title: The homeostatic set point of the hypothalamus-pituitary-thyroid axis--maximum curvature theory for personalized euthyroid targets.
abstract: BACKGROUND
  Despite rendering serum free thyroxine (FT4) and thyrotropin (TSH) within the normal population ranges broadly defined as euthyroidism, many patients being treated for hyperthyroidism and hypothyroidism persistently experience subnormal well-being discordant from their pre-disease healthy euthyroid state. This suggests that intra-individual physiological optimal ranges are narrower than laboratory-quoted normal ranges and implies the existence of a homeostatic set point encoded in the hypothalamic-pituitary-thyroid (HPT) axis that is unique to every individual.
  
  
  METHODS
  We have previously shown that the dose-response characteristic of the hypothalamic-pituitary (HP) unit to circulating thyroid hormone levels follows a negative exponential curve. This led to the discovery that the normal reference intervals of TSH and FT4 fall within the 'knee' region of this curve where the maximum curvature of the exponential HP characteristic occurs. Based on this observation, we develop the theoretical framework localizing the position of euthyroid homeostasis over the point of maximum curvature of the HP characteristic.
  
  
  RESULTS
  The euthyroid set points of patients with primary hypothyroidism and hyperthyroidism can be readily derived from their calculated HP curve parameters using the parsimonious mathematical model above. It can be shown that every individual has a euthyroid set point that is unique and often different from other individuals.
  
  
  CONCLUSIONS
  In this treatise, we provide evidence supporting a set point-based approach in tailoring euthyroid targets. Rendering FT4 and TSH within the laboratory normal ranges can be clinically suboptimal if these hormone levels are distant from the individualized euthyroid homeostatic set point. This mathematical technique permits the euthyroid set point to be realistically computed using an algorithm readily implementable for computer-aided calculations to facilitate precise targeted dosing of patients in this modern era of personalized medicine.
authors.affiliation: Department of Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Republic of Singapore. melvin_leow@nuhs.edu.sg.
authors.forename: Melvin Khee-Shing
authors.initials: MK
authors.lastname: Leow
authors.forename: Simon L
authors.initials: SL
authors.lastname: Goede
mesh_terms: D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D010902:Pituitary Gland / Q000473:pathology*; D057285:Precision Medicine; D012044:Regression Analysis; D015203:Reproducibility of Results; D013959:Thyroid Diseases / Q000473:pathology* / Q000503:physiopathology; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000473:pathology*; D013972:Thyrotropin / Q000378:metabolism
chemical_list: D013972:Thyrotropin
references.citation: Thyroid. 2003 Jan;13(1):3-126
references.pmid: 12625976
references.citation: J Thyroid Res. 2013;2013:148157
references.pmid: 23762775
references.citation: Eur J Endocrinol. 2013 Jun 07;169(1):73-82
references.pmid: 23641017
references.citation: J Clin Endocrinol Metab. 2013 Sep;98(9):3562-71
references.pmid: 23824418
references.citation: Eur J Endocrinol. 2010 Nov;163(5):839-40; discussion 841
references.pmid: 20671135
references.citation: PLoS One. 2011;6(8):e22552
references.pmid: 21829633
references.citation: Math Biosci. 2014 Mar;249:1-7
references.pmid: 24480737
references.citation: J Clin Endocrinol Metab. 1990 Sep;71(3):553-8
references.pmid: 2203796
references.citation: Clin Endocrinol (Oxf). 2002 Nov;57(5):577-85
references.pmid: 12390330
references.citation: Comput Math Methods Med. 2013;2013:831275
references.pmid: 24082916
references.citation: Clin Chem. 2011 Jan;57(1):122-7
references.pmid: 21097676
references.citation: J Clin Endocrinol Metab. 2005 Sep;90(9):5483-8
references.pmid: 16148345
references.citation: J Theor Biol. 2007 Sep 21;248(2):275-87
references.pmid: 17602707
references.citation: J Clin Endocrinol Metab. 2008 Apr;93(4):1224-30
references.pmid: 18230665
references.citation: Metabolism. 1998 Oct;47(10):1194-8
references.pmid: 9781620
references.citation: Thyroid Res. 2012 Jan 26;5(1):1
references.pmid: 22280879
references.citation: Bull Math Biol. 2014 Jun;76(6):1270-87
references.pmid: 24789568
references.citation: Crit Rev Clin Lab Sci. 1984;20(3):243-83
references.pmid: 6373146
references.citation: Eur J Endocrinol. 2010 Jun;162(6):1123-9
references.pmid: 20299491
references.citation: J Clin Endocrinol Metab. 1988 Mar;66(3):588-92
references.pmid: 3350909
references.citation: J Clin Endocrinol Metab. 2013 Jul;98(7):2936-43
references.pmid: 23671314
references.citation: Am J Physiol. 1992 Feb;262(2 Pt 2):F320-5
references.pmid: 1539688
references.citation: Endocr Pract. 2012 Nov-Dec;18(6):988-1028
references.pmid: 23246686
references.citation: Fed Proc. 1985 Jan;44(1 Pt 2):177-81
references.pmid: 2981739
references.citation: J Hypertens. 2012 Mar;30(3):592-9
references.pmid: 22227818
references.citation: Endocr Pract. 2011 May-Jun;17(3):456-520
references.pmid: 21700562
references.citation: Mol Endocrinol. 2009 May;23(5):600-9
references.pmid: 19196836
references.citation: Thyroid. 2000 Dec;10(12):1107-11
references.pmid: 11201857
references.citation: J Theor Biol. 1999 Jul 7;199(1):105-12
references.pmid: 10419763
references.citation: Biomed Eng Online. 2010 Jan 11;9:4
references.pmid: 20064256
references.citation: Exp Clin Endocrinol Diabetes. 2007 Apr;115(4):261-7
references.pmid: 17479444
references.citation: J Clin Pathol. 2012 May;65(5):463-5
references.pmid: 22287691
references.citation: Biol Res. 2003;36(2):211-21
references.pmid: 14513716