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Original thread: http://www.definitivemind.com/forums/showthread.php?t=254
@wolverine 1394 wrote:
Dr. Mariano, do T4 and T3 cross the blood brain barrier only as free T4 and free T3? Or do all forms of T4 and T3 get across? Some forms easier than others?
Since T4 and T3, in whatever form, are all measurements of serum concentrations, can Total T4, Free T4, Total T3, and/or Free T3 (or some combination) be used to infer CSF concentrations?
I believe that this becomes an issue when desiccated thyroid is used as sole replacement therapy. Often this results in normal (or high normal) Free T4, Free T3, and Total T3, but markedly sub-normal Total T4. In this scenario, if CNS hypothyroidism were suspected (and I’m not sure what symptoms would differentiate CNS from peripheral hypothyroidism), would it be desirable, e.g., to achieve a normal Total T4 by decreasing the dose of desiccated thyroid and adding pure T4?
Thanks.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 AlbuminT4 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.
Seems like straight T3 isn’t too bad for Bipolar symptoms either.
@AlexanderDenmark 1465 wrote:
Seems like straight T3 isn’t too bad for Bipolar symptoms either.
T3 is useful for depression.
Bipolar Depression and Major Depressive Disorder have an underlying pathophysiology which is essentially identical. Thus, T3 is useful.
In Mania, however, T4 is much more useful in stabilizing mood. In would be interesting one day to determine why this is so. Perhaps this would then tell us what causes mood to cycle between mania and depression. Historically, in studies, this difference in responsiveness has turned out to be the case.
How large a percentage of people do you reckon who suffer from disorders on the depresssion and anxiety spectrum(MDD, Bipolar, OCD, GAD etc) do you reckon suffer from a low thyroid disorder? Do you reckon that the thyroid disorder is a cause in itself(genetic, sporadic inheritence) or somehow secondary and caused by the mental disorder or unhealthy lifestyle?
@AlexanderDenmark 1507 wrote:
How large a percentage of people do you reckon who suffer from disorders on the depresssion and anxiety spectrum(MDD, Bipolar, OCD, GAD etc) do you reckon suffer from a low thyroid disorder? Do you reckon that the thyroid disorder is a cause in itself(genetic, sporadic inheritence) or somehow secondary and caused by the mental disorder or unhealthy lifestyle?
I’ve read as much as 50% of those diagnosed with MANY mental illness actually have thryoid and adrenal problems. What’s so sad is that Dr’s focus so much on the mental illness and write scripts only for antidepressants and antianxiety’s , only making our symptoms worse in many cases
I’m no expert by any means, I can only go by what’ I’ve researched and my own situationlI actually feel for the first time in many many years, hope of getting well.
@allie 1630 wrote:
I’ve read as much as 50% of those diagnosed with MANY mental illness actually have thryoid and adrenal problems. What’s so sad is that Dr’s focus so much on the mental illness and write scripts only for antidepressants and antianxiety’s , only making our symptoms worse in many cases
I’m no expert by any means, I can only go by what’ I’ve researched and my own situationlI actually feel for the first time in many many years, hope of getting well.
hope you do get well!!!
I am new here, but totally agree with you, so many docs just hand crap out all the time without even running the app. blood/sugar/ and what ever else tests they can, instead they hand you the “quick fix” or the “get outa my hair” bottle of pills or what have you just to have you return in a few weeks/months to get more?
Thats absurd! I am a veteran and have had it done to me a few times at the VA office, it disturbs me, instead of getting to the root of the problems, they cover them up with meds,
I am all for fixing the problems if it is deemed neccessary by the doc after the app. tests have been ran.
Here is what my personal observations are armour and t4/t3 combo.
1) Armour in my body converts t4 to t3 at a rapid rate causing destabilization in my mood very similar to a mania state, but not depressed state
2) Since removing armour and replacing it with generic t4 and cytomel I have notice as well as my freinds a much more level mood swings, Due to a few days of running low on cortisol I tend to fly off the handle but rather in stable mood. high t3 to t4 ratio makes me more likely to flip out and get my NE/adrenaline going which takes a while to calm down. Basically high t3 to low t4 makes me more agitated state. It also makes my emotions very flat and zombie like where I do not feel that “love feeling”
3) low t4 to t3 ratio makes me feel depressed more so of feeling worthless, low self esteem, but makes me emotional freak constantly crying all the time for no reason when e2 is unbalanced
4) When a person e2 is low conversion of t4 to t3 is also accelerated this can also feed into the emotional imbalance as well.
5) general observation in clients/patients. When thyroid gets properly regulated I am seeing a reduction in e2 levels and men that have used armidex are not longer requiring it. I believe this has to do with as thyroid improves it helps to increase methylation which helps to metabolize e2 and also its metabolites properly. I use methyl forms of folate and b-12 to help this pathway depending upon where the balance may reside.
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