Etiology
Etiologies of central hypothyroidism are numerous and reflect dysfunction of the pituitary, hypothalamus, or hypothalamic-pituitary portal circulation. Pituitary mass lesions, especially pituitary adenomas such as growth hormone (GH)- or adrenocorticotropic hormone (ACTH)-secreting adenomas, are the most common cause.[1][5] Other mass lesions that can result in central hypothyroidism include cysts, meningiomas, dysgerminomas, craniopharyngiomas, and tumor metastases to the pituitary gland.
Infiltrative disorders may also affect hypothalamic/pituitary function and include infectious (tuberculosis, syphilis, fungal infections, toxoplasmosis) and noninfectious etiologies (sarcoidosis, hemochromatosis, histiocytosis).[1][6] Catastrophic (acute) causes of central hypothyroidism include head trauma, pituitary apoplexy, and Sheehan syndrome (postpartum pituitary necrosis).[1][7] Iatrogenic causes include cranial surgery or radiation, and drugs such as the anticonvulsant oxcarbazepine.[1] Several rare genetic defects may also cause central hypothyroidism.[1] Candidate genes include TSHB, TRHR, IGSF1, and TBL1X.[3] Lymphocytic hypophysitis is a rare etiology.[1][8]
Pathophysiology
Pituitary thyroid-stimulating hormone (TSH) is a glycoprotein that is produced and secreted by the anterior pituitary to promote thyroidal biosynthesis and secretion of the thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) by the thyroid gland.[9] The secretion of TSH is regulated by thyrotropin-releasing hormone (TRH) and the peripheral thyroid hormones. TRH is a tripeptide released into the hypothalamic-pituitary portal vessels and transported to the anterior pituitary, where it promotes the synthesis and secretion of TSH.[10] Conversely, T3 and T4 act on the anterior pituitary in a negative feedback loop, inhibiting the synthesis and secretion of TSH. T3 and T4 also act at the hypothalamic level to inhibit the secretion of TRH.[11] Other soluble factors that affect TSH secretion include dopamine, glucocorticoids, and somatostatin. In central hypothyroidism, TSH production and/or secretion is impaired due to hypothalamic and/or pituitary dysfunction. This can occur as a result of deficient stimulation of the anterior pituitary by TRH, deficient synthesis and secretion of TSH by the anterior pituitary, or secretion of biologically ineffective TSH, as in some genetic diseases.[12][13][14][15][16]
Pathologically, hypothyroid signs and symptoms arise from the accumulation of glycosaminoglycans in interstitial tissues due to decreased metabolism. The clinical manifestations of central hypothyroidism are related to low levels of T3 and T4 and, therefore, are similar to primary hypothyroidism. In addition, individuals with central hypothyroidism may have concomitant derangements in one or more pituitary hormones, including adrenocorticotropic hormone (ACTH), gonadotropin (luteinising hormone and follicle-stimulating hormone), growth hormone, and prolactin deficiencies. Concomitant dysfunction of the posterior pituitary results in diabetes insipidus because of antidiuretic hormone deficiency. If central hypothyroidism is caused by a functioning pituitary adenoma, symptoms of ACTH, growth hormone, and/or prolactin excess may be present.
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