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http://jcem.endojournals.org/cgi/content/full/86/10/4814

The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 10 4814-4817

Copyright © 2001 by The Endocrine Society

Suppression of Serum TSH by Graves' Ig: Evidence for a Functional Pituitary TSH Receptor

Leon J. S. Brokken, Jolanda W. C. Scheenhart, Wilmar M. Wiersinga and Mark F. Prummel

Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Leon J. S. Brokken, Department of Endocrinology, F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: [email protected]

Abstract

Antithyroid treatment for Graves' hyperthyroidism restores euthyroidismclinically within 1-2 months, but it is well known that TSH levels can remain suppressed for many months despite normal free T4 and T3 levels. This has been attributed to a delayed recovery of the pituitary-thyroid axis. However, we recently showed that the pituitary contains a TSH receptor through which TSH secretion may be down-regulated via a paracrine feedback loop. In Graves' disease, TSH receptor autoantibodies may also bind this pituitary receptor, thus causing continued TSH suppression. This hypothesiswas tested in a rat model. Rat thyroids were blocked by methimazole,and the animals were supplemented with L-T4. They were theninjected with purified human IgG from Graves' diseasepatients at two different titers or with IgG from a healthycontrol (thyroid hormone binding inhibitory Ig, 591, 127, and< 5 U/liter). Despite similar T4 and T3 levels, TSH levels were indeed lower in the animals treated with high TSH receptor autoantibodies containing IgGs; the 48-h mean TSH concentration(mean ± SEM; n = 8) was 11.6 ± 1.3 ng/ml comparedwith 16.2 ± 0.9 ng/ml in the controls (P < 0.01).The intermediate strength TSH receptor autoantibody-treatedanimals had levels in between the other two groups (13.5 ±2.0 ng/ml). We conclude that TSH receptor autoantibodies can directly suppress TSH levels independently of circulating thyroid hormone levels, suggesting a functioning pituitary TSH receptor.

GRAVES' DISEASE IS an autoimmune thyroid disorder characterizedby circulating Ig directed against the TSH receptor (TSH-R)(1, 2). The majority of these TSH-R autoantibodies (TRAb) act as agonists by mimicking TSH binding leading to Graves' hyperthyroidism and goiter. Antithyroid drug treatment usuallyrestores euthyroidism within 4-6 wk in patients with hyperthyroidism(3). However, it may take much longer for TSH values to normalize. Many treated Graves' disease patients who are clinically euthyroid and have normal T4 and T3 serum levels continue to show decreased TSH levels (4, 5).

The explanation for this continued suppression of TSH is unknown, but it is usually attributed to a delayed recovery of the pituitary-thyroid axis (6). We offer an alternative explanation, involving a direct effect of TRAb on TSH secretion by the pituitary. We have recently postulated that in addition to a negative feedback control by T4 levels, TSH secretion is influenced through a negative ultra-short-loop feedback mechanism within the pituitary. We indeed demonstrated that the TSH-R is expressed in the human anterior pituitary on folliculo-stellate (FS) cells (7). When TSH is secreted by the thyrotrophs, it can bind to this receptor on FS cells, which then signal the thyrotrophs to decrease their TSH secretion. That the FS cells are involved in this feedback control is likely, because they are well known for their paracrine regulatory capabilities (8, 9). Apart from this physiological control, the TSH-R on FS cells may also bind circulating TRAb, which, by mimicking TSH, subsequently can cause a decrease in TSH secretion independently of thyroid hormone levels. Such a mechanism may very well be responsible for the low TSH levels observed in otherwise euthyroid Graves' patients receiving antithyroid drug treatment. TRAb often remain present in patients treated for Graves' disease (10, 11) and can be responsible for the long-term suppression of TSH.

To test this hypothesis, we used a modified long-acting thyroid stimulatorbioassay in which we measured the plasma TSH response to the administrationof TRAb in rats that were unable to mount a thyroid responseto TRAb because of prior antithyroid drug treatment
 

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Blocking TSH-R antibodies (blocking TRAb) block the receptor, preventing TSH from stimulating these receptors which can result in both low thyroid hormone levels as well as low TSH (in the latter case because the receptor is occupied by antibody). Some patients have both autoantibody types, that is, both stimulating and blocking TSH-R Ab. Depending on the "profile" of these autoantibodies at any point in the disease, the patient can experience either hyperthyroidism (more stimulating TRAb than blocking TRAb) or hypothyroidism (more blocking TRAb).What's important here is that the cause is autoimmune in nature, whatever the autoantibody type or metabolic consequences.

Here's the link to that last paragraph:
http://graves.medshelf.org/New_Antibody_Discovered
 

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http://www.thyroid.org/patients/notes/march02/02_03_5.html

Thyrotropin-receptor antibodies in patients with hyperthyroidism caused by Graves' disease inhibit thyrotropin secretion

The background of the study. Patients who have hyperthyroidism have low serum thyrotropin (TSH) concentrations. When the patients are treated, serum TSH concentrations rise to normal or above. In some patients the recovery of TSH secretion is delayed. This study was done to determine if the TSH receptor-stimulating antibodies present in the serum of patients with hyperthyroidism caused by Graves' disease inhibit TSH secretion.

How the study was done. The effect of TSH receptor-stimulating antibodies on TSH secretion was studied in rats. The rats were given immunoglobulins (IgG) purified from the serum of a normal subject and patients with hyperthyroidism caused by Graves' disease; the latter had high serum concentrations of TSH receptor-stimulating antibodies. Blood samples were collected for measurement of plasma TSH 1, 2, 4, 8, 24, and 48 hours after the injections.

The results of the study. After the injections of IgG, the 48-hour mean plasma TSH concentration in the rats that received the IgG prepared from the serum of patients with hyperthyroidism was lower than in the rats that received the normal IgG.

The conclusions of the study. In patients with hyperthyroidism caused by Graves' disease, TSH secretion may be inhibited not only by the high serum T4 concentrations, but also by TSH receptor-stimulating antibodies.

The original article. Brokken LJS, Scheenhart JWC, Wiersinga WM, Prummel MF. Suppression of serum TSH by Graves' Ig: evidence for a functional pituitary receptor. J Clin Endocrinol Metab 2001;86:4814-7.
 

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http://www.hormonerestoration.com/Thyroid.html

Here is the paragraph that mentions a bit about it with an author cited in brackets:

"Even when doctors do prescribe thyroid hormone, they usually prescribe only
T4 (Synthroid®, Levoxyl®). It must be converted to T3 to become active. They give T4 in low doses that just "normalize" the TSH to any value within the reference range. The result is an almost universal undertreatment of thyroid insufficiency because the hypothalamic-pituitary axis is more easily suppressed by oral thyroid hormones than it is by the normal continuous T4 and T3 secretion by the normal thyroid gland. Once-daily oral thyroid replacement produces a large spike in serum levels and this over-suppresses the TSH for more than 24 hours. With the usual TSH-normalizing T4 therapy, free T3 levels remain relatively low (Escobar-Morreale 1996).
Often they are lower than before the T4 therapy was started leaving a patient more hypothyroid than before therapy!
{Also, when the TSH is reduced by thyroid replacement, so is T4-to-T3 conversion reduced throughout the body. (Kabadi 2006)}
Some conventional thyroid specialists are aware of this and do recommend giving enough T4 to push the TSH to the bottom of the reference range or a bit lower and to push the FT4 to at or above the top of its reference range, but most doctors are unaware of this, causing them to undertreat most of their patients."
 

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Last 4 posts were from my Notes file. Hope this helps. Brokken would be a good "search". He's done a ton of research,.
 

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Another thought I had is they should test you more often in case the autoimmune attack is suppressing TSH by spilling hormone temporarily. But then it goes back to hypo afterwards.
 

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Discussion Starter · #27 ·
Thank you! Very helpful!
 

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Discussion Starter · #28 ·
Happy surprise! New endo left things alone, even with the low TSH, and ordered 88mcg tabs to make dosing easier than my patched together dosing. She did go on to talk a fair amount about the correlation between low TSH and atrial fibrillation (she's married to a cardiologist.) But for now she's willing to wait and watch.
 
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YEA!!!

She did go on to talk a fair amount about the correlation between low TSH and atrial fibrillation (she's married to a cardiologist.) But for now she's willing to wait and watch.
Now it's your job to "educate" her on "normal or in range" FT-4 and FT-3 and low TSH. I have been low TSH for over 15 years - have had no increase in my osteopenia nor any heart issues. What the medical community fails to SEE is that low TSH with mid range FT-4 and FT-3 is completely normal. Did you ask for the TBII test? Keep that one in your back pocket if not as Im sure in your case it will be positive since your TSH falls once your Frees rise
 

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My guess is you fall into a situation where TSH is not a good indicator. Maybe it has to do with your historical procedures.
 

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It's a blocking antibody thing -
 

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Discussion Starter · #32 ·
I, too, think I have a blocking antibody thing going on, especially given how challenging it's been to get FT4 up to mid-range and keep it there. Now, given her "talk" about how sensitive TSH is and the a-fib connection, etc, I expect that at some point she will want to see TSH higher. And of course there's the possibility that she's taking the watch and see attitude for this round so as not to get me riled up right out of the gate with the first visit. But I'll try to assume the best intentions, and also keep that TBII suggestion tucked away should I need it. Thank you so much for your support! (I was really worried about a new endo.)
 

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I'm telling you.... you will never get a Endo to work with a low TSH - you need to find a GP.

Easiest way to work around all of this is to go to a integrative type doc - get your med's straightened out and then transition to a GP so insurance covers your visits. However, with the new healthcare - none of my semi annual visits are covered anyway and I pay out of pocket. Lab;s are always covered at an integrative doc and they tend to straighten out any other imbalances you have
 

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Discussion Starter · #34 ·
Yes, I believe you, and I expect this is just the honeymoon phase, but I'll go with it while I can. I'm not sure my GP would treat low TSH any differently than the endo, so I'll have to keep in mind that I might need a new GP, too. Such a journey...
 

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I saw 2 different GP's at the same time - alternated who I saw for prescription refills - this was over 10 years ago but it gave me the med's I needed to dial in my set dose. When they both freaked about TSH I had 1 of them run the TBII test. That worked for awhile then it was like she had amnesia and freaked again about the low TSH. That's when I found my current DO who treated a friend for Graves disease. He wasn't concerned about my TSH and told me as long as my FT-4 and FT-3 were within the ranges he didn't have any issue with it.

Taking it one step further - he started running semi annual DEXA scans ( which I now postpone to 3-4 years) and am living proof that having little to no TSH has not impacted my bones. I started with osteopenia ( family history and also years of not being diagnosed with Graves, and the fact I never drank milk after my teens and was low on D forever) anyway - my osteopenia is stable. I now take proper calcium, D and Magnesium and so far it seems to be working despite my lack of TSH.

If I was dosed using TSH I would be completely hypo.

Keep the faith - keep trying - eventually you will find a doc to treat your hormone replacement properly
 
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