Thyroid-Stimulating Hormone Regulation and Transcription in Hypothyroidism

Thyroid hormones play essential roles in mammalian life, especially in neurodevelopment (Porterfield & Hendrich, 1993). This fact is clearly shown in patients with neurological deficits from endemic cretinism, who reside in iodine-deficient areas (DeLong et at., 1985). In addition to neurological impairments, thyroid dysfunctions, such as hyperthyroidism and hypothyroidism, lead to a wide variety of clinical manifestations. Hypothyroidism is defined as deficient thyroid hormone action. It is caused most often by decreased thyroid hormone production, although in rare cases it is caused by reduced tissue responsiveness to or consumptive degradation of the hormone (Huang et al., 2000; Refetoff, Weiss, & Usala, 1993). There are two types of deficient thyroid hormone production: primary (thyroidal) hypothyroidism and central hypothyroidism. The former is commonly caused by iodine deficiency (DeLong et al., 1985) or chronic autoimmune thyroiditis, known as Hashimoto’s thyroiditis (Dayan & Daniels, 1996). In iodine-sufficient areas, Hashimoto’s thyroiditis is a major cause of primary hypothyroidism. The loss of functional follicles caused by intrathyroidal lymphocytic infiltration is attributable to impaired thyroid hormone production. Central hypothyroidism is due to reduced thyroid stimulation by thyroid-stimulating hormone (TSH) resulting from pituitary disease (secondary hypothyroidism) or hypothalamic disease (tertiary hypothyroidism) (Lania et al., 2008). Pituitary macroadenomas or radiotherapy of brain tumours and pituitary adenomas are frequently associated with insufficient TSH production in adults (Rose, 2001). In some cases of central hypothyroidism, abnormally glycosylated TSH with a reduced bioactivity is secreted (Faglia et al., 1979; Taylor & Weintraub, 1989). Because thyroid hormones negatively regulate pituitary TSH synthesis, decreased serum thyroid hormone concentrations lead to the stimulation of TSH production. Therefore, in primary hypothyroidism, serum TSH levels are increased, even at the stage of subclinical hypothyroidism (Fatourechi, 2009). By contrast, an increase in serum TSH is generally not observed in central hypothyroidism because of the impaired hypothalamic-pituitarythyroid axis. Based on these observations, serum TSH serves as a useful indicator for the presence and the type of hypothyroidism. Therefore, measurements of TSH are quite useful in clinical practice (Ladenson et al., 2000).