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Research Articles and Papers on:

Graves Disease



HOT THYROIDOLOGY (www.hotthyroidology.com), October , No 1 , 2003

The physiological and clinical relevance of the TSH Receptor in the anterior pituitary

Mark F. Prummel, Leon JS Brokken
Department of Endocrinology and Metabolism, Academic Medical Center, F5-171 , Amsterdam , The Netherlands

Although there usually is a good negative correlation between free T4 and TSH levels, there are some notorious exceptions in which the feedback system between fT4 and TSH seems to be disrupted. Most clinicians will be aware of the fact that TSH levels can remain low, despite clinical euthyroidism and normal concentrations of T4 and T3, in patients treated for Graves' hyperthyroidism.1 This situation is attributed to a delayed recovery of the pituitary-thyroid axis after a prolonged state of thyrotoxicosis.2

This explanation seemed to us unlikely for various reasons. First, TSH levels increase within weeks after discontinuation of T4 therapy in patients treated with TSH supressive doses of T4 for thyroid cancer, suggesting that the pituitary-thyroid axis can revive fast. Secondly, not all patients treated for Graves' hyperthyroidism show this phenomenon of long-term TSH suppression. And thirdly, a decreased level of TSH after a one year course of antithyroid drugs is an independent risk factor for recurrence of hyperthyroidism upon discontinuation of antithyroid drugs.3 These clinical observations suggest that the long-term TSH suppression in Graves' disease is a specific feature of a subset of Graves' patients: those likely to relapse after antithyroid drug therapy, e.g. patients with persisting TSH Receptor Stimulating Immunoglobulins (TSI).

We hypothesized that TSI are responsible for the prolonged TSH suppression observed in a subset of Graves' patients. The implication would be that TSI could decrease TSH secretion independently of thyroid status, at the central (hypothalamus/pituitary) level. Because the pituitary gland is outside the blood-brain barrier and the hypothalamus is not, we postulated that the TSI may act on the pituitary level decreasing TSH secretion. A requisite for this hypothesis is that the pituitary contains a TSH R.




Long-term TSH suppression during otherwise successful treatment of Graves' disease has always been attributed to a delayed recovery of the pituitary-thyroid axis. Less experienced clinicians regard it as proof for still existing "subclinical" hyperthyroidism and act accordingly by increasing the methimazole dosage or decreasing T4 substitution.

The above mentioned experiments have clearly shown that prolonged TSH suppression is very likely to be caused by an interaction between the pituitary TSH-R and circulating TSH-R autoantibodies, which can remain present in about half of treated Graves' patients. Low TSH levels in clinically euthyroid patients with normal T4 and T3 levels thus do not indicate persisting low-grade hyperthyroidism, but should instead be seen as an indication for continued TSI activity.

A low TSH value in such patients may be regarded as a positive "bio-assay" for TSI activity and explain why decreased TSH values are an independent risk factor for a relapse of Graves' hyperthyroidism after a course of antithyroid drugs.




Thyroid radiation doses are “much too high”
New Scientist 6th March 2004
We don’t often report news about over-activity but I felt that this was too good to pass!  The Swedish Radiation Protection Authority (SSI) reported that many hospitals around the world are ignoring international recommendations to minimise patients’ exposure to radiation.  People with Graves Disease are given radioactive iodine-131 to destroy all or part of the gland.   Helene Jonsson, an SSI inspector is concerned that doctors don’t optimise the radiation dose for individuals.  Doctors should take the size of the thyroid gland into account when they give iodine-131 because thyroid glands vary in size and there is a chance of developing cancer in later life if too much is given, especially in young people. 

She analyzed 187 cases of Graves Disease between 1984 and 1988 where the doses had been individually optimised.  She concluded that if the patients had instead been given a fixed dose, 370 megabecquerels, they would have received an average of two and a half times as much radiation as they needed (Radiation Protection Dosimetry, vol 108,p 107).  Keith Baverstock, an expert on radiation and health at the University of Kuopio in Finland, states, “Iodine-131 is highly toxic to young children, increasing the risk of thyroid cancer even at low doses.”

President of the Royal College of Radiologists in the UK, states, “It is likely that some patients will get more than they need, but it is better than failing to treat the disease.”


Relations of Thyroid Function to Body Weight: Cross-sectional and Longitudinal Observations in a Community-Based Sample

Abstract summarised from:
Arch Intern Med. 2008; 168(6): 587-592
Caroline S. Fox, MD, MPH; Michael J. Pencina, PhD; Ralph B. D’Agostino, PhD; Joanne M. Murabito, MD; Ellen W. Seely, MD; Elizabeth N. Pearce, MD; Ramachandran S. Vasan, MD

Background: Overt hypothyroidism and hyperthyroidism may be associated with weight gain and loss. We assessed whether variations in thyroid function within the reference (physiologic) range are associated with body weight.

Methods:  Patients taking part in the Framingham Offspring Study who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had TSH levels of 0.5 to 5.0 and follow-up levels of 0.5 to 10.0 were included in this study. TSH concentrations were related to body weight and body weight change during 3.5 years of follow-up.

Results:  Weight increased progressively from 64.5 to 70.2 kg in the people who were in the lowest to highest quarters of the TSH range in women and from 82.8 (lowest quarter) to 85.6 kg (highest quartier) in men. During 3.5 years of follow-up the average body weight increased by 1.5 (5.6) kg in women and 1.0 (5.0) kg in men. Baseline TSH levels were not associated with weight change during follow-up. However, an increase in TSH concentration at follow-up was positively associated with weight gain in women (0.5-2.3 kg across increasing quarters of TSH levels) and men (0.4-1.3 kg across quarters of TSH levels).

Conclusions:  Thyroid function (as assessed by serum TSH concentration) within the reference range is associated with body weight in both sexes. Our findings raise the possibility that modest increases in serum TSH concentrations within the reference range may be associated with weight gain.