- Douglas S Ross, MD
Douglas S Ross, MD
- Section Editor — Thyroid Disease
- Professor of Medicine
- Harvard Medical School
The overwhelming majority of patients who have hypothyroidism have thyroid disease (primary hypothyroidism). Central hypothyroidism refers to thyroid hormone deficiency due to a disorder of the pituitary, hypothalamus, or hypothalamic-pituitary portal circulation. Pituitary thyroid-stimulating hormone (TSH) production is regulated in part by thyrotropin-releasing hormone (TRH), which is secreted from the paraventricular nucleus in the hypothalamus. TRH is released into portal blood vessels and transported to the anterior pituitary gland where it regulates the synthesis, glycosylation, and release of TSH (figure 1). TSH stimulates the synthesis and secretion of triiodothyronine (T3) and thyroxine (T4). (See "Thyroid hormone synthesis and physiology".)
Hypothalamic-pituitary tumors can cause central hypothyroidism by compression of the hypothalamus or pituitary, which results in a decrease in TRH or TSH secretion, or by disrupting signalling between the hypothalamus and pituitary. Other causes of central hypothyroidism include lymphocytic hypophysitis, Sheehan syndrome, traumatic brain injury, subarachnoid hemorrhage, and infiltrative disorders. Patients with central hypothyroidism frequently have other pituitary hormone deficiencies.
The clinical features, diagnosis, and treatment of central hypothyroidism will be reviewed here. The approach to patients with primary, subclinical, and congenital hypothyroidism is reviewed separately. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Treatment of hypothyroidism" and "Subclinical hypothyroidism in nonpregnant adults" and "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism".)
Central hypothyroidism is a rare cause of hypothyroidism, estimated to occur in 1:20,000 to 1:80,000 in the general population . The causes of central hypothyroidism are the same as the causes of hypopituitarism (table 1) [2,3]. (See "Causes of hypopituitarism".)
Pituitary mass lesions, especially pituitary adenomas, are the most common cause of central hypothyroidism . Pituitary tumors can cause hypothyroidism by compression of pituitary thyrotrophs, interruption of the hypothalamic-pituitary portal blood flow, or rarely by acute hemorrhage or infarction resulting in pituitary apoplexy [2,3]. Other mass lesions that can cause central hypothyroidism include cysts and abscesses, meningiomas and dysgerminomas, metastatic tumors, and craniopharyngiomas, which may enter the sella or remain suprasellar.
- Persani L. Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 2012; 97:3068.
- Samuels MH, Ridgway EC. Central hypothyroidism. Endocrinol Metab Clin North Am 1992; 21:903.
- Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab 2008; 4:683.
- Bates AS, Van't Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996; 81:1169.
- CureSearch: Children's Oncology Group. http://www.survivorshipguidelines.org/ (Accessed on March 23, 2011).
- Bhandare N, Kennedy L, Malyapa RS, et al. Primary and central hypothyroidism after radiotherapy for head-and-neck tumors. Int J Radiat Oncol Biol Phys 2007; 68:1131.
- Thodou E, Asa SL, Kontogeorgos G, et al. Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol Metab 1995; 80:2302.
- Benvenga S, Vigo T, Ruggeri RM, et al. Severe head trauma in patients with unexplained central hypothyroidism. Am J Med 2004; 116:767.
- Schoenmakers N, Alatzoglou KS, Chatterjee VK, Dattani MT. Recent advances in central congenital hypothyroidism. J Endocrinol 2015; 227:R51.
- Pfäffle RW, DiMattia GE, Parks JS, et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992; 257:1118.
- Collu R, Tang J, Castagné J, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 1997; 82:1561.
- Hayashizaki Y, Hiraoka Y, Tatsumi K, et al. Deoxyribonucleic acid analyses of five families with familial inherited thyroid stimulating hormone deficiency. J Clin Endocrinol Metab 1990; 71:792.
- Dacou-Voutetakis C, Feltquate DM, Drakopoulou M, et al. Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone beta-subunit gene. Am J Hum Genet 1990; 46:988.
- Medeiros-Neto G, Herodotou DT, Rajan S, et al. A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest 1996; 97:1250.
- Bonomi M, Proverbio MC, Weber G, et al. Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. J Clin Endocrinol Metab 2001; 86:1600.
- Muthukrishnan J, Harikumar KV, Verma A, Modi K. Central hypothyroidism. Indian J Pediatr 2010; 77:94.
- Hermanns P, Couch R, Leonard N, et al. A novel deletion in the thyrotropin Beta-subunit gene identified by array comparative genomic hybridization analysis causes central congenital hypothyroidism in a boy originating from Turkey. Horm Res Paediatr 2014; 82:201.
- Gharib H, Abboud CF. Primary idiopathic hypothalamic hypothyroidism. Report of four cases. Am J Med 1987; 83:171.
- Yamakita N, Komaki T, Takao T, et al. Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion. J Clin Endocrinol Metab 2001; 86:1054.
- Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999; 340:1075.
- Agha A, Walker D, Perry L, et al. Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol (Oxf) 2007; 66:72.
- Porretti S, Giavoli C, Ronchi C, et al. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory? J Clin Endocrinol Metab 2002; 87:2042.
- Alexopoulou O, Beguin C, De Nayer P, Maiter D. Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol 2004; 150:1.
- Beck-Peccoz P, Amr S, Menezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med 1985; 312:1085.
- Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 2000; 85:3631.
- Miura Y, Perkel VS, Papenberg KA, et al. Concanavalin-A, lentil, and ricin lectin affinity binding characteristics of human thyrotropin: differences in the sialylation of thyrotropin in sera of euthyroid, primary, and central hypothyroid patients. J Clin Endocrinol Metab 1989; 69:985.
- Samuels MH, Lillehei K, Kleinschmidt-Demasters BK, et al. Patterns of pulsatile pituitary glycoprotein secretion in central hypothyroidism and hypogonadism. J Clin Endocrinol Metab 1990; 70:391.
- Caron PJ, Nieman LK, Rose SR, Nisula BC. Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endocrinol Metab 1986; 62:960.
- Ferretti E, Persani L, Jaffrain-Rea ML, et al. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999; 84:924.
- http://www.pathology.leedsth.nhs.uk/dnn_bilm/Investigationprotocols/Pituitaryprotocols/TRHTest.aspx (Accessed on September 13, 2012).
- Hartoft-Nielsen ML, Lange M, Rasmussen AK, et al. Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Horm Res 2004; 61:53.
- Surks MI, DeFesi CR. Normal serum free thyroid hormone concentrations in patients treated with phenytoin or carbamazepine. A paradox resolved. JAMA 1996; 275:1495.
- Connacher AA, Borsey DQ, Browning MC, et al. The effective evaluation of thyroid status in patients on phenytoin, carbamazepine or sodium valproate attending an epilepsy clinic. Postgrad Med J 1987; 63:841.
- Russo M, Scollo C, Pellegriti G, et al. Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism. Clin Endocrinol (Oxf) 2016; 84:614.
- Uy HL, Reasner CA, Samuels MH. Pattern of recovery of the hypothalamic-pituitary-thyroid axis following radioactive iodine therapy in patients with Graves' disease. Am J Med 1995; 99:173.
- Vagenakis AG, Braverman LE, Azizi F, et al. Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med 1975; 293:681.
- Slawik M, Klawitter B, Meiser E, et al. Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J Clin Endocrinol Metab 2007; 92:4115.
- Shimon I, Cohen O, Lubetsky A, Olchovsky D. Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid 2002; 12:823.
- Koulouri O, Auldin MA, Agarwal R, et al. Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine. Clin Endocrinol (Oxf) 2011; 74:744.
- Gordon MB, Gordon MS. Variations in adequate levothyroxine replacement therapy in patients with different causes of hypothyroidism. Endocr Pract 1999; 5:233.
- CLINICAL FEATURES
- Clinical manifestations
- Laboratory findings
- - Thyroid function tests
- - TRH stimulation test
- - Other
- DIFFERENTIAL DIAGNOSIS
- TSH slightly high
- TSH low
- TSH normal
- Transient central hypothyroidism
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS