The TSAb stimulating antibody can lower TSH despite euthyroid status.

According to scientific research, the Graves’ TSH receptor-stimulating antibody (TSAb) can directly manipulate the TSH—independently of thyroid hormone levels.

For many decades, scientists have been very puzzled by the fact that “TSH can remain suppressed after treatment for Graves’ disease, even in the setting of biochemical and clinical euthyroidism” (Yu & Faranhi, 2015). 

In other words, during treatment, a Graves’ patient’s TSH may be inappropriately suppressed or inappropriately lowered by the TSAb antibody, without any biochemical or clinical evidence hyperthyroidism.

TSH-Receptor antibodies can override the classic negative feedback loop between thyroid hormones and TSH.

It also means that if a doctor is treating a Graves’ patient by TSH alone, the patient may be severely underdosed in their effort to raise TSH into normal range while TSAb antibodies are weighing it down.

The most common thyroid antibodies to TPO (thyroid peroxidase) and TG (thyroglobulin) do not have this effect (Fröhlich & Wahl, 2017).

Only the TSAb has the power to overstimulate the pituitary gland’s TSH receptors and thereby suppress TSH without raising T4 and/or T3.

Scientists have traditionally called this phenomenon “delayed TSH recovery.” It was formerly theorized that longstanding hyperthyroidism had depleted the pituitary thyrotrophs that secrete TSH, and that the pituitary just needed time to recover.

However, that old theory of pituitary “recovery” from hyperthyroid oppression has now been discredited.

As of 2019, we have confirmation that antibodies can cause TSH suppression. In some people the antibodies persist longer than in others. Scientists like Paragliola have changed their language to “delayed TSH normalization.”

I’ve recently talked about research placing TSH-Receptor antibodies (TRAb) across the full spectrum of thyroid autoimmunity. All Graves’ and Atrophic Thyroiditis patients have had TRAb at some time or other.

Up to 20% of Hashimoto’s patients can have either the stimulating or the blocking antibody, too (Fröhlich & Wahl, 2017), which means that thousands of Hashimoto’s patients’ TRAbs remain overlooked.

In this post, however, I’ll have to focus mainly on Graves’ disease research because that’s where the science is narrowly focused at this time.

I’ll show the details of the “problem” that scientists have noticed for decades—the surprising degree to which Graves’ patients’ TSH is affected by TSAb, at various phases before and during different type of Graves’ thyroid therapy. TSH can be suppressed even after a full thyroidectomy, and even when thyroid hormones are not only normal, but low.

Brokken and team on TSAb-TSH effects

Brokken, Wiersinga & Prummel wrote a series of three articles in the early 2000s demonstrating Graves’ antibody effects on TSH. These were published in The Journal of Clinical Endocrinology & Metabolism as well as the American Thyroid Association’s journal called Thyroid.

First, in 2001, these three men and a fourth, named Scheenhart, published a study in rats. Their data demonstrated that injecting mice with blood from healthy controls and two different concentrations of TRAb from hyperthyroid patients over-suppressed TSH in an inverse linear manner, and did so independently of T3 and T4.

Next, in 2003, they published a human clinical trial showing the same effect in humans on pharmaceutical therapy.

Then finally, in 2004, under Prummel as lead author, they reiterated their research findings from 2001 and 2003, further emphasizing the theory of the antibody’s effects on TSH.

In their clinical study, most of their 45 Graves’ patients were treated with methimazole + LT4 pharmaceuticals, and 4 patients with PTU + LT4.

After 3 months of therapy for Graves’ disease,

• “25 patients had become negative for the TBII test (<12 u/L) whereas in 20 TBII could still be detected.”
• “Both groups had entirely similar levels of T4 and T3, but the TBII-positive patients had significantly lower TSH concentrations (median, 0.09; range, < 0.01–4.30 mU/L) than the TBII-negative subjects (median, 0.84; range, 0.01–4.20; p = 0.015; Fig. 4).”
• “In fact, the TSH concentrations only correlated with TBII levels (r = -0.424; p = 0.004) and not with free T4 or T3 values.”’

Prummel and colleagues asserted for a third time in their 2004 article, “These data strongly support the hypothesis that TBII can lower TSH levels directly by binding to the pituitary TSHR [TSH-Receptor].”

The TSAb antibody, as measured indirectly by the TBII test, still showed a TSH-suppressive tendency.

The dots in the graph showed that being positive vs. negative on the TBII test made a difference in TSH. It also made a difference in the distribution of FT4, but not the average FT4.

However, Brokken and team’s results were biased by the fact that they did not succeed at normalizing all patients’ T3 or T4, and yet they averaged all the results of this large, diverse group. 

Data in their Table 1 showed that “After treatment,” the patients’

• TSH averaged 0.37 and ranged from <0.01 to 4.30 (ref 0.4 to 4.0).
• Total T4 ranged from 3.5 to 17.9 (ref 5.4 to 11.7).
• Total T3 ranged from 81 to 237 ng/dL (ref 80–179 ng/dl).
• Free T4 ranged from 0.4 to 2.0 (ref 0.8 to 1.9)
• Free T3-Index (not a FT3 test) ranged from 78-175 (ref 80 to 179).

As seen in the list above (data obtained from the table), some patients were hypothyroid (T4 and FT4 far below reference) and others still hyperthyroid in biochemistry (T4 and FT4 far above reference).

But mathematically, the population’s averages were within range, and on this basis alone, they claimed to have accomplished their goals. However, they did not show the severity of the manifestation in some individuals.

It’s unfortunate that we are not given TSH-FT4 ratios for individual patients to see the TSH-FT4 disjoint they saw, because a low TSH could have been in the same patient who had a low FT4 result.

Their scatterplot graph with its trendline, however, clearly reveals the strong correlation they mentioned:

The TSH test was correlated with the results of the TBII antibody test, and TSH secretion was not responding normally to T4 and T3 levels in blood.

By 2004, Prummel, Brokken and Wiersinga had realized that it was more specifically the TSAb stimulating antibody, revealed by more precise TSI tests, that had this effect:

• “If TSI [TSH-receptor stimulating antibodies] are still present in serum of patients rendered euthyroid by antithyroid treatment they might cause TSH suppression by binding to the pituitary TSHR. This would explain why TSH remains suppressed in some hyperthyroid patients rendered euthyroid by antithyroid therapies.”

Kabadi and Premachandra on TSAb-TSH effects

In 2007, Kabadi and Premachandra described the TSH-Receptor-Stimulating antibody effects even more powerfully than Brokken, Wiersinga and Prummel did.

This is partly because they used a more precise stimulating antibody test than Brokken and team did, and partly because they divided their patients into quartiles (four groups) by TSH levels, two things that Brokken and team did not do.

Kabadi & Premachandra stated their claims boldly and clearly at the opening of their introduction:

• “The serum thyrotropin (thyroid-stimulating hormone or TSH) level remains suppressed always before and frequently after treatment of patients with antithyroid drugs or radioiodine (131I) ablation, irrespective of clinical thyroid state or free thyroxine (T4) and triiodothyronine (T3) concentrations.”
• “In many of these patients, the serum TSH level remains subnormal despite attainment of a clinical euthyroid state, confirmed by normal serum levels of both free T4 and T3.
• “Moreover, in a few patients, serum TSH levels are noted to be subnormal even in the presence of low free T4 and low T3 concentrations.”
• “It is likely that the continuing presence of thyroid-stimulating immunoglobulin (TSI) may account for this observed lack of normal feedback between thyroid hormones and pituitary thyrotrophs, as described previously.”

Kabadi and Premachandra also gathered a more diverse group of Graves’ disease patients than those on pharmaceutical therapy. They enrolled people with Graves disease:

• regardless of their thyroid hormone levels,
• regardless of their treated or untreated state, and
• regardless of whether they were euthyroid due to therapy or natural remission of their disease.

As they analyzed all cohorts, they could see degrees of TSH over-suppression and analyze its relationship to TSH-Receptor Stimulating antibodies, this time measured more specifically by the TSI test.

They discovered (my italics added):

• “Serum TSH is frequently suppressed after treatment with antithyroid drugs or radioiodine (131I), irrespective of clinical thyroid function as expressed by increased, normal, or decreased free T4 and T3 concentrations.”
• “Relationships between free T4 and T3 levels on one hand and TSI or TSH levels on the other were not significant, with a considerable variability in free T4 and T3 levels being noted in individual study groups.”
• “In an individual patient with Graves’ disease, the serum TSH level may be more reflective of the circulating TSI concentration than is thyroid gland function as expressed by free T4 and T3 concentrations and therefore may be as reliable a predictor of remission as TSI [the Thyroid Stimulating Immunoglobulin test].”

When TSH is not elevated despite “decreased” T4 and T3 (below 0.72 ng/dL), that paradox is descriptive of a type of central hypothyroidism — but this is not caused by pituitary or hypothalamic failure, but by antibody stimulation of these organs.

Instead of seeing the consistent TSH-FT4 inverse relationship expected in a normal HPT axis, they saw randomness and variability in TSH’s relationship to T3 and T4 at all levels of TSH. Even in the cohort of full TSH suppression, TSH had no reliable relationship to the patients’ Free T4 and Free T3.

Despite the chaos they saw in TSH-FT4 relationships, they found a strong, orderly TSH-TSI test inverse relationship.

Having a suppressed TSH basically turned TSH testing into a proxy for the Graves’ antibody status, not a reflection of biochemical thyroid status.

In other words, in Graves’ disease, TSH testing was not really measuring thyroid gland function, but rather measuring TRAb antibody activity, as measured by the TSI test—a test that focuses on the TSAb stimulating antibody alone.

A normal TSH was a good “predictor of remission,” while a suppressed TSH indicated less likelihood of remission, or at least a longer delay.

The scientific literature then turned its focus on predicting the length of the delay to TSH normalization.

Paragoglia, 2019: TSAb-TSH effects after a thyroidectomy

Even more recently, Paragliola et al, 2019 performed their own study of TSH-Receptor antibodies in thyroidectomized Graves’ Disease patients.

They also summarized a lot more literature published to date associating TRAb with TSH oversuppression (my italics added):

• “There is evidence reported in literature that TrAb play a role in regulating TSH secretion. In fact, … it has been proposed that TrAb may be involved in the regulation of negative feedback.”
• “The first observations have been reported in Guinea pigs, in which lower TSH levels have been detected after the injection of IgG from patients with Graves’ ophthalmopathy.”
• “In a clinical study evaluating the thyroid status during treatment with thionamides [anti-thyroid medications], higher TrAb values are significantly correlated with suppressed TSH, as confirmed also by other authors.”
• “An inverse relationship between TrAb and TSH levels may be observed both in euthyroid rats and in euthyroid humans, remarking an active role by autoantibodies in suppressing TSH.”

Notice that in the passage above, the TRAb antibodies not only regulate TSH but in “euthyroid” rats and humans suppress TSH regardless of circulating T4 and T3.

In the body of Paragliola’s article, it was noted that

• “in the medical treatment of Graves’ disease, serum TSH levels may remain low or suppressed for several months to years, despite normalization of FT3 and FT4.”

As a result of TSH oversuppression in Graves’ patients post-therapy, Paragliola et al give this advice to doctors who treat Graves’ disease:

• “In fact, in patients affected by Graves’ disease, the TSH value alone cannot be considered as the ‘gold standard’ in evaluating the efficacy of the LT4 replacement therapy during the first months after surgery [thyroidectomy]…. the mean time to TSH normalization in the majority of these patients is about 17 months.”

Paragliola cannot be more explicit in the bolded part of the quotation: We must hesitate to consider TSH alone the “gold standard” for assessing effective therapy in treating Graves’ disease, even after a thyroidectomy.

However, as the quotation goes on, Paragliola and team backpedal and attempt to limit the scope of their doubt of the TSH.

The word “months” is a misleading choice when saying TSH alone can’t assess “the efficacy of the LT4 replacement therapy during the first months after surgery.” To clearly state it in everyday language, they should have said “during the first year and a half,” since 17 months is almost a year and a half.

But why quibble over average duration? Doctors like Paragliola and Chung are very interested in predicting an end date for TRAb-mediated TSH manipulation because they desperately want TSH to normalize so that they can consider their treatment a complete success.

How could a final end date on antibody expression be reasonable?

Seventeen months to TSH normalization was just an average: “In our study,” says Paragliola and team,

“TSH recovery [had] been reached in 78.9% of patients [by] 20 months after surgery.”

And even 20 months is not the end of the story for the remaining 21.1% of patients. Paragliola and team also report in their “Discussion” section that

“The larger cohort study [by Chung et al, 2006] retrospectively evaluated patients for as long as 30 months, showing that 85.7% of patients have recovered TSH at 30 months” after therapy.

This means that 14.3% of Chung et al’s 167 Graves’ Disease patients with TBII titres pre-treatment continued to have suppressed TSH at 30 months (2.5 years) after anti-thyroid drug therapy with propylthiouracil (PTU) and/or and Methimazole (MMI).

In contrast to TSH, their T3 and T4 levels had been normalized by 3 months of anti-thyroid therapy. So their euthyroid vs. hyper/hypo status can still be judged by FT3 and FT4 testing and wise test interpretation of those values.

Chung’s study, cited by Paragoglia above, lasted only 36 months (3 years) and then the story ended. What happened to the 15% that hadn’t recovered normal TSH function?

Moreover, in my previous article on TRAb remissions and fluctuations, Lesho and Jones’ (1997) six case studies reveal the antibody tug-of-war in action in individuals over many years. Read those case studies, and below, to understand how the fluctuations continue.

A major lesson to be learned here is that even despite a therapy as apparently “final” as a thyroidectomy, there is no such thing as an “antibody-ectomy,” and delayed TSH normalization is unpredictable.

Once a Graves’ patient, always a Graves’ patient.

You may have had a thyroidectomy, but there is no such thing as an antibody-ectomy.

The terms “delay” and “normalization” used by these researchers hints that they desire their confidence in TSH to be restored, because doctors really wish to master and control this disease by looking at the TSH number only.

But the fact is, antibody effects on TSH are still possible even if the most obvious victim, the thyroid gland, is subdued or eliminated. Antibody fluctuations can occur in any patient who is susceptible to producing TRAb. Just as you can’t predict TRAbs coming, you can’t predict if or when they’ll be going.

A person remains predisposed to forming TRAb whenever they are triggered.

The TRAb antibody can certainly disappear and go into remission, but in some patients, it persists or fluctuates in response to stimuli we are just beginning to understand.

The clinical implications of this effect are significant. First of all, it means that TSH testing alone is not enough in patients who are susceptible to TSAb antibody activity.

Secondly, the good news is that it means that you don’t need an antibody test to see the antibody at work. All you need to do is

• look for a very abnormal relationship between the TSH and your Free T4 and Free T3 levels,
• look for unreasonable fluctuations and mismatches in the lab history over time in the context of thryoid med dosing, and
• understand how the TSH receptor antibody works not just to distort thyroid gland function, but distort TSH “autoregulation” itself through this ultrashort feedback loop.

When fluctuations occur while taking Graves’ disease medication, one adjusts the medication. Similarly, when fluctuations occur when taking thyroid hormones, one adjusts their doses.

It’s easier to manage TSAb fluctuations in hypothyroid therapy when FT4 is moderately low and one uses a LT3 as a “flexible topper.” This is because T4 clearance rates are much slower than this antibody’s speed of fluctuation, and because supplementary LT3 dosing is capable of being tweaked over days or weeks instead of months.

Given the millions of patients worldwide affected by the TSAb, it’s urgent to disseminate this information, to acknowledge the importance of thyroid hormone testing in monitoring autoimmune thyroid therapy, and to enhance clinicians’ laboratory test interpretation skills.

Coming soon

In a follow-up post, I’ll explain the various mechanisms by which the antibody works on the pituitary secretion of TSH, giving more direct quotations from the researchers themselves and explaining what they mean.

At that point, I’ll finally be able to feature the hypothyroid side of TRAb antibody TSH manipulation. First, one can see it in the excessive TSH levels in “blocking-type hypothyroidism” prior to therapy. After that, one can see it in hypothyroid patients whose TSH continues to fluctuate abnormally high during thyroid therapy.

In a later post, I’ll discuss the debates in the field. I’ll illustrate why misunderstanding still persists about the antibody-driven TSH effects, why these effects vary from patient to patient, and why it’s so difficult for some scientists and doctors to accept that this TRAb antibody is such a powerful manipulator of TSH in both hyperthyroid therapy and hypothyroid therapy.

References

Brokken, L. J., Scheenhart, J. W., Wiersinga, W. M., & Prummel, M. F. (2001). Suppression of serum TSH by Graves’ Ig: Evidence for a functional pituitary TSH receptor. The Journal of Clinical Endocrinology and Metabolism, 86(10), 4814–4817. https://doi.org/10.1210/jcem.86.10.7922

Brokken, J. S., Wiersinga, M., & Prummel, F. (2003). Thyrotropin Receptor Autoantibodies Are Associated with Continued Thyrotropin Suppression in Treated Euthyroid Graves’ Disease Patients. The Journal of Clinical Endocrinology & Metabolism, 88(9), 4135–4138. https://doi.org/10.1210/jc.2003-030430

Chung, Y. J., Lee, B. W., Kim, J.-Y., Jung, J. H., Min, Y.-K., Lee, M.-S., Lee, M.-K., Kim, K.-W., & Chung, J. H. (2006). Continued suppression of serum TSH level may be attributed to TSH receptor antibody activity as well as the severity of thyrotoxicosis and the time to recovery of thyroid hormone in treated euthyroid Graves’ patients. Thyroid: Official Journal of the American Thyroid Association, 16(12), 1251–1257. https://doi.org/10.1089/thy.2006.16.1251

Fröhlich, E., & Wahl, R. (2017). Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases. Frontiers in Immunology, 8. https://doi.org/10.3389/fimmu.2017.00521

Lesho, E., & Jones, R. E. (1997). Hypothyroid Graves’ disease. Southern Medical Journal, 90(12), 1201–1203. https://doi.org/10.1097/00007611-199712000-00007

Prummel, M. F., Brokken, L. J. S., & Wiersinga, W. M. (2004). Ultra short-loop feedback control of thyrotropin secretion. Thyroid: Official Journal of the American Thyroid Association, 14(10), 825–829. https://doi.org/10.1089/thy.2004.14.825

Yu, H., & Farahani, P. (2015). Thyroid stimulating hormone suppression post-therapy in patients with Graves’ disease: A systematic review of pathophysiology and clinical data. Clinical and Investigative Medicine. Medecine Clinique Et Experimentale, 38(2), E31-44.