Mechanisms Related to the Pathophysiology and Management of Central Hypothyroidism

Masanobu Yamada; Masatomo Mori


Nat Clin Pract Endocrinol Metab. 2008;4(12):683-694. 

In This Article

Summary and Introduction

Central hypothyroidism (CH) is defined as hypothyroidism due to insufficient stimulation of the thyroid gland by TSH, for which secretion or activity can be impaired at the hypothalamic or pituitary levels. Patients with CH frequently present with multiple other pituitary hormone deficiencies. In addition to classic CH induced by hypothalamic-pituitary tumors or Sheehan syndrome, novel causes include traumatic brain injury or subarachnoid hemorrhage, bexarotene (a retinoid X receptor agonist) therapy, neonates being born to mothers with insufficiently controlled Graves disease, and lymphocytic hypophysitis. Growth hormone therapy, which may be used in children and adults, is now also recognized as a possible cause of unmasking CH in susceptible individuals. In addition, mutations in genes, such as TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, LHX4 and TSHB, have been associated with CH. The difficulty in making a clear diagnosis of CH is that the serum TSH levels can vary; values are normal in most cases, but in some might be low or slightly elevated. Levels of endogenous T4 in serum might also be subnormal. Appropriate doses of levothyroxine for T4 replacement therapy have not been confirmed, but might need to be higher than presently used empirically in patients with CH and should be adjusted according to age and other hormone deficiencies, to achieve free T4 concentrations in the upper end of the normal range.

Hypothyroidism is a common disorder and is most frequently caused by primary hypothyroidism. Characteristic laboratory findings for primary hypothyroidism are subnormal levels of thyroid hormone and raised TSH levels (caused by normal feedback regulation) in serum. Central hypothyroidism (CH) results from disturbance to the thyroid stimulation system. The precise prevalence of CH is unknown, but it is thought to be much lower than that of primary hypothyroidism. However, CH arises from a number of hypothalamic and pituitary disorders, the most frequent of which is pituitary adenoma.[1] Given that the prevalence of pituitary adenomas in the general population is greater than 10%, the true prevalence of CH might be much higher than that reported.[2] Approximately 15% of 300 of our patients with pituitary adenomas examined in the past year have had CH. Van Tijn et al.[3] reported the incidence of congenital CH to be 1 per 16,404 neonates, with 13.5% among these having permanent hypothyroidism.

Traumatic brain injury, subarachnoid hemorrhage, lymphocyte hypophysitis, or Sheehan syndrome, any time up to several decades previously, might cause CH and lead to deficiency in secretion of multiple pituitary hormones. A full, detailed history should, therefore, be taken and tests done for a variety of hormone deficiencies. The characteristic order and prevalence of the disturbances of pituitary hormones differs in different disorders and might help to identify the origin of the CH.

In general practice, serum TSH is the best indicator for detecting hypothyroidism and hyperthyroidism and for monitoring treatments of thyroid disorders. This approach works, however, only if the hypothalamic-pituitary-thyroid axis is normal. Conversely, the strategy of first-line TSH measurement can miss patients with CH.

In this Review, we focus on prevalence of CH and thyroid hormone status, particularly serum TSH level in each disorder, and discuss appropriate management.


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