A Rare Form of Hypothyroidism

Shehzad Basaria, MD, and Milena Braga, MD


South Med J. 2002;95(5) 

In This Article


Central hypothyroidism is a rare disorder with a prevalence of 0.0002% to 0.005%.[1] Most commonly, it is encountered along with multiple pituitary hormone deficiencies resulting from pituitary surgery, apoplexy, radiation exposure, pituitary and other intracranial tumors, infiltrative systemic diseases. or autoimmune conditions such as lymphocytic hypophysitis.[2] Comprehensive laboratory evaluation in our patient showed normal levels of all the other pituitary hormones. Although a normal IGF-I level does not exclude the diagnosis of growth hormone (GH) deficiency, provocative tests for GH secretion were not done.

Isolated thyrotropin deficiency is extremely rare.[3] It is seen equally in both sexes and has a bimodal peak. The first peak is seen in childhood and the second in adults between the ages of 30 and 60 years. In children, mutations in Pit-1 gene, Prop-1 gene, and thyrotropin beta subunit gene can result in cretinism.[4] However, these mutations usually result in multiple pituitary hormone deficiencies. The causes of isolated thyrotropin deficiency in adults include mutations in TRH receptor, increased somatostatinergic or dopaminergic tone, and an increase in cerebral opioid activity. The role of opioids is further substantiated by the fact that pretreatment with naloxone increases thyrotropin response to TRH stimulation.[5]

As compared with euthyroid subjects, patients with central hypothyroidism show a decrease in nocturnal surge of thyrotropin secretion.[6] In many patients, thyrotropin may be in the normal range or even slightly elevated with a frankly low free T4 level. It is believed that this thyrotropin is biologically inactive because of abnormal glycosylation of the molecule.[7]

Patients with isolated central hypothyroidism have symptoms similar to those in patients with primary hypothyroidism. However, the presence of a nonpalpable thyroid gland is a clue to the diagnosis of central hypothyroidism. The laboratory values generally confirm the diagnosis. Regardless of the severity of symptoms, imaging of the pituitary gland is mandatory, and MRI with gadolinium is the preferred imaging modality.

The TRH stimulation test helps to distinguish secondary from tertiary hypothyroidism.[8] In the former, there is absence or blunting of thyrotropin response to TRH, since there is no thyrotropin reserve in the pituitary. In hypothalamic disease, there is a delayed and exaggerated response to TRH because the thyrotrophs take some time to "wake up" after a prolonged lack of stimulation by endogenous TRH. In euthyroid subjects, the thyrotropin peak is usually seen 15 to 20 minutes after TRH injection. Since TRH also results in stimulation of prolactin secretion, prolactin is used as a control against the thyrotropin response.[9] The absence of response of both these hormones points toward consideration of multiple pituitary hormone deficiencies. As a rule, the normal response of prolactin is several-fold higher in magnitude than the normal thyrotropin response. The prolactin response to TRH is higher in women because of the influence of estrogen. The thyrotropin response also declines with aging.[10] Table 2 illustrates the pattern of response of thyrotropin to TRH.

Patients should be given replacement doses of L-thyroxine. There is no role for thyrotropin monitoring in judging the adequacy of replacement dose. This should be assessed by monitoring free T4 levels. The level of free T4 should be kept in the normal range, and the dose should be titrated to avoid side effects. It is important to rule out adrenal insufficiency before thyroxine replacement is initiated, since it can result in adrenal crisis in patients with partial or absolute cortisol deficiency.

A variety of drugs can cause alterations in thyroid function tests. Our patient was taking two antidepressants that were serotonin reuptake inhibitors. Although the case of an adolescent who was taking sertraline and had a low total T4 value has been reported, free T4 and thyrotropin levels were normal, as were results of the TRH test.[11] The low total T4 in that patient was attributed to a competition for TBG binding between the drug and thyroid hormone. Similarly, many other antidepressants have been shown to decrease TRH synthesis in rat hypothalamic neurons.[12] Even if we assume that this mechanism applies to humans, the response to TRH test should be exaggerated, implying tertiary hypothyroidism. Our patient had low thyrotropin and low free T4 levels, and results of the TRH test were consistent with secondary hypothyroidism.