Pituitary/Hypothalamic Dysfunction

Central hypothyroidism is an important complication of pituitary disease and, because TSH levels are not useful, the diagnosis and therapeutic considerations are difficult.

Central hypothyroidism is defined as a reduction in circulating thyroid hormone as a result of inadequate stimulation of a normal thyroid gland by TSH and may be secondary, due to pituitary disease, or tertiary, due to hypothalamic dysfunction. Causes include all pathologic processes that affect the hypothalamus or pituitary including tumors, Sheehan's syndrome, idiopathic hypopituitarism and infiltrative diseases, such as sarcoidosis, histiocytosis and lymphocytic hypophysitis. Radiation-induced central hypothyroidism is common in patients irradiated for pituitary tumors. Tsang et al. retrospectively examined records of 160 patients who had received radiation for non-functioning pituitary adenomas 8 to 22 years before and found that 65% required thyroid replacement therapy, with 23% of patients' hypothyroidism directly attributable to the radiation therapy received [1]. In addition, hypothyroidism is common in patients receiving radiation for nasopharyngeal or paranasal sinus tumors and brain tumors. Constine et al. evaluated the endocrine function of 32 patients who had received radiation for brain tumors, including gliomas, medulloblastomas and ependymomas, from 2 to 13 years before, and found that 65% had low free T4 levels. The probability of hypothyroidism depended on the amount of radiation received, with doses of more than 5000 rads (50 Gy) to the pituitary and hypothalamus necessary for the development of hypothyroidism. Moreover, the longer the interval since irradiation, the more likely a patient was to have developed hypothyroidism [2]. Therefore, the percentage of patients developing hypothyroidism may have been even higher had the follow-up been longer. In addition, because the onset of hypothyroidism may occur years after the administration of the radiation, constant vigilance for the signs and symptoms of hypothyroidism in this population is imperative and yearly monitoring of thyroid hormone levels obligatory.

As in primary hypothyroidism, the symptoms of central hypothyroidism include fatigue, apathy, weight gain, dry skin, constipation and cold intolerance. Signs include periorbital edema, cool extremities, delayed relaxation of the deep tendon reflexes and bradycardia.
The signs and symptoms of central hypothyroidism mimic those of several other common conditions, and this disorder is therefore difficult to diagnose. A low free T4 or free T4 index and a low TSH in the setting of pituitary disease and signs and symptoms of hypothyroidism point in a straightforward manner to the diagnosis of central hypothyroidism. Unfortunately, however, the TSH is most commonly in the normal range in cases of central hypothyroidism, creating a confusing picture. Research has shown that, in some of these cases, a bio-inactive TSH resulting from abnormal glycosylation of the TSH molecule [3-6] explains the higher than expected TSH levels. Therefore, although the serum TSH is measured as normal in routine assays, performed by immunoradiometric assay (IRMA) or immunochemiluminometric assay (ICMA), only a small proportion of the TSH molecules function normally. Although these "normal" TSH values can confound the diagnosis of central hypothyroidism, it should be noted that a "normal" or slightly high TSH is inappropriate when circulating thyroid hormone levels are low, and that in cases of primary hypothyroidism, the TSH would be expected to be much higher. Therefore, TSH is not a useful screen for the diagnosis of this disorder.

The management of central hypothyroidism is further complicated by the fact that the TSH cannot be used to monitor therapeutic response to L-thyroxine therapy. When pituitary pathology is not present, the TSH provides an accurate method of assessing the appropriateness of circulating thyroid hormone levels for each particular patient. However, pituitary or hypothalamic pathology often interrupts the feedback mechanism by preventing normal release of TSH and/or TRH. The consequences of this are two-fold. First, patients with pituitary pathology or who have been irradiated cannot be screened for hypothyroidism with TSH levels alone, as a normal TSH often belies central hypothyroidism. Moreover, the usually routine monitoring of thyroid replacement becomes more problematic. Inadequate replacement doses of l-thyroxine often result in markedly subnormal TSH values. Therefore, TSH values are not reliable as an accurate reflection of thyroid status, and a free T4 or free T4 index must be used to adjust the replacement dose. However, as in primary hypothyroidism, when appropriately diagnosed and treated, management of central hypothyoidism can result in prompt resolution of symptoms.