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Mechanisms related to the pathophysiology and management of central hypothyroidism

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 683–694 (2008)Cite this article

Abstract

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.

Key Points

  • In many cases of central hypothyroidism (CH) serum TSH level remains normal, but CH should always be investigated if serum TSH levels are inappropriately low along with subnormal T4 levels

  • Most cases of central hypothyroidism are accompanied by other hormone deficiencies, which should be examined, particularly those of the adrenocorticotropic hormone–adrenal axis

  • Important causes are pituitary adenoma (for which hypothalamic–pituitary–thyroid axis and adrenal axis function should be assessed), post-traumatic brain injury and subarachnoid hemorrhage

  • To evaluate the biological activity of circulating TSH, the increment of serum free T3 in the TSH-releasing hormone test might be used, but a normal result does not exclude CH

  • Appropriate doses of levothyroxine for central hypothyroidism might be higher than empirical doses currently used to achieve serum free T4 levels in the normal range

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Figure 1: The hypothalamic–pituitary–thyroid axis.
Figure 2: Proposed algorithm for the diagnosis and confirmation of central hypothyroidism.
Figure 3: Proposed algorithm for the treatment of central hypothyroidism.

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Acknowledgements

We thank K Horiguchi and R Umezawa for their help collating and analyzing articles.

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  1. in the Department of Medicine and Molecular Science, M Yamada is Associate Professor, and M Mori is Professor and Chairman, Gunma University Graduate School of Medicine, Gunma, Japan.,

    Masanobu Yamada & Masatomo Mori

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Correspondence to Masanobu Yamada.

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Yamada, M., Mori, M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Rev Endocrinol 4, 683–694 (2008). https://doi.org/10.1038/ncpendmet0995

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