The most common cause of a reduced TSH in a non-hospitalized patient is thyroid hormone excess. This may be due to endogenous hyperthyroidism or excess exogenous thyroid hormone. The degree of suppression of basal TSH is in proportion to the degree and duration of the excess thyroid hormone. The reduced TSH is the pathophysiological manifestation of the activation of the negative feedback loop.

While a low TSH in the presence of elevated thyroid hormones is logical, it results from multiple causes. Prolonged excessive thyroid hormone causes physiological "atrophy" of the thyroid stimulatory limb of the hypothalamic-pituitary thyroid axis. Thus, TRH synthesis is reduced, TRH mRNA in the PVN is absent, TRH receptors in the thyrotroph may be reduced; and the concentration of TSH β and α subunits and both mRNAs in the thyrotroph are virtually undetectable. Therefore, it is not surprising that several months are usually required for the re-establishment of TSH secretion after the relief of thyrotoxicosis. This is especially well seen in patients with Graves' disease after surgery or radioactive iodine, in whom TSH remains suppressed despite a rapid return to a euthyroid or even hypothyroid functional status. [360, 361] Since TRH infusion will not increase TSH release in this situation, it is clear that the thyrotroph is transiently dysfunctional. [362] A similar phenomenon occurs after excess thyroid hormone treatment is terminated, and after the transient hyperthyroidism associated with subacute or some variants of autoimmune thyroiditis, though the period of suppression is shorter under the latter circumstances. [363] This cause of reduced circulating thyroid hormones and reduced or normal TSH should be distinguishable from central hypothyroidism by the history.

Severe illness is a common cause of TSH suppression although it is not often confused with thyrotoxicosis. Quantitation of thyroid hormones will generally resolve the issue. [294] Patients receiving high-dose glucocorticoids acutely may also have suppressed TSH values although chronic glucocorticoid therapy does not cause sufficient TSH suppression to produce hypothalamic-pituitary hypothyroidism (see above).

Exogenous dopamine suppresses TSH release. Infusion of 5-7.5 mg/Kg/min to normal volunteers causes an approximately 50% reduction in the concentrations of TSH and consequent small decreases in serum T4 and T3 concentrations. [327] In critically ill patients, this effect of dopamine can be superimposed on the suppressive effects of acute illness on thyroid function, reducing T4 production to even lower levels.331 Dopamine is sufficiently potent to suppress TSH to normal levels in sick patients with primary hypothyroidism. [327] This needs to be kept in mind when evaluating severely ill patients for this condition. Dopamine antagonists such as metoclopramide or domperidone cause a small increase in TSH in humans. However, somewhat surprisingly, patients receiving the dopamine agonist bromergocryptine, do not become hypothyroid. Although L-dopa causes a statistically significant reduction in the TSH response to TRH, patients receiving this drug also remain euthyroid. [333]

Studies in animals have suggested that pharmacological amounts of retinoids may decrease serum TSH concentration (see also paragraph “Effect of Thyroid Hormone on TSH Secretion”). [78, 364] Recently, severe central hypothyroidism associated with very low serum TSH concentration has been reported in patients with cutaneous T-cell lymphoma treated with high-dose bexarotene, a retinoid X receptor-selective ligand able to suppress TSH secretion. [365]

The capacity of hCG to function as a thyroid stimulator is discussed in Chapter 14. This may be manifested in patients with normal pregnancy as a slightly subnormal TSH during the first trimester (0.2 - 0.4 mU/L) or by frank, though mild, hyperthyroidism in patients with choriocarcinoma or molar pregnancy. [366]

Patients with acute psychosis or depression and those with agitated psychoses may have high thyroid hormone levels and suppressed or elevated TSH values. The etiology of the alterations in TSH are not known. Those receiving lithium for bipolar illness may also have elevated TSH values due to impairment of thyroid hormone release. Patients with underlying autoimmune thyroid disease or multi-nodular goiter are especially susceptible. [367] A small fraction of elderly patients, particularly males, have subnormal TSH levels with normal serum thyroid hormone concentrations. It is likely that this reflects mild thyrotoxicosis if it is found to be reduced on repeated determinations.

Congenital central hypothyroidism with low serum TSH may result from mutations affecting TSH β gene or the Pit-1 gene (see paragraphs “The Thyroid-Stimulating Hormone Molecule” and “Role of Pit-1 and its splicing variants in the regulation of TSH β gene expression”).

Primary hypothyroidism is the most common cause of an elevated serum TSH. The serum free T4 is low normal or reduced in such patients but the serum free T3 values remain normal until the level of thyroid function has markedly deteriorated. [101] Another common cause of an elevated TSH in an iodine-sufficient environment is the transient elevation which occurs during the recovery phase after a severe illness. [305, 306] In such patients a "reawakening" of the hypothalamic-pituitary thyroid axis occurs pari passu with the improvement in their clinical state. In general, such patients do not have underlying thyroid dysfunction. Iodine deficiency is not a cause of elevated TSH in Central and North America but may be in certain areas of Western Europe, South America, Africa and Asia.

The remainder of the conditions associated with an elevated TSH are extremely rare. Inherited (autosomal recessive) forms of partial (euthyroid hyperthyrotropinemia) or complete (congenital hypothyroidism) TSH resistance have been recently described associated to inactivating point mutations of the TSH receptor gene. [368, 369] Interestingly, inherited dominant forms of partial TSH resistance have also been described in the absence of TSH receptor gene mutations. [370, 371]No TSH nor Gsa gene mutations were detected in these excetpional cases. [370] and the underlying molecular defect(s) remain(s) to be elucidated. More frequently, in a patient who has an elevated serum FT4, the presence of TSH at normal or increased levels should lead to a search for either resistance to thyroid hormone or a thyrotroph tumor. Hypothalamic-pituitary dysfunction may be associated with normal or even modest increases in TSH are explained by the lack of normal TSH glycosylation in the TRH-deficient patient. The diagnosis is generally made by finding a serum free T4 index which is reduced to a greater extent than expected from the coincident serum TSH. Psychiatric illness may be associated with either elevated or suppressed TSH, but the abnormal values are not usually in the range normally associated with symptomatic thyroid dysfunction. The effect of glucocorticoids to suppress TSH secretion has already been mentioned. This is of relevance in patients with Addison's disease in whom TSH may be slightly elevated in the absence of primary thyroid disease.

Lastly, while most of the artifacts have been eliminated from the immunometric TSH assays, there remains the theoretical possibility of an elevated value due to the presence of endogenous antimouse gamma globulin antibodies. [372, 373] These antibodies, like TSH, can complex the two TSH antibodies resulting in artificially elevated serum TSH assay results in euthyroid patients. Such artifacts can usually be identified by finding non-linear results upon assay of serial dilutions of the suspect serum with that from patients with a suppressed TSH.