 may be used medicinally to reach “hyperthyroid” levels – based on TSH measurements – in psychiatry to stabilize mood in bipolar disorder. Speculating: perhaps, in bipolar disorder, there is a gene mutation in one of the thyroid transport molecules which selectively impairs T3 transport.

If a person is having problems with a T3 treatment or Armour Thyroid Treatment (which is primarily a T3 treatment), then perhaps adding a T4 treatment would be useful. Some patients benefit from combinations of thyroid treatments (e.g. T3 + T4, Armour Thyroid + Levothyroxine) better than single treatments alone.

After reading your comments, Dr. Mariano, it seems that you are saying that even if free serum T4 measurements look consistently good (e.g., 0.8-0.9), that doesn’t necessarily imply that T4 concentrations in the brain will be good. Particularly if total serum T4 runs low (e.g, 4.0). And the best way to encourage good brain levels of T4 is to optimize total serum T4 to at least 8.0. Is that correct? And if so, is it tricky to add levothyroxine to an Armour regimen without raising T3 too high? Thanks.

[wolverine]

@DrMariano 1405 wrote:

The original question was about the addition of T4 to an Armour Thyroid Treatment.

And I used major depressive disorder and bipolar disorder as to examples where there is a difference between response to a T4 versus T3 treatment to due differences in brain thyroid hormone signaling and metabolism versus body thyroid hormone signaling and metabolism.

In both major depressive disorder and bipolar disorder, hypothyroidism may occur both in the brain and in the body. For example, nearly every person I see who has bipolar disorder has low thyroid signaling in the body. Thus, many physical signs of hypothyroidism such as low body temperature, dry skin, slow heart rate, slow deep tendon reflexes, etc. can be found in such patients. The late Broda Barnes, M.D. determined this in the 1970s (see his book, Hypothyroidism: The Unsuspected Illness for information).

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Myalgias may have causes other than low thyroid hormone signaling. For example, the brain (including the blood brain barrier) and the immune system may produce excessive pro-inflammatory cytokines (the signals of the immune system) in an interplay in response to other factors (metabolic-nutritional problems, conditions which raise sympathetic nervous system activity, conditions that increase pro-inflammatory cytokine signaling including other cytokines, etc). This may produce the sensation of muscular pain from abnormal sensory signaling from the peripheral sensory nerves (a neuropathic pain syndrome) or the sensation of muscle pain from central nervous system circuitry (a central pain syndrome).

As an aside: what we call Tension-Type Headaches, from a neurological perspective is actually a hallucination. There is no muscular tension where the pain is located. It is a centrally-generated pain condition. Treatments that work include non-steroidal anti-inflammatory medications. Usually, people don’t call them antipsychotics. But in this case, they are. Tension-type headaches are real in that they are a commonly experienced condition that people can relate to. But technically, they are hallucinations also. They are normal hallucinations, just like dreams are normal hallucinations.

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Low body temperature may be contributed to by low thyroid hormone in the body. However, it may also be contributed to by metabolic problems.

Thyroid hormone is a signal. The cell that receives will act on it depending on its capacity to act. If there are metabolic-nutritional deficits, then it may not be able to act on the thyroid signal well. Thus symptoms of hypothyroidism may occur.

Examples including iron-deficiency, Vitamin A deficiency, selenium deficiency, mutations of the thyroid hormone transporter molecules, deficiencies in intracellular thyroid binding proteins, mutations in the thyroid hormone receptor, mutations in mitochondrial DNA which impair response to thyroid hormone (hypothyroidism Type 2), etc.

Do you think that the presence of axial muscle trigger points and spasticity could be related to brain hypothyroidism? Also, could brain hypothyroidism exacerbate spinal radiculopathy?

[wolverine]

Thank you, Dr. Mariano, for shedding so much light on what is apparently an extraordinarily complex set of processes.

In dishinguishing between CNS and peripheral hypothyroid symptoms, are you saying that mood disorders would likely be indicative of the former? How about myalgias and low temperatures…CNS or peripheral?

[wolverine]

@JanSz 1189 wrote:

My thoughts (I am not a doctor, not even close).

Per dr Mariano past recomendations, it is good to have Ferritin(100-150)

iodine + selenium

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=(219-97)*2/3+97=178

Your TotalT3=167 lacking
it is (slightly) less than 2/3 of range
In recent LEF magazine they recomend thyroid management to achieve TT3 higher than 2/3 of range

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to be tested ReverseT3 and antibodies

manage suplementation to achieve

RT3 in lower half of range
0.5
Off hand, there is a good possibility that 3Grains is too much as it totally suppresses TSH.
So possibly 2.5Grains would work better.

.

Ferritin

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> 142 (24-336)
Reverse T3

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> 17 (11-32)
Thyroglobulin AB—> <20 (<20)
Anti-TPO AB

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> <10 (<35)

Since my pituitary can’t produce much TSH (I’m secondary), my doc isn’t worried about total TSH suppression.

[wolverine]

@DrMariano 1181 wrote:

When I believe a person has suboptimal thyroid signaling which requires thyroid hormone treatment (some can instead correct by improving iodine, addressing HPA Axis dysregulation, etc.), then I use either T4, Armour Thyroid, T3, or some combination of these.

—

Armour Thyroid is primarily a T3 treatment. The loss of native T4 production often is not made up by the T4 component of Armour Thyroid.

The question is: will this cause a problem in a patient?

It depends on the patient.

Many people can get along with Armour Thyroid quite well. The T3 component of Armour Thyroid generally gives it a noticeable kick when it comes to brain function in general than a pure T4 treatment (Levothyroxine), a sharper sense of well-being. But this does not occur with everyone.

For example, the rest of the system may not allow a heavily T3 treatment to work. If adrenal function is compromised, for example (which is common in mental illness), then the additional T3 may destabilize the system, causing anxiety, irritability, fatigue, stress, etc. In such a patient, a T4 only treatment may be a better choice.

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My initial rule of thumbs regarding thyroid hormone levels are rules of thumb. There are always exceptions to a rule of thumb. But as a rule of thumb, it provides a starting point.

Thyroid signaling problems can be caused by problems not related to thyroid gland function. This is called Non-Thyroid Illness affecting thyroid function. This is a common problem in mental illness.

One use of my rule of thumb is as a screening tool to determine if a person needs thyroid hormone replacement or if the problems causing thyroid hormone signaling dysfunction are elsewhere in the system. For example, if T4 is already greater than 8.0, I may decided to forgo thyroid hormone treatment and instead improve functioning in the rest of the system to eventually improve thyroid signaling.

—-

T3 generally be taken once a day with up to a 24-hour half-life generally. But the half-life varies. Some people have shorter half-lives for T3 and thus they have to take their T3-containing thyroid treatment more frequently.

Again, treatment depends on the person and needs to be customized to the person.

Thanks, Dr. Mariano. BTW, I’ve also been diagnosed with secondary hypogonadism and secondary hypoadrenalism (the latter on the basis of an insulin hypoglycemia test), and take supplemental testosterone, HCG, hydrocortisone, Florinef, DHEA, and pregnenolone.

I think I’m doing reasonably well with my Armour regimen. What symptoms might I experience if my CNS thyroid signaling were suboptimal?

[wolverine]

@hardasnails1973 1177 wrote:

Your T-4 being low looks strange. By taking armour more then 2 times a day is over kill and you are risking absorption from issues from food or any supplements. One would also look at the cortisol levels as this could have a major impact of thyroid signaling at the tissue. You could have hyper thyroid levels in the blood but at the tissue could have cellular deficiency. One may want to look at taking 90mg BID which will keep a more even keel. The logic that you are using is that t3 life is about 6-8 hours, but you forgot about the conversion to t4 to t3 which compensates for this idea. If you were taking t-3 on its own then yes every 8 hours may be recommended. According to Dr.Lowe and Gina Honeyman t-3 can be administered once a day and people be fine with it. The ideology behind this is that the best absorption occurs in the morning on an empty stomach. In theory then dosages in the mid afteroon should be actually larger then the morning because there may be competition from food or vitamins. If you are taking armour 3 times a day then you are really putting your self at risk of reduces absorption of thyroid meds. Instead of armour one may want to add in some t-4 to level bring the 2 levels back into more even level. May be reducing armour to 2 grains and then adding 100 mcgs of t-4 may be what may be needed by your Dr to level things out. Many thyroid boards would suggest increase your armour to 3.5 grains but this will drive t-3 even higher which in your case is not needed (unless you are getting pooling from low cortisol). When you mention adding in t-4 to the mix they get their panties in a bunch. Adding t-4 is taboo, but in some clinical cases may help to alleviate some of the symptoms that have not cleared up on current protocol.

At this time I’m not having any untoward symptoms under my current protocol. My question is whether a total T4 of 4.0 and a free T4 of 0.8 indicate that I have a sufficiently large pool of serum T4 to insure adequate brain levels of free T4 and ultimately free T3.

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