, Volume 18, Issue 1, pp 169–175 | Cite as

Central hypothyroidism in adults: better understanding for better care

  • Solange Grunenwald
  • Philippe CaronEmail author


Central hypothyroidism (CH) is a rare cause of hypothyroidism generally related to a hypothalamic–pituitary disorder or arising as an iatrogenic complication. In adults, CH may be secondary to quantitative and/or qualitative alterations in thyroid-stimulating hormone (TSH) secretion. The disease is difficult to diagnose clinically because it lacks specific clinical signs and these may be masked by other anterior pituitary hormone secretion deficiencies. In patients with long-standing and marked CH, a diagnosis may be made based on low free T4 levels and normal, low or moderately increased TSH levels. In patients with early-stage or moderate CH, exploration of the circadian TSH cycle, determination of TSH response after a TRH test or recombinant TSH injection, estimation of TSH index, or evaluation of peripheral indexes of thyroid hormone metabolism may be required to establish a diagnosis. Regarding treatment, patients should receive levothyroxine replacement therapy, but hormone objectives during follow-up need to be precisely determined in order to reduce cardiovascular risks and to improve the quality of life of patients.


Central hypothyroidism Pathophysiology Causes Diagnosis Treatment Levothyroxine Free T4 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Lania A, Persani L, Beck-Peccoz P (2008) Central hypothyroidism. Pituitary 11:181–186PubMedCrossRefGoogle Scholar
  2. 2.
    Persani L (2012) Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab 97:3068–3078PubMedCrossRefGoogle Scholar
  3. 3.
    Tagami T, Kimura H, Ohtani S et al (2011) Multi-center study on the prevalence of hypothyroidism in patients with hypercholesterolemia. Endocr J 58:449–457PubMedCrossRefGoogle Scholar
  4. 4.
    Wardle CA, Fraser WD, Squire CR (2001) Pitfalls in the use of thyrotropin concentration as a first-line thyroid-function test. Lancet 357:1013–1014PubMedCrossRefGoogle Scholar
  5. 5.
    Sell MA, Schott M, Tharandt L et al (2008) Functional central hypothyroidism in the elderly. Aging Clin Exp Res 20:207–210PubMedCrossRefGoogle Scholar
  6. 6.
    Caron PJ, Nieman LK, Rose SR et al (1986) Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endocrinol Metab 62:960–964PubMedCrossRefGoogle Scholar
  7. 7.
    Rose SR, Manasco PK, Pearce S et al (1990) Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic–pituitary disorders. J Clin Endocrinol Metab 70:1750–1755PubMedCrossRefGoogle Scholar
  8. 8.
    Persani L (1998) Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid 8:941–946PubMedCrossRefGoogle Scholar
  9. 9.
    Horimoto M, Nishikawa M, Ishihara T et al (1995) Bioactivity of thyrotropin (TSH) in patients with central hypothyroidism: comparison between in vivo 3,5,3′-triiodothyronine response to TSH and in vitro bioactivity of TSH. J Clin Endocrinol Metab 80:1124–1128PubMedGoogle Scholar
  10. 10.
    Persani L, Ferretti E, Borgato S et al (2000) Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 85:3631–3635PubMedGoogle Scholar
  11. 11.
    Beck-Peccoz P, Persani L (1994) Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol 131:331–340PubMedCrossRefGoogle Scholar
  12. 12.
    Beck-Peccoz P, Amr S, Menezes-Ferreira MM et al (1985) Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med 312:1085–1090PubMedCrossRefGoogle Scholar
  13. 13.
    Caturegli P, Newschaffer C, Olivi A et al (2005) Autoimmune hypophysitis. Endocr Rev 26:599–614PubMedCrossRefGoogle Scholar
  14. 14.
    Bensing S, Hulting AL, Höög A, Ericson K, Kämpe O (2007) Lymphocytic hypophysitis: report of two biopsy-proven cases and one suspected case with pituitary autoantibodies. J Endocrinol Invest 30:153–162PubMedCrossRefGoogle Scholar
  15. 15.
    Yamamoto M, Iguchi G, Takeno R et al (2011) Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans. J Clin Invest 121:113–119PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Juszczak A, Gupta A, Karavitaki N et al (2012) Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. Eur J Endocrinol 167:1–5PubMedCrossRefGoogle Scholar
  17. 17.
    Loeffler JS, Shih HA (2011) Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 96:1992–2003PubMedCrossRefGoogle Scholar
  18. 18.
    Littley MD, Shalet SM, Beardwell CG et al (1989) Radiation-induced hypopituitarism is dose-dependent. Clin Endocrinol (Oxf) 31:363–373CrossRefGoogle Scholar
  19. 19.
    Brabant G, Toogood AA, Shalet SM et al (2012) Hypothyroidism following childhood cancer therapy: an under-diagnosed complication. Int J Cancer 130:1145–1150PubMedCrossRefGoogle Scholar
  20. 20.
    Kokshoorn NE, Wassenaar MJ, Biermasz NR et al (2010) Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values. Eur J Endocrinol 162:11–18PubMedCrossRefGoogle Scholar
  21. 21.
    Tanriverdi F, De Bellis A, Battaglia M et al (2010) Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity? Eur J Endocrinol 162:861–867PubMedCrossRefGoogle Scholar
  22. 22.
    Daffara F, De Francia S, Reimondo G et al (2008) Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 15:1043–1053PubMedCrossRefGoogle Scholar
  23. 23.
    Zatelli MC, Gentilin E, Daffara F et al (2010) Therapeutic concentrations of mitotane (o, p′-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model. Endocrinology 151:2453–2461PubMedCrossRefGoogle Scholar
  24. 24.
    Sharma V, Hays WR, Wood WM et al (2006) Effects of rexinoids on thyrotrope function and the hypothalamic–pituitary–thyroid axis. Endocrinology 147:1438–1451PubMedCrossRefGoogle Scholar
  25. 25.
    Haugen BR (2009) Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab 23:793–800PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Jorgensen JO, Moller J, Laursen T, Orskov H, Christiansen JS, Weeke J (1994) Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults. Clin Endocrinol 41:609–614CrossRefGoogle Scholar
  27. 27.
    Agha A, Walker D, Perry L et al (2007) Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients. Clin Endocrinol 66:72–77Google Scholar
  28. 28.
    Vigersky RA, Filmore-Nassar A, Glass AR (2006) Thyrotropin suppression by metformin. J Clin Endocrinol Metab 91:225–227PubMedCrossRefGoogle Scholar
  29. 29.
    Cappelli C, Rotondi M, Pirola I et al (2009) TSH-lowering effect of metformin in type 2 diabetic patients: differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care 32:1589–1590PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Cappelli C, Rotondi M, Pirola I et al (2012) Thyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol 167:261–265PubMedGoogle Scholar
  31. 31.
    Lupoli R, Di Minno A, Tortora A, Ambrosino P, Arianna Lupoli G, Di Minno MN (2014) Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies. J Clin Endocrinol Metab 99:E143–E148PubMedCrossRefGoogle Scholar
  32. 32.
    Lopez M, Varela L, Vasquez MJ et al (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16:1001–1008PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Brenta G, Danzi S, Klein I (2007) Potential therapeutic applications of thyroid hormone analogs. Nat Clin Pract Endocrinol Metab 3:632–640PubMedCrossRefGoogle Scholar
  34. 34.
    Alkemade A, Unmehopa UA, Wiersinga WM et al (2005) Glucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus. J Clin Endocrinol Metab 90:323–327PubMedCrossRefGoogle Scholar
  35. 35.
    Collu R, Tang J, Castagné J et al (1997) A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 82:1561–1565PubMedGoogle Scholar
  36. 36.
    Bonomi M, Busnelli M, Beck-Peccoz P et al (2009) A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med 360:731–734PubMedCrossRefGoogle Scholar
  37. 37.
    Medeiros-Neto G, Herodotou DT, Rajan S et al (1996) A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest 97:1250–1256PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Brumm H, Pfeufer A, Biebermann H, Schnabel D, Deiss D, Grüters A (2002) Congenital central hypothyroidism due to homozygous thyrotropin beta 313 delta mutation is caused by a founder effect. J Clin Endocrinol Metab 87:4811–4816PubMedCrossRefGoogle Scholar
  39. 39.
    Alatzoglou KS, Dattani MT (2009) Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum Dev 85:705–712PubMedCrossRefGoogle Scholar
  40. 40.
    Sun Y, Bak B, Schoenmakers N et al (2012) Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet 44:1375–1381PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Joustra SD, Schoenmakers N, Persani L et al (2013) The IGSF1 deficiency syndrome: characteristics of male and female patients. J Clin Endocrinol Metab 98:4942–4952PubMedCrossRefGoogle Scholar
  42. 42.
    Alexopoulou O, Beguin C, De Nayer P et al (2004) Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients. Eur J Endocrinol 150:1–8PubMedCrossRefGoogle Scholar
  43. 43.
    Barbesino G, Sluss PM, Caturegli P (2012) Central hypothyroidism in a patient with pituitary autoimmunity: evidence for TSH-independent thyroid hormone synthesis. J Clin Endocrinol Metab 97:345–350PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Ferretti E, Persani L, Jaffrain-Rea ML et al (1999) Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 84:924–929PubMedGoogle Scholar
  45. 45.
    Faglia G, Beck-Peccoz P, Ferrari C, Ambrosi B, Spada A, Travaglini P, Paracchi S (1973) Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders. J Clin Endocrinol Metab 37:595–601PubMedCrossRefGoogle Scholar
  46. 46.
    Yamakita N, Komaki T, Takao T et al (2001) Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion. J Clin Endocrinol Metab 86:1054–1060PubMedCrossRefGoogle Scholar
  47. 47.
    Jostel A, Rydert WD, Shalet SM (2009) The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH index. Clin Endocrinol 71:529–534CrossRefGoogle Scholar
  48. 48.
    Filipsson H, Nystrom E, Johannsson G (2008) Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism. Eur J Endocrinol 159:153–160PubMedCrossRefGoogle Scholar
  49. 49.
    Doin FC, Rosa-Borges M, Martins MR et al (2012) Diagnosis of subclinical central hypothyroidism in patients with hypothalamic–pituitary disease by Doppler echocardiography. Eur J Endocrinol 166:631–640PubMedCrossRefGoogle Scholar
  50. 50.
    Klose M, Marina D, Hartoft-Nielsen ML et al (2013) Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients. J Clin Endocrinol Metab 98:3802–3810PubMedCrossRefGoogle Scholar
  51. 51.
    Slawik M, Klawitter B, Meiser E et al (2007) 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 92:4115–4122PubMedCrossRefGoogle Scholar
  52. 52.
    Koulouri O, Auldin MA, Agarwal R et al (2011) 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) 74:744–749CrossRefGoogle Scholar
  53. 53.
    Beck-Peccoz P (2011) Treatment of central hypothyroidism. Clin Endocrinol 74:671–672CrossRefGoogle Scholar
  54. 54.
    Shimon I, Cohen O, Lubetsky A et al (2002) Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism. Thyroid 12:823–827PubMedCrossRefGoogle Scholar
  55. 55.
    Carrozza V, Csako G, Yanovski JA et al (1999) Levothyroxine replacement therapy in central hypothyroidism: a practice report. Pharmacotherapy 19:349–355PubMedCrossRefGoogle Scholar
  56. 56.
    Porretti S, Giavoli C, Ronchi C et al (2002) Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T4 therapy become mandatory? J Clin Endocrinol Metab 87:2042–2045PubMedCrossRefGoogle Scholar
  57. 57.
    Arafah BM (2001) Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 344:1743–1749PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Cardiovascular and Metabolic Unit, Department of Endocrinology and Metabolic DiseasesCHU LarreyToulouse CedexFrance

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