At a Glance

Thyroid stimulating hormone (TSH) secreting pituitary adenoma (TSH-oma) or central hyperthyroidism is very rare and has a prevalence of about one case per million. These comprise about 1% of pituitary adenomas. Most patients are middle aged, although the condition has been documented over a wide age range (8-80 years of age). The condition results from the autonomous functioning of a TSH producing pituitary adenoma, with resultant increase in thyroid hormone levels in the presence of a normal or elevated TSH level.

More than 90% of patients present with a goiter (even in patients with a history of thyroidectomy, due to the growth of the thyroid gland following overstimulation with TSH), symptoms of hyperthyroidism (21%), or symptoms related to pressure or biochemical effects arising from the pituitary adenoma, such as visual field defects (35%), headache (21%), menstrual disorders (33% of women), galactorrhea (28% of women) and acromegaly (16%). Symptoms of cardiotoxicosis or atrial fibrillation are rare. About one-third of the patients have a previous history of a thyroidectomy, or thyroid ablation usually due to a misdiagnosis.

The majority of TSH-omas secrete TSH alone (72%), and about one-fourth show concomitant secretion of Growth Hormone (16%) or Prolactin (10%).

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What tests should I request to confirm my clinical Dx? In addition, what follow-up tests might be useful?

The finding of a measurable or elevated TSH in the presence of high free T4 (FT4) and free T3 (FT3) is very suggestive, providing that interferences affecting these assays have been excluded by discussing with the clinical laboratory. T4 and T3 levels are also elevated, but these tests are less useful, since their levels can be affected by drugs and conditions that affect their binding protein (TBG) concentrations. Sex hormone binding globulin (SHBG) levels are increased in TSH-omas (macroadenomas; >10 mm size), as are alpha subunit levels. In microadenomas (<10 mm in size), the alpha subunit levels can frequently be normal (60% of cases) even though the ratio of alpha subunit/TSH molar ratio is increased in TSH-omas (80% of patients overall). When possible, age- and sex-specific alpha subunit/TSH ratios should be utilized.

High resolution CT scanning and/or MRI can be diagnostic, especially in the diagnosis of macroadenomas (>10 mm size), although microadenomas can be harder to detect by radiologic examination. SHBG levels are typically increased in TSH-omas.(Table 1)

Table 1.
High High

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

If the clinical picture is not supportive of the biochemical results, the laboratory director should be contacted to rule out certain conditions, such as macro-TSH, auto-antibodies to TSH or to thyroxine, or heterophilic antibodies, which may interfere with TSH and thyroxine assays. Typically, FT4 and FT3 are less sensitive to antibody or other interference, as opposed to T4 and T3, and equilibrium dialysis based methods, as well as two-step immunoassay methods, are less problematic, as opposed to “one-step” methods.

What Lab Results are Absolutely Confirmatory?

Measurable or elevated TSH along with elevated FT4, FT3 is diagnostic of TSH-oma, if resistance to thyroid hormone (RTH) and assay interferences can be excluded. Radiologic tests, such as MRIs and CT scan, can be diagnostic, especially in the presence of a macroadenoma.

Additional Issues of Clinical Importance

The main condition that needs to be excluded is peripheral resistance to thyroid hormone (PRTH). PRTH is a type of RTH, characterized by hyperthyroidism. In RTH, there is usually a family history, and molecular testing of the TR-beta gene shows a mutation. SHBG, alpha subunit of TSH, alpha subunit/TSH molar ratio are normal in RTH, as are the pituitary CT/MRI findings.

The T3-suppression test and the TRH tests are positive in RTH. In the T3-suppression test, T3 is provided (80-100 mg, for 8-10 days), following which TSH levels are suppressed in RTH but not in TSH-oma. The test is contraindicated in the aged and those with coronary heart disease. The TRH test is safer, and post TRH, TSH, and alpha subunit levels do not increase in TSH-oma but do increase in RTH. Carboxyterminal telopeptide of type I collagen is increased in TSH-omas because of increased bone turnover in hyperthyroidism due to TSH-oma but is normal in PRTH.

In patients who are on thyroxine replacement therapy, the presence of measurable TSH may also reflect incorrect dosing and/or poor compliance. Invasive microadenomas are more common in patients who have undergone thyroidectomy or thyroid ablation due to a misdiagnosis.

Errors in Test Selection and Interpretation

Pituitary scintigraphy with radiolabeled octreotide (octreoscan) can successfully localize pituitary adenomas expressing somatostatin receptors; however, the specificity of the technique is low, as it does not distinguish between different types of pituitary masses.

In patients with hyperthyroidism, discrepancies between TSH and alpha subunit responses to TRH are typical of pituitary adenomas cosecreting other pituitary hormones (e.g., GH, PRL).

An important consideration when looking at CT scans and MRI data is the possibility of an “incidentaloma,” the incidental finding of a pituitary adenoma, that may or may not be responsible for the patient’s symptoms.