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    <h1>Thyroid: Therapies, Confusion, and Fraud</h1>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
<p>From the <a href="https://raypeat.com/articles/articles/thyroid.shtml" target="_blank">original article</a> in 2006. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
<p>I. Respiratory-metabolic defect</p><p>
II. 50 years of commercially motivated fraud</p><p>
III. Tests and the "free hormone hypothesis"</p><p>
IV. Events in the tissues</p><p>
V.  Therapies</p><p>
VI. Diagnosis</p>
 
<h2>I. Respiratory defect</h2>
<p> 
Broda Barnes, more than 60 years ago, summed up the major effects of
hypothyroidism on health very neatly when he pointed out that if
hypothyroid people don't die young from infectious diseases, such as
tuberculosis, they die a little later from cancer or heart disease.  He did
his PhD research at the University of Chicago, just a few years after Otto
Warburg, in Germany, had demonstrated the role of a "respiratory defect" in
cancer.  At the time Barnes was doing his research, hypothyroidism was
diagnosed on the basis of a low basal metabolic rate, meaning that only a
small amount of oxygen was needed to sustain life.  This deficiency of
oxygen consumption involved the same enzyme system that Warburg was
studying in cancer cells.</p><p> 
Barnes experimented on rabbits, and found that when their thyroid glands
were removed, they developed atherosclerosis, just as hypothyroid people
did.  By the mid-1930s, it was generally known that hypothyroidism causes
the cholesterol level in the blood to increase; hypercholesterolemia was a
diagnostic sign of hypothyroidism.  Administering a thyroid supplement,
blood cholesterol came down to normal exactly as the basal metabolic rate
came up to the normal rate.  The biology of atherosclerotic heart disease
was basically solved before the second world war.</p><p> 
Many other diseases are now known to be caused by respiratory defects.
Inflammation, stress, immunodeficiency, autoimmunity, developmental and
degenerative diseases, and aging, all involve significantly abnormal
oxidative processes.  Just brief oxygen deprivation triggers processes that
lead to lipid peroxidation, producing a chain of other oxidative reactions
when oxygen is restored.  The only effective way to stop lipid peroxidation
is to restore normal respiration.</p><p> 
Now that dozens of diseases are known to involve defective respiration, the
idea of thyroid's extremely broad range of actions is becoming easier to
accept.</p>
 
<h2>II. 50 years of fraud</h2>
<p>  
Until the second world war, hypothyroidism was diagnosed on the basis of
BMR (basal metabolic rate) and a large group of signs and symptoms.  In the
late 1940s, promotion of the (biologically inappropriate) PBI
(protein-bound iodine) blood test in the U.S. led to the concept that only
5% of the population were hypothyroid, and that the 40% identified by
"obsolete" methods were either normal, or suffered from other problems such
as sloth and gluttony, or "genetic susceptibility" to disease.  
During the same period, thyroxine became available, and in healthy young
men it acted "like the thyroid hormone."  Older practitioners recognized
that it was not metabolically the same as the traditional thyroid
substance, especially for women and seriously hypothyroid patients, but
marketing, and its influence on medical education, led to the false idea
that the standard Armour thyroid USP wasn't properly standardized, and that
certain thyroxine products were; despite the fact that both of these were
shown to be false.</p><p> 
By the 1960s, the PBI test was proven to be irrelevant to the diagnosis of
hypothyroidism, but the doctrine of 5% hypothyroidism in the populaton
became the basis for establishing the norms for biologically meaningful
tests when they were introduced. </p><p>
Meanwhile, the practice of measuring serum iodine, and equating it with
"thyroxine the thyroid hormone," led to the practice of examining only the
iodine content of the putative glandular material that was offered for sale
as thyroid USP.  This led to the substitution of materials such as
iodinated casein for desiccated thyroid in the products sold as thyroid
USP.  The US FDA refused to take action, because they held that a
material's iodine content was enough to identify it as "thyroid USP." 
In this culture of misunderstanding and misrepresentation, the mistaken
idea of hypothyroidism's low incidence in the population led to the
acceptance of dangerously high TSH (thyroid stimulating hormone) activity
as "normal."  Just as excessive FSH (follicle stimulating hormone) has been
shown to have a role in ovarian cancer, excessive stimulation by TSH
produces disorganization in the thyroid gland. </p>
 
<h2>III. Tests &amp; the "free hormone hypothesis"</h2>
<p>
After radioactive iodine became available, many physicians would administer
a dose, and then scan the body with a Geiger counter, to see if it was
being concentrated in the thyroid gland.  If a person had been eating
iodine-rich food (and iodine was used in bread as a preservative/dough
condition, and was present in other foods as an accidental contaminant),
they would already be over saturated with iodine, and the gland would fail
to concentrate the iodine.  The test can find some types of metastatic
thyroid cancer, but the test generally wasn't used for that purpose.
Another expensive and entertaining test has been the thyrotropin release
hormone (TRH) test, to see if the pituitary responds to it by increasing
TSH production.  A recent study concluded that "TRH test gives many
misleading results and has an elevated cost/benefit ratio as compared with
the characteristic combination of low thyroxinemia and non-elevated TSH."
(Bakiri, Ann. Endocr (Paris) 1999), but the technological drama, cost, and
danger (Dokmetas, et al., J Endocrinol Invest 1999 Oct; 22(9): 698-700) of
this test is going to make it stay popular for a long time.  If the special
value of the test is to diagnose a pituitary abnormality, it seems
intuitively obvious that overstimulating the pituitary might not be a good
idea (e.g., it could cause a tumor to grow). </p><p>
Everything else being equal, as they say, looking at the amount of
thyroxine and TSH in the blood can be informative.  The problem is that
it's just a matter of faith that "everything else" is going to be equal.
The exceptions to the "rule" regarding normal ranges for thyroxine and TSH
have formed the basis for some theories about "the genetics of thyroid
resistance," but others have pointed out that, when a few other things are
taken into account, abnormal numbers for T4, T3, TSH, can be variously
explained. </p><p>
The actual quantity of T3, the active thyroid hormone, in the blood can be
measured with reasonable accuracy (using radioimmunoassay, RIA), and this
single test corresponds better to the metabolic rate and other meaningful
biological responses than other standard tests do.  But still, this is only
a statistical correspondence, and it doesn't indicate that any particular
number is right for a particular individual. </p><p>
Sometimes, a test called the RT3U, or resin T3 uptake, is used, along with
a measurement of thyroxine.  A certain amount of radioactive T3 is added to
a sample of serum, and then an adsorbent material is exposed to the
mixture of serum and radioactive T3.  The amount of radioactivity that
sticks to the resin is called the T3 uptake.  The lab report then gives a
number called T7, or free thyroxine index.  The closer this procedure is
examined, the sillier it looks, and it looks pretty silly on its face.. 
The idea that the added radioactive T3 that sticks to a piece of resin will
correspond to "free thyroxine," is in itself odd, but the really
interesting question is, what do they mean by "free thyroxine"? 
Thyroxine is a fairly hydrophobic (insoluble in water) substance, that will
associate with proteins, cells, and lipoproteins in the blood, rather than
dissolving in the water.  Although the Merck Index describes it as
"insoluble in water," it does contain some polar groups that, in  the right
(industrial or laboratory) conditions, can make it slightly water soluble.
This makes it a little different from progesterone, which is simply and
thoroughly insoluble in water, though the term "free hormone" is often
applied to progesterone, as it is to thyroid.  In the case of progesterone,
the term "free progesterone" can be traced to experiments in which serum
containing progesterone (bound to proteins) is separated by a (dialysis)
membrane from a solution of similar proteins which contain no progesterone. 
Progesterone "dissolves in" the substance of the membrane, and the serum
proteins, which also tend to associate with the membrane, are so large that
they don't pass through it.  On the other side, proteins coming in contact
with the membrane pick up some progesterone.  The progesterone that passes
through is called "free progesterone," but from that experiment, which
gives no information on the nature of the interactions between progesterone
and the dialysis membrane, or about its interactions with the proteins, or
the proteins' interactions with the membrane, nothing is revealed about the
reasons for the transmission or exchange of a certain amount of
progesterone.  Nevertheless, that type of experiment is used to interpret
what happens in the body, where there is nothing that corresponds to the
experimental set-up, except that some progesterone is associated with some
protein. </p><p>
The idea that the "free hormone" is the active form has been tested in a
few situations, and in the case of the thyroid hormone, it is clearly not
true for the brain, and some other organs.  The protein-bound hormone is,
in these cases, the active form; the associations between the "free
hormone" and the biological processes and diseases will be completely
false, if they are ignoring the active forms of the hormone in favor of the
less active forms.  The conclusions will be false, as they are when T4 is
measured, and T3 ignored.  Thyroid-dependent processes will appear to be
independent of the level of thyroid hormone; hypothyroidism could be caller
hyperthyroidism. </p><p>
Although progesterone is more fat soluble than cortisol and the thyroid
hormones, the behavior of progesterone in the blood illustrates some of the
problems that have to be considered for interpreting thyroid physiology.
When red cells are broken up, they are found to contain progesterone at
about twice the concentration of the serum.  In the serum, 40 to 80% of the
progesterone is probably carried on albumin.  (Albumin easily delivers its
progesterone load into tissues.)  Progesterone, like cholesterol, can be
carried on/in the lipoproteins, in moderate quantities.  This leaves a very
small fraction to be bound to the "steroid binding globulin."  Anyone who
has tried to dissolve progesterone in various solvents and mixtures knows
that it takes just a tiny amount of water in a solvent to make progesterone
precipitate from solution as crystals; its solubility in water is
essentially zero.  "Free" progesterone would seem to mean progesterone not
attached to proteins or dissolved in red blood cells or lipoproteins, and
this would be zero.  The tests that purport to measure free progesterone
are measuring something, but not the progesterone in the watery fraction of
the serum. </p><p>
The thyroid hormones associate with three types of simple proteins in the
serum: Transthyretin (prealbumin), thyroid binding globulin, and albumin.
A very significant amount is also associated with various serum
lipoproteins, including HDL, LDL, and VLDL (very low density lipoproteins). 
A very large portion of the thyroid in the blood is associated with the
red blood cells.  When red cells were incubated in a medium containing
serum albumin, with the cells at roughly the concentration found in the
blood, they retained T3 at a concentration 13.5 times higher than that of
the medium.  In a larger amount of medium, their concentration of T3 was 50
times higher than the medium's.  When laboratories measure the hormones in
the serum only, they have already thrown out about 95% of the thyroid
hormone that the blood contained. </p><p>
The T3 was found to be strongly associated with the cells' cytoplasmic
proteins, but to move rapidly between the proteins inside the cells and
other proteins outside the cells. </p><p>
When people speak of hormones travelling "on" the red blood cells, rather
than "in" them, it is a concession to the doctrine of the impenetrable
membrane barrier. </p><p>
Much more T3 bound to albumin is taken up by the liver than the small
amount identified in vitro as free T3 (Terasaki, et al., 1987).  The
specific binding of T3 to albumin alters the protein's electrical
properties, changing the way the albumin interacts with cells and other
proteins.  (Albumin becomes electrically more positive when it binds the
hormone; this would make the albumin enter cells more easily.  Giving up
its T3 to the cell, it would become more negative, making it tend to leave
the cell.)   This active role of albumin in helping cells take up T3 might
account for its increased uptake by the red cells when there were fewer
cells in proportion to the albumin medium.  This could also account for the
favorable prognosis associated with higher levels of serum albumin in
various sicknesses. </p><p>
When T3 is attached chemically (covalently, permanently) to the outside of
red blood cells, apparently preventing its entry into other cells, the
presence of these red cells produces reactions in other cells that are the
same as some of those produced by the supposedly "free hormone."  If T3
attached to whole cells can exert its hormonal action, why should we think
of the hormone bound to proteins as being unable to affect cells?
The idea of measuring the "free hormone" is that it supposedly represents
the biologically active hormone, but in fact it is easier to measure the
biological effects than it is to measure this hypothetical entity.  Who
cares how many angels might be dancing on the head of a pin, if the pin is
effective in keeping your shirt closed?  </p>
  <h2>IV. Events in the tissues</h2>
  <p>
   Besides the effects of commercial deception, confusion about thyroid has
resulted from some biological clichés.  The idea of a "barrier membrane"
around cells is an assumption that has affected most people studying cell
physiology, and its effects can be seen in nearly all of the thousands of
publications on the functions of thyroid hormones.  According to this idea,
people have described a cell as resembling a droplet of a watery solution,
enclosed in an oily bag which separates the internal solution from the
external watery solution.   The cliché is sustained only by neglecting the
fact that proteins have a great affinity for fats, and fats for proteins;
even soluble proteins, such as serum albumin, often have interiors that are
extremely fat-loving.  Since the structural proteins that make up the
framework of a cell aren't "dissolved in water" (they used to be called
"the insoluble proteins"), the lipophilic phase isn't limited to an
ultramicroscopically thin surface, but actually constitutes the bulk of the
cell. </p><p>
Molecular geneticists like to trace their science from a 1944 experiment
that was done by Avery., et al.  Avery's group knew about an earlier
experiment, that had demonstrated that when dead bacteria were added to
living bacteria, the traits of the dead bacteria appeared in the living
bacteria.  Avery's group extracted DNA from the dead bacteria, and showed
that adding it to living bacteria transferred the traits of the dead
organisms to the living. </p><p>
In the 1930s and 1940s, the movement of huge molecules such as proteins and
nucleic acids into cells and out of cells wasn't a big deal; people
observed it happening, and wrote about it.  But in the 1940s the idea of
the barrier membrane began gaining strength, and by the 1960s nothing was
able to get into cells without authorization.  At present, I doubt that any
molecular geneticist would dream of doing a gene transplant without a
"vector" to carry it across the membrane barrier.  </p><p>
Since big molecules are supposed to be excluded from cells, it's only the
"free hormone" which can find its specific port of entry into the cell,
where another cliché says it must travel into the nucleus, to react with a
specific site to activate the specific genes through which its effects will
be expressed. </p><p>
I don't know of any hormone that acts that way.  Thyroid, progesterone, and
estrogen have many immediate effects that change the cell's functions long
before genes could be activated. </p><p>
Transthyretin, carrying the thyroid hormone, enters the cell's mitochondria
and nucleus (Azimova, et al., 1984, 1985).  In the nucleus, it immediately
causes generalized changes in the structure of chromosomes, as if preparing
the cell for major adaptive changes.  Respiratory activation is immediate
in the mitochondria, but as respiration is stimulated, everything in the
cell responds, including the genes that support respiratory metabolism.
When the membrane people have to talk about the entry of large molecules
into cells, they use terms such as "endocytosis" and "translocases," that
incorporate the assumption of the barrier.  But people who actually
investigate the problem generally find that "diffusion," "codiffusion," and
absorption describe the situation adequately (e.g., B.A. Luxon, 1997;
McLeese and Eales, 1996).  "Active transport" and "membrane pumps" are
ideas that seem necessary to people who haven't studied the complex forces
that operate at phase boundaries, such as the boundary between a cell and
its environment. </p>
 
<h2>V. Therapy</h2>
<p>
Years ago it was reported that Armour thyroid, U.S.P., released T3 and T4,
when digested, in a ratio of 1:3, and that people who used it had much
higher ratios of T3 to T4 in their serum, than people who took only
thyroxine.  The argument was made that thyroxine was superior to thyroid
U.S.P., without explaining the significance of the fact that healthy people
who weren't taking any thyroid supplement had higher T3:T4 ratios than the
people who took thyroxine, or that our own thyroid gland releases a high
ratio of T3 to T4.  The fact that the T3 is being used faster than T4,
removing it from the blood more quickly than it enters from the thyroid
gland itself, hasn't been discussed in the journals, possibly because it
would support the view that a natural glandular balance was more
appropriate to supplement than pure thyroxine. </p><p>
The serum's high ratio of T4 to T3 is a pitifully poor argument to justify
the use of thyroxine instead of a product that resembles the proportion of
these substances secreted by a healthy thyroid gland, or maintained inside
cells.  About 30 years ago, when many people still thought of thyroxine as
"the thryoid hormone," someone was making the argument that "the thyroid
hormone" must work exclusively as an activator of genes, since most of the
organ slices he tested didn't increase their oxygen consumption when it was
added.  In fact, the addition of thyroxine to brain slices suppressed their
respiration by 6% during the experiment.  Since most T3 is produced from T4
in the liver, not in the brain, I think that experiment had great
significance, despite the ignorant interpretation of the author.  An excess
of thyroxine, in a tissue that doesn't convert it rapidly to T3, has an
antithyroid action.  (See Goumaz, et al, 1987.)  This happens in many women
who are given thyroxine; as their dose is increased, their symptoms get
worse.  </p><p>
The brain concentrates T3 from the serum, and may have a concentration 6
times higher than the serum (Goumaz, et al., 1987), and it can achieve a
higher concentration of T3 than T4.  It takes up and concentrates T3, while
tending to expel T4.  Reverse T3 (rT3) doesn't have much ability to enter
the brain, but increased T4 can cause it to be produced in the brain.
These observations suggest to me that the blood's T3:T4 ratio would be very
"brain favorable" if it approached more closely to the ratio formed in the
thyroid gland, and secreted into the blood.  Although most synthetic
combination thyroid products now use a ratio of four T4 to one T3, many
people feel that their memory and thinking are clearer when they take a
ratio of about three to one.  More active metabolism probably keeps the
blood ratio of T3 to T4 relatively high, with the liver consuming T4 at
about the same rate that T3 is used. </p><p>
Since T3 has a short half life, it should be taken frequently.  If the
liver isn't producing a noticeable amount of T3, it is usually helpful to
take a few micorgrams per hour.  Since it restores respiration and
metabolic efficiency very quickly, it isn't usually necessary to take it
every hour or two, but until normal temperature and pulse have been
achieved and stabilized, sometimes it's necessary to take it four or more
times during the day.  T4 acts by being changed to T3, so it tends to
accumulate in the body, and on a given dose, usually reaches a steady
concentration after about two weeks.  </p><p>
An effective way to use supplements is to take a combination T4-T3 dose,
e.g., 40 mcg of T4 and 10 mcg of T3 once a day, and to use a few mcg of T3
at other times in the day.  Keeping a 14-day chart of pulse rate and
temperature allows you to see whether the dose is producing the desired
response.  If the figures aren't increasing at all after a few days, the
dose can be increased, until a gradual daily increment can be seen, moving
toward the goal at the rate of about 1/14 per day.</p><p>
 
<h2>VI. Diagnosis</h2>
<p>
In the absence of  commercial techniques that reflect thyroid physiology
realistically, there is no valid alternative to diagnosis based on the
known physiological indicators of hypothyroidism and hyperthyroidism. The
failure to treat sick people because of one or another blood test that
indicates "normal thyroid function," or the destruction of patients'
healthy thyroid glands because one of the tests indicates hyperthyroidism,
isn't acceptable just because it's the professional standard, and is
enforced by benighted state licensing boards. </p><p>
Toward the end of the twentieth century, there has been considerable
discussion of "evidence-based medicine."  Good judgment requires good
information, but there are forces that would over-rule individual judgment
as to whether published information is applicable to certain patients.  In
an atmosphere that sanctions prescribing estrogen or insulin without
evidence of an estrogen deficiency or insulin deficiency, but that
penalizes practitioners who prescribe thyroid to correct symptoms, the
published "evidence" is necessarily heavily biased.  In this context,
"meta-analysis" becomes a tool of authoritarianism, replacing the use of
judgment with the improper use of statistical analysis. </p><p>
Unless someone can demonstrate the scientific invalidity of the methods
used to diagnose hypothyroidism up to 1945, then they constitute the best
present evidence for evaluating hypothyroidism, because all of the blood
tests that have been used since 1950 have been.shown to be, at best, very
crude and conceptually inappropriate methods.  </p><p>
Thomas H. McGavack's 1951 book, The Thyroid, was representative of the
earlier approach to the study of thyroid physiology.  Familiarity with the
different effects of abnormal thyroid function under different conditions,
at different ages, and the effects of gender, were standard parts of
medical education that had disappeared by the end of the century.
Arthritis, irregularities of growth, wasting, obesity, a variety of
abnormalities of the hair and skin, carotenemia, amenorrhea, tendency to
miscarry, infertility in males and females,  insomnia or somnolence,
emphysema, various heart diseases, psychosis, dementia, poor memory,
anxiety, cold extremities, anemia, and many other problems were known
reasons to suspect hypothyroidism.  If the physician didn't have a device
for measuring oxygen consumption, estimated calorie intake could provide
supporting evidence.  The Achilles' tendon reflex was another simple
objective measurement with a very strong correlation to the basal metabolic
rate.  Skin electrical resistance, or whole body impedance wasn't widely
accepted, though it had considerable scientific validity. </p><p>
A therapeutic trial was the final test of the validity of the diagnosis: If
the patient's symptoms disappeared as his temperature and pulse rate and
food intake were normalized, the diagnostic hypothesis was confirmed.  It
was common to begin therapy with one or two grains of thyroid, and to
adjust the dose according to the patient's response.  Whatever objective
indicator was used, whether it was basal metabolic rate, or serum
cholesterol. or core temperature, or reflex relaxation rate, a simple chart
would graphically indicate the rate of recovery toward normal health.
</p> 
 
<h2>References</h2>
<small>
<p>
McGavack, Thomas Hodge.: The thyroid,: St. Louis, Mosby, 1951.  646 p.
ill.Several chapters contributed by various authors.Call Numbers WK200
M145t 1951 (Rare Book).</p><p>
Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated transport of
thyroid hormones through the rat blood-brain barrier: primary role of
albumin-bound hormone. Pardridge WM.</p><p>
Endocrinology 1987 Apr;120(4):1590-6. Brain cortex reverse triiodothyronine
(rT3) and triiodothyronine concentrations under steady state infusions of
thyroxine and rT3. Goumaz MO, Kaiser CA, Burger A.G.</p><p>
J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain
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shown that the fraction of hormone or drug that is plasma protein bound is
readily available for transport through the brain endothelial wall, i.e.,
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Endocrinology 113(1), 391-8, 1983, Stimulation of sugar transport in
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Endocrinology 1987 Sep; 121(3): 1185-91.  Stereospecificity of
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Mech Ageing Dev 1990 Mar 15;52(2-3):141-7. Blood-brain transport of
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Endocrinology 1987 Sep;121(3):1185-91.  Stereospecificity of
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Endocrinology 1980 Dec;107(6):1705-10.  Transport of thyroid and steroid
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role of protein-bound hormone. Pardridge WM, Mietus LJ.
Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated transport of
thyroid hormones through the rat blood-brain barrier: primary role of
albumin-bound hormone. Pardridge WM. </p><p>
Endocrinology 1975 Jun;96(6):1357-65. Triiodothyronine binding in rat
anterior pituitary, posterior pituitary, median eminence and brain. Gordon
A, Spira O.</p><p>
Endocr Rev 1989 Aug;10(3):232-74. The free hormone hypothesis: a
physiologically based mathematical model. Mendel CM.
Biochim Biophys Acta 1991 Mar 4;1073(2):275-84. Transport of steroid
hormones facilitated by serum proteins. Watanabe S, Tani T, Watanabe S,
Seno M Kanagawa.</p><p>
D Novitzky, H Fontanet, M Snyder, N Coblio, D Smith, V Parsonnet, Impact of
triiodothyronine on the survival of high-risk patients undergoing open
heart surgery, Cardiology, 1996, Vol 87, Iss 6, pp 509-515.
Biochim Biophys Acta 1997. Jan 16;1318(1-2):173-83  Regulation of the
energy coupling in mitochondria by some steroid and thyroid hormones.
Starkov AA, Simonyan RA, Dedukhova VI, Mansurova SE, Palamarchuk LA,
Skulachev VP</p><p>
Thyroid 1996 Oct;6(5):531-6. Novel actions of thyroid hormone: the role of
triiodothyronine in cardiac transplantation. Novitzky D.
Rev Med Chil 1996 Oct;124(10):1248-50. [Severe cardiac failure as
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Pena M, Lopez Moreno JM.</p><p>
Cardiology 1996 Nov-Dec;87(6):509-15. Impact of triiodothyronine on the
survival of high-risk patients undergoing open heart surgery. Novitzky D,
Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V
Curr Opin Cardiol 1996 Nov;11(6):603-9. The use of thyroid hormone in
cardiac surgery. Dyke C</p><p>
N Koibuchi, S Matsuzaki, K Ichimura, H Ohtake, S Yamaoka.  Ontogenic
changes in the expression of cytochrome c oxidase subunit I gene in the
cerebellar cortex of the perinatal hypothyroid rat.  Endocrinology, 1996,
Vol 137, Iss 11,  pp 5096-5108.</p><p>
Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors.
Translocation of thyroid hormones through plasma membranes]. [Article in
Russian] Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A.
The in vivo translocation of thyroxine-binding blood serum prealbumin
(TBPA) was studied. It was found that the TBPA-hormone complex
penetrates-through the plasma membrane into the cytoplasm of target cells.
Electron microscopic autoradiography revealed that blood serum TBPA is
localized in ribosomes of target cells as well as in mitochondria, lipid
droplets and Golgi complex. Negligible amounts of the translocated TBPA is
localized in lysosomes of the cells insensitive to thyroid hormones (spleen
macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm
demonstrated that one of them has the antigenic determinants common with
those of TBPA. It was shown autoimmunoradiographically that the structure
of TBPA is not altered during its translocation.</p><p>
Am J Physiol 1997 Sep;273(3 Pt 1):C859-67. Cytoplasmic codiffusion of fatty
acids is not specific for fatty acid binding protein. Luxon BA, Milliano MT
[The nature of thyroid hormone receptors. Intracellular functions of
thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD;
Kalontarov AI; Makhmudova AA, Biokhimiia 1985 Nov;50(11):1926-32. The
effect of tyroxin-binding prealbumin (TBPA) of blood serum on the template
activity of chromatin was studied. It was found that the values of binding
constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M,
respectively. The receptors isolated from 0.4 M KCl extract of chromatin
and mitochondria as well as hormone-bound TBPA cause similar effects on the
template activity of chromatin. Based on experimental results and the
previously published comparative data on the structure of TBPA, nuclear,
cytoplasmic and mitochondrial receptors of thyroid hormones as well as on
translocation across the plasma membrane and intracellular transport of
TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of
the true thyroid hormone receptor. It was shown that T3-bound TBPA caused
histone H1-dependent conformational changes in chromatin. Based on the
studies with the interaction of the TBPA-T3 complex with spin-labeled
chromatin, a scheme of functioning of the thyroid hormone nuclear receptor
was proposed.</p><p>
[The nature of thyroid hormone receptors. Thyroxine- and
triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD;
Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Sep;49(9):1478-85.
T4- and T3-binding proteins of rat liver were studied. It was found that
the external mitochondrial membranes and matrix contain a protein whose
electrophoretic mobility is similar to that of thyroxine-binding blood
serum prealbumin (TBPA) and which binds either T4 or T3. This protein is
precipitated by monospecific antibodies against TBPA. The internal
mitochondrial membrane has two proteins able to bind thyroid hormones, one
of which is localized in the cathode part of the gel and binds only T3,
while the second one capable of binding T4 rather than T3 and possessing
the electrophoretic mobility similar to that of TBPA.</p><p>
Radioimmunoprecipitation with monospecific antibodies against TBPA revealed
that this protein also the antigenic determinants common with those of
TBPA. The in vivo translocation of 125I-TBPA into submitochondrial
fractions was studied. The analysis of densitograms of submitochondrial
protein fraction showed that both TBPA and hormones are localized in the
same protein fractions. Electron microscopic autoradiography demonstrated
that 125I-TBPA enters the cytoplasm through the external membrane and is
localized on the internal mitochondrial membrane and matrix.</p><p>
[The nature of thyroid hormone receptors. Translocation of thyroid
hormones through plasma membranes]. Azimova ShS; Umarova GD; Petrova OS;
Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Aug;49(8):1350-6.. The in vivo
translocation of thyroxine- binding blood serum prealbumin (TBPA) was
studied. It was found that the TBPA-hormone complex penetrates-through the
plasma membrane into the cytoplasm of target cells. Electron microscopic
autoradiography revealed that blood serum TBPA is localized in ribosomes of
target cells as well as in mitochondria, lipid droplets and Golgi complex.
Negligible amounts of the translocated TBPA is localized in lysosomes of
the cells insensitive to thyroid hormones (spleen macrophages). Study of
T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one
of them has the antigenic determinants common with those of TBPA. It was
shown autoimmunoradiographically that the structure of TBPA is not altered
during its translocation. Endocrinology 1987 Apr;120(4):1590-6 Brain
cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations
under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA,
Burger AG.</p><p>
Gen Comp Endocrinol 1996 Aug;103(2):200-8 Characteristics of the uptake of
3,5,3'-triiodo-L-thyronine and L-thyroxine into red blood cells of rainbow
trout (Oncorhynchus mykiss). McLeese JM, Eales JG. </p><p>
Prog Neuropsychopharmacol Biol Psychiatry 1998 Feb;22(2):293-310. Increase
in red blood cell triiodothyronine uptake in untreated unipolar major
depressed patients compared to healthy volunteers. Moreau X, Azorin JM,
Maurel M, Jeanningros R.</p><p>
Prog Neuropsychopharmacol Biol Psychiatry 1998 Feb;22(2):293-310. Increase
in red blood cell triiodothyronine uptake in untreated unipolar major
depressed patients compared to healthy volunteers. Moreau X, Azorin JM,
Maurel M, Jeanningros R. </p><p>
Biochem J 1982 Oct 15;208(1):27-34. Evidence that the uptake of
tri-iodo-L-thyronine by human erythrocytes is carrier-mediated but not
energy-dependent. Docter R, Krenning EP, Bos G, Fekkes DF, Hennemann G. 
J Clin Endocrinol Metab 1990 Dec;71(6):1589-95. Transport of thyroid
hormones by human erythrocytes: kinetic characterization in adults and
newborns. Osty J, Valensi P, Samson M, Francon J, Blondeau JP.  
J Endocrinol Invest 1999 Apr;22(4):257-61. Kinetics of red blood cell T3
uptake in hypothyroidism with or without hormonal replacement, in the rat.
Moreau X, Lejeune PJ, Jeanningros R.
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