Skip to main content
SpringerLink
Log in

The Hypothalamic-Pituitary-Thyroid Axis: Physiological Regulation and Clinical Implications

  • Chapter
  • First Online:
The Thyroid and Its Diseases

Abstract

Thyroid hormone (TH) is essential for normal growth and differentiation as well as control of energy homeostasis and metabolism during adult life. Tight regulation of the thyroid function can be achieved through the development of the hypothalamic-pituitary-thyroid (HPT) axis, a neuroendocrine loop consisting of a negative feedback mechanism between circulating TH levels and the hypothalamus and pituitary gland. When circulating TH levels are low, the HPT axis is activated simultaneously at multiple levels to increase both the TRH production in the hypothalamus and the TSH production in pituitary. The entire HPT axis is suppressed when circulating TH levels are high. The effects of TH in the hypothalamus and pituitary are primarily mediated by T3, the majority of T3 being produced locally in the presence of type 2 deiodinase (DIO2) from circulating T4. Each individual has a physiological HPT axis set point determined mainly by genetic factors where it functions optimally.

Since TSH is easily measurable in the peripheral circulation, it has become the main laboratory test used to interpret thyroid function and monitor patients with hypo- and hyperthyroidism. Several clinical states can affect the normal regulation of the HPT axis, such co-administered medications, illness, food deprivation, and cold. Further research will help us better understand how to interpret the function of the HPT axis in these conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Fekete C, Lechan RM. Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr Rev. 2014;35(2):159–94.

    Article  CAS  PubMed  Google Scholar 

  2. Fliers E, Boelen A, van Trotsenburg AS. Central regulation of the hypothalamo-pituitary-thyroid (HPT) axis: focus on clinical aspects. Handb Clin Neurol. 2014;124:127–38.

    Article  CAS  PubMed  Google Scholar 

  3. Nillni EA. Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. Front Neuroendocrinol. 2010;31(2):134–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Medici M, Visser WE, Visser TJ, Peeters RP. Genetic determination of the hypothalamic-pituitary-thyroid axis: where do we stand? Endocr Rev. 2015;36(2):214–44.

    Article  CAS  PubMed  Google Scholar 

  5. Nikrodhanond AA, Ortiga-Carvalho TM, Shibusawa N, Hashimoto K, Liao XH, Refetoff S, Yamada M, Mori M, Wondisford FE. Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis. J Biol Chem. 2006;281(8):5000–7.

    Article  CAS  PubMed  Google Scholar 

  6. Chiamolera MI, Wondisford FE. Minireview: thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology. 2009;150(3):1091–6.

    Article  CAS  PubMed  Google Scholar 

  7. Yamada M, Saga Y, Shibusawa N, Hirato J, Murakami M, Iwasaki T, Hashimoto K, Satoh T, Wakabayashi K, Taketo MM, Mori M. Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. Proc Natl Acad Sci U S A. 1997;94(20):10862–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Beck-Peccoz P, Persani L, Calebiro D, Bonomi M, Mannavola D, Campi I. Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. Best Pract Res Clin Endocrinol Metab. 2006;20(4):529–46.

    Article  CAS  PubMed  Google Scholar 

  9. Joseph-Bravo P, Jaimes-Hoy L, Uribe RM, Charli JL. 60 years of neuroendocrinology: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary-thyroid axis. J Endocrinol. 2015;227(3):X3.

    Article  CAS  PubMed  Google Scholar 

  10. Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med. 1985;312(17):1085–90.

    Article  CAS  PubMed  Google Scholar 

  11. Yamada M, Satoh T, Mori M. Mice lacking the thyrotropin-releasing hormone gene: what do they tell us? Thyroid. 2003;13(12):1111–21.

    Article  CAS  PubMed  Google Scholar 

  12. Roelfsema F, Veldhuis JD. Thyrotropin secretion patterns in health and disease. Endocr Rev. 2013;34(5):619–57.

    Article  CAS  PubMed  Google Scholar 

  13. Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab. 2009;23(6):793–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Costa-e-Sousa RH, Hollenberg AN. Minireview: the neural regulation of the hypothalamic-pituitary-thyroid axis. Endocrinology. 2012;153(9):4128–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hoermann R, Midgley JE, Larisch R, Dietrich JW. Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment. Front Endocrinol (Lausanne). 2015;6:177.

    Article  Google Scholar 

  16. Rothacker KM, Brown SJ, Hadlow NC, Wardrop R, Walsh JP. Reconciling the log-linear and non-log-linear nature of the TSH-free T4 relationship: intra-individual analysis of a large population. J Clin Endocrinol Metab. 2016;101(3):1151–8.

    Article  CAS  PubMed  Google Scholar 

  17. Abdalla SM, Bianco AC. Defending plasma T3 is a biological priority. Clin Endocrinol. 2014;81(5):633–41.

    Article  CAS  Google Scholar 

  18. Biondi B, Wartofsky L. Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? J Clin Endocrinol Metab. 2012;97(7):2256–71.

    Article  CAS  PubMed  Google Scholar 

  19. Fliers E, Kalsbeek A, Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis. Eur J Endocrinol. 2014;171(5):R197–208.

    Article  CAS  PubMed  Google Scholar 

  20. Roelfsema F, Pijl H, Kok P, Endert E, Fliers E, Biermasz NR, Pereira AM, Veldhuis JD. Thyrotropin secretion in healthy subjects is robust and independent of age and gender, and only weakly dependent on body mass index. J Clin Endocrinol Metab. 2014;99(2):570–8.

    Article  CAS  PubMed  Google Scholar 

  21. Russell W, Harrison RF, Smith N, Darzy K, Shalet S, Weetman AP, Ross RJ. Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels. J Clin Endocrinol Metab. 2008;93(6):2300–6.

    Article  CAS  PubMed  Google Scholar 

  22. Boelen A, Wiersinga WM, Fliers E. Fasting-induced changes in the hypothalamus-pituitary-thyroid axis. Thyroid. 2008;18(2):123–9.

    Article  CAS  PubMed  Google Scholar 

  23. Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. 2014;24(10):1456–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Vella KR, Ramadoss P, Lam FS, Harris JC, Ye FD, Same PD, O’Neill NF, Maratos-Flier E, Hollenberg AN. NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. Cell Metab. 2011;14(6):780–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol. 2010;316(2):165–71.

    Article  CAS  PubMed  Google Scholar 

  26. Reinehr T, Isa A, de Sousa G, Dieffenbach R, Andler W. Thyroid hormones and their relation to weight status. Horm Res. 2008;70(1):51–7.

    Article  CAS  PubMed  Google Scholar 

  27. Svare A, Nilsen TI, Bjøro T, Asvold BO, Langhammer A. Serum TSH related to measures of body mass: longitudinal data from the HUNT study, Norway. Clin Endocrinol. 2011;74(6):769–75.

    Article  CAS  Google Scholar 

  28. Fliers E, Guldenaar SE, Wiersinga WM, Swaab DF. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab. 1997;82(12):4032–6.

    CAS  PubMed  Google Scholar 

  29. Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev. 2011;32(5):670–93.

    Article  CAS  PubMed  Google Scholar 

  30. de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015;225(3):R67–81.

    Article  PubMed  CAS  Google Scholar 

  31. Kaptein EM, Sanchez A, Beale E, Chan LS. Clinical review: thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J Clin Endocrinol Metab. 2010;95(10):4526–34.

    Article  CAS  PubMed  Google Scholar 

  32. Galli E, Pingitore A, Iervasi G. The role of thyroid hormone in the pathophysiology of heart failure: clinical evidence. Heart Fail Rev. 2010;15(2):155–69.

    Article  CAS  PubMed  Google Scholar 

  33. Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, L’abbate A, Mariotti R, Iervasi G. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2008;93(4):1351–8.

    Article  CAS  PubMed  Google Scholar 

  34. Klemperer JD. Thyroid hormone and cardiac surgery. Thyroid. 2002;12(6):517–21.

    Article  CAS  PubMed  Google Scholar 

  35. Van den Berghe G, Wouters P, Weekers F, Mohan S, Baxter RC, Veldhuis JD, Bowers CY, Bouillon R. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab. 1999;84(4):1311–23.

    PubMed  Google Scholar 

  36. Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011;21(1):5–11.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92(12):4575–82.

    Article  CAS  PubMed  Google Scholar 

  38. Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, Audit, and Research Study (TEARS). J Clin Endocrinol Metab. 2013;98(3):1147–53.

    Article  CAS  PubMed  Google Scholar 

  39. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292(21):2591–9.

    Article  CAS  PubMed  Google Scholar 

  40. Bowers J, Terrien J, Clerget-Froidevaux MS, Gothié JD, Rozing MP, Westendorp RG, van Heemst D, Demeneix BA. Thyroid hormone signaling and homeostasis during aging. Endocr Rev. 2013;34(4):556–89.

    Article  CAS  PubMed  Google Scholar 

  41. Veldhuis JD. Changes in pituitary function with ageing and implications for patient care. Nat Rev Endocrinol. 2013;9(4):205–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Over R, Mannan S, Nsouli-Maktabi H, Burman KD, Jonklaas J. Age and the thyrotropin response to hypothyroxinemia. J Clin Endocrinol Metab. 2010;95(8):3675–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Alkemade A, Unmehopa UA, Wiersinga WM, Swaab DF, Fliers E. Glucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus. J Clin Endocrinol Metab. 2005;90(1):323–7.

    Article  CAS  PubMed  Google Scholar 

  44. Samuels MH, Luther M, Henry P, Ridgway EC. Effects of hydrocortisone on pulsatile pituitary glycoprotein secretion. J Clin Endocrinol Metab. 1994;78(1):211–5.

    CAS  PubMed  Google Scholar 

  45. Brabant A, Brabant G, Schuermeyer T, Ranft U, Schmidt FW, Hesch RD, von zur Mühlen A. The role of glucocorticoids in the regulation of thyrotropin. Acta Endocrinol. 1989;121(1):95–100.

    Article  CAS  Google Scholar 

  46. Samuels MH. Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study. J Clin Endocrinol Metab. 2000;85(4):1388–93.

    CAS  PubMed  Google Scholar 

  47. Samuels MH, Henry P, Ridgway EC. Effects of dopamine and somatostatin on pulsatile pituitary glycoprotein secretion. J Clin Endocrinol Metab. 1992;74(1):217–22.

    CAS  PubMed  Google Scholar 

  48. Agner T, Hagen C, Andersen AN, Djursing H. Increased dopaminergic activity inhibits basal and metoclopramide-stimulated prolactin and thyrotropin secretion. J Clin Endocrinol Metab. 1986;62(4):778–82.

    Article  CAS  PubMed  Google Scholar 

  49. Pinto LP, Hanna FW, Evans LM, Davies JS, John R, Scanlon MF. The TSH response to domperidone reflects the biological activity of prolactin in macroprolactinaemia and hyperprolactinaemia. Clin Endocrinol. 2003;59(5):580–4.

    Article  CAS  Google Scholar 

  50. Beck-Peccoz P, Persani L, Mannavola D, Campi I. Pituitary tumours: TSH-secreting adenomas. Best Pract Res Clin Endocrinol Metab. 2009;23(5):597–606.

    Article  CAS  PubMed  Google Scholar 

  51. Mannavola D, Persani L, Vannucchi G, Zanardelli M, Fugazzola L, Verga U, Facchetti M, Beck-Peccoz P. Different responses to chronic somatostatin analogues in patients with central hyperthyroidism. Clin Endocrinol. 2005;62(2):176–81.

    Article  CAS  Google Scholar 

  52. Graeppi-Dulac J, Vlaeminck-Guillem V, Perier-Muzet M, Dalle S, Orgiazzi J. Endocrine side-effects of anti-cancer drugs: the impact of retinoids on the thyroid axis. Eur J Endocrinol. 2014;170(6):R253–62.

    Article  CAS  PubMed  Google Scholar 

  53. Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med. 1999;340(14):1075–9.

    Article  CAS  PubMed  Google Scholar 

  54. Miller J, Carney P. Central hypothyroidism with oxcarbazepine therapy. Pediatr Neurol. 2006;34(3):242–4.

    Article  PubMed  Google Scholar 

  55. Zatelli MC, Ambrosio MR, Bondanelli M, Degli Uberti E. Pituitary side effects of old and new drugs. J Endocrinol Investig. 2014;37(10):917–23.

    Article  CAS  Google Scholar 

  56. Lupoli R, Di Minno A, Tortora A, Ambrosino P, Lupoli GA, Di Minno MN. Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies. J Clin Endocrinol Metab. 2014;99(1):E143–8.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Alina Gavrila & Anthony N. Hollenberg

Authors
  1. Alina Gavrila
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony N. Hollenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony N. Hollenberg .

Editor information

Editors and Affiliations

  1. Department of Nuclear Medicine, Philipps University Marburg, Marburg, Germany

    Markus Luster

  2. Unit of Endocrinology Diabetes and Metabolism, Evgenidion Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Leonidas H. Duntas

  3. Georgetown University School of Medicine, Washington, DC, USA

    Leonard Wartofsky

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gavrila, A., Hollenberg, A.N. (2019). The Hypothalamic-Pituitary-Thyroid Axis: Physiological Regulation and Clinical Implications. In: Luster, M., Duntas, L., Wartofsky, L. (eds) The Thyroid and Its Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-72102-6_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-72102-6_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-72100-2

  • Online ISBN: 978-3-319-72102-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation