Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Interconnection between circadian clocks and thyroid function


Circadian rhythmicity is an approximately 24-h cell-autonomous period driven by transcription–translation feedback loops of specific genes, which are referred to as ‘circadian clock genes’. In mammals, the central circadian pacemaker, which is located in the hypothalamic suprachiasmatic nucleus, controls peripheral circadian clocks. The circadian system regulates virtually all physiological processes, which are further modulated by changes in the external environment, such as light exposure and the timing of food intake. Chronic circadian disruption caused by shift work, travel across time zones or irregular sleep–wake cycles has long-term consequences for our health and is an important lifestyle factor that contributes to the risk of obesity, type 2 diabetes mellitus and cancer. Although the hypothalamic–pituitary–thyroid axis is under the control of the circadian clock via the suprachiasmatic nucleus pacemaker, daily TSH secretion profiles are disrupted in some patients with hypothyroidism and hyperthyroidism. Disruption of circadian rhythms has been recognized as a perturbation of the endocrine system and of cell cycle progression. Expression profiles of circadian clock genes are abnormal in well-differentiated thyroid cancer but not in the benign nodules or a healthy thyroid. Therefore, the characterization of the thyroid clock machinery might improve the preoperative diagnosis of thyroid cancer.

Key points

  • The hypothalamic–pituitary–thyroid axis is controlled by the central circadian pacemaker located in the suprachiasmatic nucleus.

  • Daily TSH secretion profiles are often disrupted in patients with hypothyroidism or hyperthyroidism.

  • Circadian dysfunction caused by shift work, travel across time zones or irregular sleep–wake cycles might be a novel lifestyle risk factor for disturbances in thyroid homeostasis in modern societies.

  • Disruption of circadian clock genes in vivo and in vitro disturbs cell cycle progression.

  • The circadian clock is thought to be disrupted in well-differentiated thyroid cancer.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Hypothalamic–pituitary–thyroid axis.
Fig. 2: The hypothalamic–pituitary–thyroid axis is under circadian regulation.
Fig. 3: The circadian transcriptional and translational feedback loop machinery in mammals.
Fig. 4: Temporal changes of plasma TSH level in human.
Fig. 5: Circadian disruption can drive thyroid diseases.
Fig. 6: Pars tuberalis-derived TSH regulates seasonal thyroid hormone function.


  1. 1.

    Fekete, C. & Lechan, R. M. Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr. Rev. 35, 159–194 (2014).

    CAS  PubMed  Google Scholar 

  2. 2.

    Ortiga-Carvalho, T. M., Chiamolera, M. I., Pazos-Moura, C. C. & Wondisford, F. E. Hypothalamus-pituitary-thyroid axis. Compr. Physiol. 6, 1387–1428 (2016).

    PubMed  Google Scholar 

  3. 3.

    Mohawk, J. A., Green, C. B. & Takahashi, J. S. Central and peripheral circadian clocks in mammals. Annu. Rev. Neurosci. 35, 445–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Scheer, F. A. J. L., Hilton, M. F., Mantzoros, C. S. & Shea, S. A. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl Acad. Sci. USA 106, 4453–4458 (2009).

    CAS  PubMed  Google Scholar 

  5. 5.

    Davidson, A. J. et al. Chronic jet- lag increases mortality in aged mice. Curr. Biol. 16, 914–916 (2006).

    Google Scholar 

  6. 6.

    Buxton, O. M. et al. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci. Transl Med. 4, 129ra43 (2012).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kettner, N. M., Katchy, C. A. & Fu, L. Circadian gene variants in cancer. Ann. Med. 46, 208–220 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bellastella, A. et al. Endocrine secretions under abnormal light-dark cycles and in the blind. Horm. Res. 49, 153–157 (1998).

    CAS  PubMed  Google Scholar 

  9. 9.

    Kalsbeek, A. & Fliers, E. Daily regulation of hormone profile. Handb. Exp. Pharmacol. 217, 185–226 (2013).

  10. 10.

    Pierce, J. G. Eli lilly lecture: The subunits of pituitary thyrotropin—their relationship to other glycoprotein hormones. Endocrinology 89, 1331–1344 (1971).

    CAS  PubMed  Google Scholar 

  11. 11.

    Shupnik, M. A., Greenspan, S. L. & Ridgway, E. C. Transcriptional regulation of thyrotropin subunit genes by thyrotropin-releasing hormone and dopamine in pituitary cell culture. J. Biol. Chem. 261, 12675–12679 (1986).

    CAS  PubMed  Google Scholar 

  12. 12.

    Vassart, G. & Dumont, J. E. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr. Rev. 13, 596–611 (1992).

    CAS  PubMed  Google Scholar 

  13. 13.

    Friesema, E. C. H. et al. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J. Biol. Chem. 278, 40128–40135 (2003).

    CAS  PubMed  Google Scholar 

  14. 14.

    Pizzagalli, F. et al. Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol. Endocrinol. 16, 2283–2296 (2002).

    CAS  PubMed  Google Scholar 

  15. 15.

    Schweizer, U., Weitzel, J. M. & Schomburg, L. Think globally: act locally. New insights into the local regulation of thyroid hormone availability challenge long accepted dogmas. Mol. Cell. Endocrinol. 289, 1–9 (2008).

    CAS  PubMed  Google Scholar 

  16. 16.

    Gereben, B. et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr. Rev. 29, 898–938 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Hollenberg, A. N. et al. The human thyrotropin-releasing hormone gene is regulated by thyroid hormone through two distinct classes of negative thyroid hormone response elements. Mol. Endocrinol. 9, 540–550 (1995).

    CAS  PubMed  Google Scholar 

  18. 18.

    Franklyn, J. A., Wood, D. F., Balfour, N. J. & Sheppard, M. C. Effect of triiodothyronine treatment on thyrotrophin β- and α-messenger RNAs in the pituitary of the euthyroid rat. Mol. Cell. Endocrinol. 60, 1–5 (1988).

    CAS  PubMed  Google Scholar 

  19. 19.

    Cohen, O., Flynn, T. R. & Wondisford, F. E. Ligand-dependent antagonism by retinoid X receptors of inhibitory thyroid hormone response elements. J. Biol. Chem. 270, 13899–13905 (1995).

    CAS  PubMed  Google Scholar 

  20. 20.

    Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).

    CAS  PubMed  Google Scholar 

  21. 21.

    Brancaccio, M. et al. Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science 192, 187–192 (2019).

    Google Scholar 

  22. 22.

    Panda, S. et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525–527 (2003).

    CAS  PubMed  Google Scholar 

  23. 23.

    Hattar, S. et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 76–81 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    CAS  PubMed  Google Scholar 

  25. 25.

    Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000).

    CAS  PubMed  Google Scholar 

  26. 26.

    Sehgal, A. Physiology flies with time. Cell 171, 1232–1235 (2017).

    CAS  PubMed  Google Scholar 

  27. 27.

    Takahashi, J. S. Molecular components of the circadian clock in mammals. Diabetes Obes. Metab. 17, 6–11 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    CAS  PubMed  Google Scholar 

  29. 29.

    Hogenesch, J. B., Gu, Y.-Z., Jain, S. & Bradfield, C. A. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    CAS  PubMed  Google Scholar 

  30. 30.

    Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ueda, H. R. et al. A transcription factor response element for gene expression during circadian night. Nature 418, 534–539 (2002).

    CAS  PubMed  Google Scholar 

  32. 32.

    Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    CAS  PubMed  Google Scholar 

  33. 33.

    Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).

    CAS  PubMed  Google Scholar 

  34. 34.

    Weeke, J. & Gundersen, H. J. Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta. Endocrinol. (Copenh) 89, 659–672 (1978).

    CAS  Google Scholar 

  35. 35.

    Copinschi, G. & Challet, E. Endocrine rhythms, the sleep-wake cycle, and biological clocks, in Endocrinology: Adult and Pediatric (Jameson, J. L. & Groot, L. De (eds)) 147-173.e9 (Elsevier, 2016).

  36. 36.

    Van Cauter, E. & Spiegel, K. Circadian and sleep control of hormonal secretions, in Regulation of sleep and circadian rhythms (Turek, F. W. & Zee, P. C. (eds)) 397–426 (Marcel Dekker, Inc., 1999).

  37. 37.

    Spiegel, K., Leproult, R. & Van Cauter, E. Impact of sleep debt on metabolic and endocrine function. Lancet 354, 1435–1439 (1999).

    CAS  PubMed  Google Scholar 

  38. 38.

    Gronfier, C. & Brandenberger, G. Ultradian rhythms in pituitary and adrenal hormones: their relations to sleep. Sleep Med. Rev. 2, 17–29 (1998).

    CAS  PubMed  Google Scholar 

  39. 39.

    Romijn, J. A. et al. Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude. J. Clin. Endocrinol. Metab. 70, 1631–1636 (1990).

    CAS  PubMed  Google Scholar 

  40. 40.

    Brabant, G. et al. Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration. J. Clin. Endocrinol. Metab. 65, 83–88 (1987).

    CAS  PubMed  Google Scholar 

  41. 41.

    Samuels, M. H., Veldhuis, J. D., Henry, P. & Ridgway, E. C. Pathophysiology of pulsatile and copulsatile release of thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and α-subunit. J. Clin. Endocrinol. Metab. 71, 425–432 (1990).

    CAS  PubMed  Google Scholar 

  42. 42.

    Samuels, M. H., Henry, P., Luther, M. & Ridgway, E. C. Pulsatile TSH secretion during 48-hour continuous TRH infusions. Thyroid 3, 201–206 (1993).

    CAS  PubMed  Google Scholar 

  43. 43.

    Brabant, G. et al. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J. Clin. Endocrinol. Metab. 70, 403–409 (1990).

    CAS  PubMed  Google Scholar 

  44. 44.

    Roelfsema, F. et al. Thyrotropin secretion profiles are not different in men and women. J. Clin. Endocrinol. Metab. 94, 3964–3967 (2009).

    CAS  PubMed  Google Scholar 

  45. 45.

    Ehrenkranz, J. et al. Circadian and circannual rhythms in thyroid hormones: determining the TSH and free T4 reference intervals based upon time of day, age, and sex. Thyroid 25, 954–961 (2015).

    CAS  PubMed  Google Scholar 

  46. 46.

    Lucke, C., Hehrmann, R., von Mayersbach, K. & von zur Muhlen, A. Studies on circadian variations of plasma TSH, thyroxine and triiodothyronine in man. Acta Endocrinol. 86, 81–88 (1977).

    CAS  PubMed  Google Scholar 

  47. 47.

    Jordan, D., Rousset, B., Perrin, F., Fournier, M. & Orgiazzi, J. Evidence for circadian variations in serum thyrotropin, 3,5,3′-triiodothyronine, and thyroxine in the rat. Endocrinology 107, 1245–1248 (1980).

    CAS  PubMed  Google Scholar 

  48. 48.

    Fukuda, H. et al. Nyctohemeral and sex-related variations in plasma thyrotropin, thyroxine, and triiodothyronine. Endocrinology 97, 1424–1431 (1975).

    CAS  PubMed  Google Scholar 

  49. 49.

    Azukizawa, M., Eugene Pekary, A., Hershman, J. M. & Parker, D. C. Plasma thyrotropin, thyroxine, and triiodothyronine relationships in man. J. Clin. Endocrinol. Metab. 43, 533–542 (1976).

    CAS  PubMed  Google Scholar 

  50. 50.

    Roelfsema, F. & Veldhuis, J. D. Thyrotropin secretion patterns in health and disease. Endocr. Rev. 34, 619–657 (2013).

    CAS  PubMed  Google Scholar 

  51. 51.

    Mazzoccoli, G. et al. The hypothalamic-pituitary-thyroid axis and melatonin: possible interactions in the control of body temperature. Neuroendocrinol. Lett. 25, 368–372 (2004).

    CAS  PubMed  Google Scholar 

  52. 52.

    Covarrubias, L. et al. In vitro TRH release from hypothalamus slices varies during the diurnal cycle. Neurochem. Res. 19, 845–850 (1994).

    CAS  PubMed  Google Scholar 

  53. 53.

    Kalsbeek, A., Fliers, E., Franke, A. N., Wortel, J. & Buijs, R. M. Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology 141, 3832–3841 (2000).

    CAS  PubMed  Google Scholar 

  54. 54.

    Zandieh Doulabi, B. et al. Diurnal variation in rat liver thyroid hormone receptor (TR)-α messenger ribonucleic acid (mRNA) is dependent on the biological clock in the suprachiasmatic nucleus, whereas diurnal variation of TRβ1 mRNA is modified by food intake. Endocrinology 145, 1284–1289 (2004).

    CAS  PubMed  Google Scholar 

  55. 55.

    Vakili, H., Jin, Y. & Cattini, P. A. Evidence for a circadian effect on the reduction of human growth hormone gene expression in response to excess caloric intake. J. Biol. Chem. 291, 13823–13833 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Aninye, I. O., Matsumoto, S., Sidhaye, A. R. & Wondisford, F. E. Circadian regulation of Tshb gene expression by Rev-Erbα (NR1D1) and nuclear corepressor 1 (NCOR1). J. Biol. Chem. 289, 17070–17077 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Fahrenkrug, J., Georg, B., Hannibal, J. & Jørgensen, H. L. Hypophysectomy abolishes rhythms in rat thyroid hormones but not in the thyroid clock. J. Endocrinol. 233, 209–216 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006).

    CAS  PubMed  Google Scholar 

  59. 59.

    Hatanaka, F. et al. Genome-wide profiling of the core clock protein BMAL1 targets reveals a strict relationship with metabolism. Mol. Cell. Biol. 30, 5636–5648 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Nikolaeva, S. et al. The circadian clock modulates renal sodium handling. J. Am. Soc. Nephrol. 23, 1019–1026 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Munroe, S. H. & Lazar, M. A. Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA. J. Biol. Chem. 266, 22083–22086 (1991).

    CAS  PubMed  Google Scholar 

  62. 62.

    Vollmers, C. et al. Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab. 16, 833–845 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Benvenga, S., Klose, M., Vita, R. & Feldt-Rasmussen, U. Less known aspects of central hypothyroidism: part 2 – congenital etiologies. J. Clin. Transl Endocrinol. 14, 5–11 (2018).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Benvenga, S., Klose, M., Vita, R. & Feldt-Rasmussen, U. Less known aspects of central hypothyroidism: part 1 – acquired etiologies. J. Clin. Transl. Endocrinol. 14, 25–33 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Biondi, B. & Cooper, D. S. The clinical significance of subclinical thyroid dysfunction. Endocr. Rev. 29, 76–131 (2008).

    CAS  PubMed  Google Scholar 

  66. 66.

    Adriaanse, R., Brabant, G., Prank, K., Endert, E. & Wiersinga, W. M. Circadian changes in pulsatile TSH release in primary hypothyroidism. Clin. Endocrinol. (Oxf). 37, 504–510 (1992).

    CAS  PubMed  Google Scholar 

  67. 67.

    Roelfsema, F. et al. Thyrotropin secretion in mild and severe primary hypothyroidism is distinguished by amplified burst mass and basal secretion with increased spikiness and approximate entropy. J. Clin. Endocrinol. Metab. 95, 928–934 (2010).

    CAS  PubMed  Google Scholar 

  68. 68.

    Moon, S. H., Lee, B. J., Kim, S. J. & Kim, H. C. Relationship between thyroid stimulating hormone and night shift work. Ann. Occup. Environ. Med. 28, 53 (2016).

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Magrini, A. et al. Shift work and autoimmune thyroid disorders. Int. J. Immunopathol. Pharmacol. 19, 31–36 (2006).

    CAS  PubMed  Google Scholar 

  70. 70.

    Adriaanse, R., Brabant, G., Endert, E. & Wiersinga, M. M. Pulsatile untreated thyrotropin pituitary release in patients disease. J. Clin. Endocrinol. Metab. 77, 205–209 (1993).

    CAS  PubMed  Google Scholar 

  71. 71.

    Rose, S. R. Cranial irradiation and central hypothyroidism. Trends Endocrinol. Metab. 12, 97–104 (2001).

    CAS  PubMed  Google Scholar 

  72. 72.

    Baenziger, J. U. & Green, E. D. Pituitary glycoprotein hormone oligosaccharides: Structure, synthesis and function of the asparagine-linked oligosaccharides on lutropin, follitropin and thyrotropin. Biochim. Biophys. Acta 947, 287–306 (1988).

    CAS  PubMed  Google Scholar 

  73. 73.

    Ikegami, K. et al. Tissue-specific posttranslational modification allows functional targeting of thyrotropin. Cell Rep. 9, 801–809 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Persani, L., Ferretti, E., Borgato, S., Faglia, G. & Beck-Peccoz, P. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J. Clin. Endocrinol. Metab. 85, 3631–3635 (2000).

    CAS  PubMed  Google Scholar 

  75. 75.

    Gesundheit, N., Magner, J. A., Chen, T. & Weintraub, B. D. Differential sulfation and sialylation of secreted mouse thyrotropin (TSH) subunits: Regulation by TSH releasing hormone. Endocrinology 119, 455–463 (1986).

    CAS  PubMed  Google Scholar 

  76. 76.

    Darzy, K. H. & Shalet, S. M. Circadian and stimulated thyrotropin secretion in cranially irradiated adult cancer survivors. J. Clin. Endocrinol. Metab. 90, 6490–6497 (2005).

    CAS  PubMed  Google Scholar 

  77. 77.

    Refetoff, S., Weiss, R. E. & Usala, S. J. The syndromes of resistance to thyroid hormone. Endocr. Rev. 14, 348–399 (1993).

    CAS  PubMed  Google Scholar 

  78. 78.

    Persani, L. et al. Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance. J. Clin. Endocrinol. Metab. 78, 1034–1039 (1994).

    CAS  PubMed  Google Scholar 

  79. 79.

    Custro, N., Scafidi, V. & Notarbartolo, A. Pituitary resistance to thyroid hormone action with preserved circadian rhythm of thyrotropin in a postmenopausal woman. J. Endocrinol. Invest. 15, 121–126 (1992).

    CAS  PubMed  Google Scholar 

  80. 80.

    Moran, C. & Chatterjee, K. Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract. Res. Clin. Endocrinol. Metab. 29, 647–657 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    DeGroot, L. J. Graves’ disease and the manifestations of thyrotoxicosis, in Endotext (Feingold, K. R. et al. (eds)) 1–77 (, Inc., 2000).

  82. 82.

    Roelfsema, F., Pereira, A. M., Keenan, D. M., Veldhuis, J. D. & Romijn, J. A. Thyrotropin secretion by thyrotropinomas is characterized by increased pulse frequency, delayed and disorderliness. J. Clin. Endocrinol. Metab. 93, 4052–4057 (2008).

    CAS  PubMed  Google Scholar 

  83. 83.

    Schull, J. et al. Effects of thyroidectomy, parathyroidectomy and lithium on circadian wheelrunning in rats. Physiol. Behav. 42, 33–39 (1988).

    CAS  PubMed  Google Scholar 

  84. 84.

    McEachron, D. L., Lauchlan, C. L. & Midgley, D. E. Effects of thyroxine and thyroparathyroidectomy on circadian wheel running in rats. Pharmacol. Biochem. Behav. 46, 243–249 (1993).

    CAS  PubMed  Google Scholar 

  85. 85.

    Beasley, L. J. & Nelson, R. J. Thyroid gland influences the period of hamster circadian oscillations. Experientia 38, 870–871 (1982).

    CAS  PubMed  Google Scholar 

  86. 86.

    Dkhissi-Benyahya, O., Gronfier, C., De Vanssay, W., Flamant, F. & Cooper, H. M. Modeling the role of mid-wavelength cones in circadian responses to light. Neuron 53, 677–687 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Gloss, B. et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β. Endocrinology 142, 544–550 (2001).

    CAS  PubMed  Google Scholar 

  88. 88.

    Peliciari-Garcia, R. A., Bargi-Souza, P., Young, M. E. & Nunes, M. T. Repercussions of hypo and hyperthyroidism on the heart circadian clock. Chronobiol. Int. 35, 147–159 (2018).

    PubMed  Google Scholar 

  89. 89.

    Amir, S. & Robinson, B. Thyroidectomy alters the daily pattern of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats. Neurosci. Lett. 407, 254–257 (2006).

    CAS  PubMed  Google Scholar 

  90. 90.

    Noguchi, T., Ikeda, M., Ohmiya, Y. & Nakajima, Y. A dual-color luciferase assay system reveals circadian resetting of cultured fibroblasts by co-cultured adrenal glands. PLOS ONE 7, e37093 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Arendt, J. Managing jet lag: Some of the problems and possible new solutions. Sleep Med. Rev. 13, 249–256 (2009).

    PubMed  Google Scholar 

  92. 92.

    Gary, K. A. et al. Total sleep deprivation and the thyroid axis: Effects of sleep and walking activity. Aviat. Space Environ. Med. 67, 513–519 (1996).

    CAS  PubMed  Google Scholar 

  93. 93.

    Hirschfeld, U. et al. Progressive elevation of plasma thyrotropin during adaptation to simulated jet lag: effects of treatment with bright light or zolpidem. J. Clin. Endocrinol. Metab. 81, 3270–3276 (1996).

    CAS  PubMed  Google Scholar 

  94. 94.

    Polyzos, S. A. et al. Serum thyrotropin concentration as a biochemical predictor of thyroid malignancy in patients presenting with thyroid nodules. J. Cancer Res. Clin. Oncol. 134, 953–960 (2008).

    CAS  PubMed  Google Scholar 

  95. 95.

    Haymart, M. R. et al. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J. Clin. Endocrinol. Metab. 93, 809–814 (2008).

    CAS  PubMed  Google Scholar 

  96. 96.

    Boelaert, K. et al. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J. Clin. Endocrinol. Metab. 91, 4295–4301 (2006).

    CAS  PubMed  Google Scholar 

  97. 97.

    Pinkerton, L. E. et al. Melanoma, thyroid cancer, and gynecologic cancers in a cohort of female flight attendants. Am. J. Ind. Med. 61, 572–581 (2018).

    PubMed  Google Scholar 

  98. 98.

    Liu, G. S. et al. Thyroid cancer risk in airline cockpit and cabin crew: a meta-analysis. Cancers Head Neck 3, 7 (2018).

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Kiessling, S. et al. Enhancing circadian clock function in cancer cells inhibits tumor growth. BMC Biol. 15, 1–18 (2017).

    Google Scholar 

  100. 100.

    Matsuo, T. et al. Control mechanism of the circadian clock for timing of cell division in vivo. Science 302, 255–260 (2003).

    CAS  PubMed  Google Scholar 

  101. 101.

    Gery, S. et al. The circadian gene Per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol. Cell 22, 375–382 (2006).

    CAS  PubMed  Google Scholar 

  102. 102.

    Kowalska, E. et al. NONO couples the circadian clock to the cell cycle. Proc. Natl Acad. Sci. USA 110, 1592–1599 (2013).

    CAS  PubMed  Google Scholar 

  103. 103.

    Jiang, W. et al. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett. 371, 314–325 (2016).

    CAS  PubMed  Google Scholar 

  104. 104.

    Lee, S., Donehower, L. A., Herron, A. J., Moore, D. D. & Fu, L. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLOS ONE 5, e10995 (2010).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Fu, L., Pelicano, H., Liu, J., Huang, P. & Lee, C. C. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111, 41–50 (2002).

    CAS  PubMed  Google Scholar 

  106. 106.

    Papagiannakopoulos, T. et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 24, 324–331 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Gallo, C. et al. The bHLH transcription factor DEC1 promotes thyroid cancer aggressiveness by the interplay with NOTCH1. Cell Death Dis. 9, 871 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Relógio, A. et al. Ras-mediated deregulation of the circadian clock in cancer. PLoS Genet. 10, e1004338 (2014).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Altman, B. J. et al. MYC disrupts the circadian clock and metabolism in cancer cells. Cell Metab. 22, 1009–1019 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Durante, C. et al. The diagnosis and management of thyroid nodules. JAMA 319, 914–924 (2018).

    PubMed  Google Scholar 

  111. 111.

    Sherman, S. I. Thyroid carcinoma. Lancet 361, 501–511 (2003).

    PubMed  Google Scholar 

  112. 112.

    Kitahara, C. M. & Sosa, J. A. The changing incidence of thyroid cancer. Nat. Rev. Endocrinol. 12, 646–653 (2016).

    PubMed  Google Scholar 

  113. 113.

    Mannic, T. et al. Circadian clock characteristics are altered in human thyroid malignant nodules. J. Clin. Endocrinol. Metab. 98, 4446–4456 (2013).

    CAS  PubMed  Google Scholar 

  114. 114.

    Nakane, Y. & Yoshimura, T. Photoperiodic regulation of reproduction in vertebrates. Annu. Rev. Anim. Biosci. 7, 173–194 (2018).

    PubMed  Google Scholar 

  115. 115.

    Ottenweller, J. E., Tapp, W. N., Pitman, D. L. & Natelson, B. H. Adrenal, thyroid, and testicular hormone rhythms in male golden hamsters on long and short days. Am. J. Physiol. Regul. Integr. Comp. Physiol. 253, R321–R328 (1987).

    CAS  Google Scholar 

  116. 116.

    Wong, C. C. et al. Influence of age, strain and season on diurnal periodicity of thyroid stimulating hormone, thyroxine, triiodothyronine and parathyroid hormone in the serum of male laboratory rats. Eur. J. Endocrinol. 102, 377–385 (1983).

    CAS  Google Scholar 

  117. 117.

    Wirz-Justice, A. Seasonality in affective disorders. Gen. Comp. Endocrinol. 258, 244–249 (2018).

    CAS  PubMed  Google Scholar 

  118. 118.

    Dopico, X. C. et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat. Commun. 6, 1–13 (2015).

    Google Scholar 

  119. 119.

    Maes, M. et al. Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers. Clin. Endocrinol. 46, 587–598 (1997).

    CAS  Google Scholar 

  120. 120.

    Smals, A. G. H., Ross, H. A. & Kloppenborg, P. W. C. Seasonal variation in serum T3 and T4 levels in man. J. Clin. Endocrinol. Metab. 44, 998–1001 (1977).

    CAS  PubMed  Google Scholar 

  121. 121.

    Bellastella, A. et al. Circannual rhythms of plasma growth hormone, thyrotropin and thyroid hormones in prepuberty. Clin. Endocrinol. 20, 531–537 (1984).

    CAS  Google Scholar 

  122. 122.

    Gullo, D. et al. Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy. Clin. Endocrinol. 87, 207–215 (2017).

    CAS  Google Scholar 

  123. 123.

    Buchinger, W., Semlitsch, G., Pongratz, R. & Rainer, B. H. F. Jahreszeitliche variationen im auftreten der hyperthyreose. Acta Med. Austriaca 27, 51–53 (2000).

    CAS  PubMed  Google Scholar 

  124. 124.

    Akslen, L. A. & Sothern, R. B. Seasonal variations in the presentation and growth of thyroid cancer. Br. J. Cancer 77, 1174–1179 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Nakao, N. et al. Thyrotrophin in the pars tuberalis triggers photoperiodic response. Nature 452, 317–322 (2008).

    CAS  PubMed  Google Scholar 

  126. 126.

    Yoshimura, T. et al. Light-induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds. Nature 426, 178–181 (2003).

    CAS  PubMed  Google Scholar 

  127. 127.

    Yamamura, T., Hirunagi, K., Ebihara, S. & Yoshimura, T. Seasonal morphological changes in the neuro-glial interaction between gonadotropin-releasing hormone nerve terminals and glial endfeet in Japanese quail. Endocrinology 145, 4264–4267 (2004).

    CAS  PubMed  Google Scholar 

  128. 128.

    Ono, H. et al. Involvement of thyrotropin in photoperiodic signal transduction in mice. Proc. Natl Acad. Sci. USA 105, 18238–18242 (2008).

    CAS  PubMed  Google Scholar 

  129. 129.

    Hanon, E. A. et al. Ancestral TSH mechanism signals summer in a photoperiodic mammal. Curr. Biol. 18, 1147–1152 (2008).

    CAS  PubMed  Google Scholar 

  130. 130.

    Bockmann, J. et al. Thyrotropin expression in hypophyseal pars tuberalis-specific cells is 3,5,3′-triiodothyronine, thyrotropin-releasing hormone, and Pit-1 independent. Endocrinology 138, 1019–1028 (1997).

    CAS  PubMed  Google Scholar 

  131. 131.

    Arendt, J. Melatonin and the Mammalian Pineal Gland. (Chapman & Hall, 1995).

  132. 132.

    Yasuo, S., Yoshimura, T., Ebihara, S. & Korf, H. W. Melatonin transmits photoperiodic signals through the MT1 melatonin receptor. J. Neurosci. 29, 2885–2889 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Heldmaier, G., Ortmann, S. & Elvert, R. Natural hypometabolism during hibernation and daily torpor in mammals. Respir. Physiol. Neurobiol. 141, 317–329 (2004).

    PubMed  Google Scholar 

  134. 134.

    Geiser, F. & Turbill, C. Hibernation and daily torpor minimize mammalian extinctions. Naturwissenschaften 96, 1235–1240 (2009).

    CAS  PubMed  Google Scholar 

  135. 135.

    Gautier, C. et al. Gene expression profiling during hibernation in the European hamster. Sci. Rep. 8, 1–17 (2018).

    CAS  Google Scholar 

  136. 136.

    Antonica, F. et al. Generation of functional thyroid from embryonic stem cells. Nature 491, 66–71 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Tamai, T. K. et al. Identification of circadian clock modulators from existing drugs. EMBO Mol. Med. 10, e8724 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Oshima, T. et al. Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. Sci. Adv. 5, 1–16 (2019).

    Google Scholar 

  139. 139.

    Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Biro, J. Specific binding of thyroid-stimulating hormone by human serum globulins. J. Endocrinol. 88, 339–349 (1980).

    Google Scholar 

  141. 141.

    Spitz, I. M. et al. Increased high-molecular-weight thyrotropin with impaired biologic activity in a euthyroid man. N. Engl. J. Med. 304, 278–282 (1981).

    CAS  PubMed  Google Scholar 

  142. 142.

    DeCherney, G. S., Gesundheit, N., Gyves, P. W., Showalter, C. R. & Weintraub, B. D. Alterations in the sialylation and sulfation of secreted mouse thyrotropin in primary hypothyroidism. Biochem. Biophys. Res. Commun. 159, 755–762 (1989).

    CAS  PubMed  Google Scholar 

  143. 143.

    Loh, T. P. et al. Macro-thyrotropin: a case report and review of literature. J. Clin. Endocrinol. Metab. 97, 1823–1828 (2012).

    CAS  PubMed  Google Scholar 

  144. 144.

    Tamaki, H. et al. Novel thyrotropin (TSH) -TSH antibody complex in a woman and her neonates. Thyroid 5, 299–304 (1995).

    CAS  PubMed  Google Scholar 

  145. 145.

    Constant, R. B. & Weintraub, B. D. Differences in the metabolic clearance of pituitary and serum thyrotropin (TSH) derived from euthyroid and hypothyroid rats: Effects of chemical deglycosylation of pituitary TSH. Endocrinology 119, 2720–2727 (1986).

    CAS  PubMed  Google Scholar 

  146. 146.

    Asa, S. L., Kovacs, K. & Bilbao, J. M. The pars tuberalis of the human pituitary. Virchows Arch. A 399, 49–59 (1983).

    CAS  Google Scholar 

Download references


This work was supported by the Japan Society for the Promotion of Science KAKENHI Grants-in-Aid for Specially Promoted Research (26000013) and for Young Scientists (B) (17K15574), the Human Frontier Science Program (RGP0030/2015) and the National Institutes of Health (PO1 AG-11412 and R01 DK-15070). The Institute of Transformative Bio-Molecules is supported by the World Premier International Research Center Initiative, Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information




All authors researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Takashi Yoshimura.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks S. Benvenga and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Ultradian rhythm

A recurrent cycle with a period shorter than 24 h.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ikegami, K., Refetoff, S., Van Cauter, E. et al. Interconnection between circadian clocks and thyroid function. Nat Rev Endocrinol 15, 590–600 (2019).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing