Hormones and signalling

Receptors and second messengers

Hormones act through receptors in the cell membrane or inside the cell ¹².

The insulin receptor is a receptor tyrosine kinase: its β subunits phosphorylate each other and then IRS proteins, which recruit phosphoinositide 3-kinase ³. Its product, the lipid second messenger PIP3, activates PDK1 and AKT ³⁴.

G-protein-coupled receptors, the largest family of membrane proteins, cross the membrane seven times ¹. The receptors for glucagon, GLP-1 and TSH and the β-adrenoceptors stimulate adenylyl cyclase, which forms cyclic AMP (cAMP) ⁴⁵. cAMP activates protein kinase A, and phosphodiesterases degrade it ¹³. The ghrelin receptor activates Gq and phospholipase C, which forms diacylglycerol and inositol 1,4,5-trisphosphate; the latter opens endoplasmic reticulum calcium channels ⁴.

Cortisol and T3 bind nuclear receptors, ligand-dependent transcription factors ²⁴. T3 binding to its receptor, which pairs with RXR on DNA, replaces a corepressor with a coactivator ⁶. The leptin receptor, a type I cytokine receptor, signals through the kinase JAK2 and STAT3 ⁴.

Insulin and glucagon

Insulin, made by beta cells of the pancreas, lowers blood sugar; glucagon, made by alpha cells, raises it ⁴.

High glucose and insulin inhibit glucagon release, and low glucose stimulates it ⁴. In muscle, AKT promotes translocation of the glucose transporter GLUT4 to the plasma membrane ³⁴. In hepatocytes, glucagon raises cAMP; protein kinase A then inactivates glycogen synthase and, through phosphorylase kinase, activates glycogen phosphorylase ⁷. Metformin acts mainly by suppressing hepatic gluconeogenesis ⁷.

Adrenaline and cortisol

Adrenaline quickens the heart and widens the airways, and the adrenal cortex releases cortisol daily and under stress ⁴⁵².

β1-Adrenoceptors stimulate heart muscle contraction, and β2-adrenoceptors relax airway smooth muscle through cAMP ⁴⁵.

Beta2-adrenoceptor signalling in airway smooth muscleAirway smooth muscle cell

ATP
Adenylyl cyclaseMg2+Gs alpha from the agonist-bound beta2 adrenoceptor activates it
Cyclic AMP
Protein kinase A holoenzymecAMP binds the regulatory subunits, which release the catalytic ones
Free protein kinase A catalytic subunits
Protein kinase A catalytic subunitATP, Mg2+KCa channels and heat shock protein 20 are further substrates
Phosphorylated myosin light-chain kinase
several stepsLess phosphorylation of the myosin regulatory light chain
Relaxed airway smooth muscle

β2-selective agonists such as salbutamol followed nonselective ones such as adrenaline, which caused tachycardia and tremor ⁵. In asthma or chronic obstructive pulmonary disease with reversible obstruction, cardioselective beta-blockers given for 3 to 28 days left forced expiratory volume in one second unchanged (−0.42% of baseline, 95% CI −3.74 to 2.91), although a single dose lowered it by 7.46% (5.59 to 9.32) against placebo ⁸.

CRH from the hypothalamus stimulates ACTH secretion by the anterior pituitary, ACTH stimulates glucocorticoid production, and glucocorticoids inhibit both in negative feedback ².

Thyroid hormones

The thyroid gland makes iodine-containing hormones; TSH, a pituitary hormone, stimulates their production, and they suppress TSH ⁶.

Thyroid hormone synthesis and activationThyroid follicle, then target tissues

Iodide in plasma
Sodium–iodide symporter (SLC5A5)2 Na+PerchlorateThyrotropin (TSH) up-regulates the symporter
Iodide in the thyroid follicle
Thyroid peroxidase (TPO)Haem b, H2O2 from dual oxidase 2 (DUOX2)Mono- and diiodotyrosyl residues form in the follicle lumen
Iodotyrosyl residues of thyroglobulin
Thyroid peroxidase (TPO)H2O2Two diiodotyrosyls couple and leave dehydroalanine; some T3 also forms
Thyroxine residues of thyroglobulin
Cathepsins B, K and LThyroglobulin proteolysis in the lumen and after endocytosis
Thyroxine (T4)
Iodothyronine deiodinases 1 and 2 (DIO1, DIO2)Outer-ring deiodination; in humans DIO2 supplies most circulating T3
Triiodothyronine (T3)
Iodothyronine deiodinase 3 (DIO3)Inner-ring deiodination inactivates T3; DIO3 also forms reverse T3 from T4
3,3′-Diiodothyronine

T4 is a prohormone; humans derive circulating T3 mainly from type 2 deiodinase ⁶. Thyroid hormone receptor β mediates the feedback: a boy and his father, heterozygous for a variant that abolished its T3 binding, had serum T4 of 24.7 and 17.9 µg/dl (normal 5.0 to 12.0) with normal TSH ⁹⁶.

Leptin, ghrelin and GLP-1

Fat tissue, the stomach and the gut release hormones that adjust appetite and insulin secretion ⁴.

Leptin from adipose tissue reduces food intake through the hypothalamus; inherited lack of leptin or its receptor causes severe obesity from an early age ⁴. Ghrelin from the stomach stimulates appetite and requires octanoylation by MBOAT4 to activate its receptor ⁴. GLP-1 from intestinal L cells stimulates glucose-dependent insulin release and lowers plasma glucagon ⁴.

References

Independent research
Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors Nature, 2009.
doi:10.1038/nature08144 PubMed 19458711
Funding and finding
Funding
This work was supported by the US National Institute of General Medical Sciences (grant F32 GM082028 to D.M.R. and grant RO1-GM083118 to B. K.), the Lundbeck Foundation (to S.G.F.R.), the National Institute of Neurological Disorders and Stroke (grant RO1-NS28471 to B.K.) and the Mather Charitable Foundation (to B. K.).
Finding
Review. GPCRs are the largest family of membrane proteins and mediate most cellular responses to hormones and neurotransmitters; all have seven membrane-spanning alpha-helical segments. At the human beta2 adrenoceptor, adrenaline and noradrenaline activate the stimulatory G-protein subunit Gs alpha, which stimulates adenylyl cyclase; cAMP accumulates and activates protein kinase A, and specific phosphodiesterases lower cAMP. Activated receptors are phosphorylated by G-protein-coupled receptor kinases and bind arrestin, which prevents G-protein activation and promotes internalisation.
Independent research
Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease Journal of Allergy and Clinical Immunology, 2013.
doi:10.1016/j.jaci.2013.09.007 PubMed 24084075
Funding and finding
Funding
This research was supported by the Intramural Research Program of the NIH, NIEHS.
Finding
Review. Glucocorticoids are synthesised and released by the adrenal cortex in a circadian manner and in response to stress under control of the hypothalamic-pituitary-adrenal axis: CRH from the hypothalamus stimulates synthesis and secretion of ACTH by the anterior pituitary, ACTH stimulates production and secretion of glucocorticoids, and glucocorticoids act on the hypothalamus and anterior pituitary to inhibit production and release of CRH and ACTH in a classic negative feedback loop. The glucocorticoid receptor (NR3C1) belongs to the nuclear receptor superfamily of ligand-dependent transcription factors; without hormone it resides mainly in the cytoplasm with hsp90, hsp70, p23, FKBP51 and FKBP52; glucocorticoid binding dissociates these proteins, and the receptor enters the nucleus and binds glucocorticoid response elements as a homodimer. Cortisol is the most abundant endogenous glucocorticoid in humans; free cortisol diffuses across the plasma membrane; 11beta-HSD2 oxidises cortisol to inactive cortisone and 11beta-HSD1 converts cortisone to cortisol.
Independent research
Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance Physiological Reviews, 2018.
doi:10.1152/physrev.00063.2017 PubMed 30067154
Funding and finding
Funding
M. C. Petersen is supported by National Institutes of Health (NIH) Medical Scientist Training Program Grant T32 GM-007205 and National Research Service Award F30 DK-104596. G. I. Shulman is supported by NIH Grants R01 DK116774, R01 DK113984, R01 DK114793, and P30 DK-45735.
Finding
Narrative review. INSR is a heterotetramer of two insulin-binding alpha subunits and two beta subunits with tyrosine kinase domains; trans-autophosphorylation of Tyr1162, Tyr1158 and Tyr1163 activates it, and it phosphorylates IRS1 and IRS2, which recruit PI3K (p85 regulatory, p110 catalytic). PIP3 recruits PDK1 and AKT, phosphorylated at Thr308 by PDK1 and at Ser473 by mTORC2. In primary human myotubes, knockdown of AKT2 but not AKT1 abrogated insulin-stimulated glucose uptake and glycogen synthesis; a partial loss-of-function AKT2 variant in about 1% of the Finnish population impairs insulin-stimulated glucose uptake and increases endogenous glucose production. AKT phosphorylation of TBC1D4 (AS160) blocks its inactivation of Rab GTPases and promotes GLUT4 storage-vesicle translocation, first reported in 1980; a truncating TBC1D4 mutation caused profound insulin resistance in one family. Glycogen synthesis accounts for about 75% of insulin-stimulated glucose disposal in human muscle; mice with GSK3 insensitive to insulin have normal insulin-stimulated glycogen synthesis, suggesting acute control mainly by glucose 6-phosphate allostery. Muscle stores energy mostly for its own use, releasing lactate and alanine. Hepatocyte glucose transport is not insulin-regulated; AKT phosphorylates FOXO1, excluding it from the nucleus and lowering G6pc and Pck1 transcription. Suppression of adipose lipolysis has an ED50 of about 20 µU/mL insulin, within a physiological range of about 5 to 60 µU/mL. Hepatic glycogen is nearly depleted after 48 h of fasting in humans, while gluconeogenic flux stays relatively constant for about 48 h. In rodents, acute insulin suppression of gluconeogenesis depends mainly on suppression of adipose lipolysis, hepatic acetyl-CoA and pyruvate carboxylase flux, and mice lacking hepatic AKT1, AKT2 and FOXO1 suppressed glucose production normally; the quantitative significance in humans remains to be explored. Insulin suppresses glucagon secretion through paracrine action in the islet.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA); National Institute of General Medical Sciences (NIGMS) [R35GM141873]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Eye Institute (NEI); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 - Research and Innovation Framework Programme [825575]; State Secretariat for Education, Research and Innovation (SERI); European Molecular Biology Laboratory (EMBL) Australia. Funding for open access charge: National Institutes of Health.
Finding
Reviewed human UniProtKB entries, release 2026_03, read through rest.uniprot.org on 2026-10-21. INS (P01308): expressed by pancreatic beta cells; decreases blood glucose. GCG (P01275): glucagon is secreted by A cells of the islets, raises plasma glucose and activates GCGR, which couples to Gs and raises cAMP; glucagon release is stimulated by hypoglycaemia and inhibited by hyperglycaemia, insulin and somatostatin; in intestinal L cells PCSK1 releases GLP-1, a potent stimulator of glucose-dependent insulin release that suppresses plasma glucagon. INSR (P06213): receptor tyrosine kinase; PI3K generates PIP3, a lipid second messenger that activates PDPK1 and then AKT; the net effect is translocation of GLUT4 from cytoplasmic vesicles to the cell membrane. GCGR (P47871), GLP1R (P43220) and TSHR (P16473): G-protein-coupled receptors that activate adenylyl cyclase; TSHR couples to Gs, and PKA phosphorylates thyroid peroxidase and the sodium/iodide symporter. ADRB1 (P08588): couples to Gs to activate adenylyl cyclase and stimulates cardiomyocyte contraction. GHSR (Q92847): ghrelin receptor coupled to Gq that modulates phospholipase C and mediates production of diacylglycerol and inositol 1,4,5-trisphosphate. PLCB1 (Q9NQ66): hydrolyses phosphatidylinositol 4,5-bisphosphate into diacylglycerol and inositol 1,4,5-trisphosphate and signals downstream of G-protein-coupled receptors; PLCB3 (Q01970) is activated by G(q) and G(11) G alpha proteins downstream of such receptors. ITPR1 (Q14643): inositol 1,4,5-trisphosphate-gated channel that releases calcium from the endoplasmic reticulum. THRB (P10828): nuclear hormone receptor and transcriptional repressor or activator with high affinity for T3 and T4. LEPR (P48357): type I cytokine receptor that signals through JAK2 and STAT3. LEP (P41159): adipose tissue is the main source; in the hypothalamus it decreases food intake and increases energy consumption; leptin deficiency causes severe hyperphagia and intractable obesity from an early age, and leptin receptor deficiency hyperphagia and severe obesity from an early age with normal serum leptin. GHRL (Q9UBU3): highest expression in stomach; ghrelin stimulates appetite and growth hormone release, and octanoylation, by GOAT/MBOAT4 (Q96T53), is essential for activation of GHSR. Thyroid pathway entries: SLC5A5 (Q92911) moves iodide into the thyroid with 2 Na+, is inhibited by perchlorate and up-regulated by thyrotropin; TPO (P07202), with haem b and H2O2 from DUOX2 (Q9NRD8), iodinates thyroglobulin tyrosines and couples two diiodotyrosines to thyroxine, leaving dehydroalanine; TG (P01266) is iodinated and coupled in the follicle lumen and cleaved by cathepsins B, L and K in the lumen and after endocytosis; DIO1 (P49895) and DIO2 (Q92813) convert T4 to T3 by outer-ring deiodination; DIO3 (P55073) converts T3 to 3,3'-diiodothyronine and T4 to reverse T3 by inner-ring deiodination.
Textbook or database
Billington CK, Penn RB, Hall IP. β2 Agonists Handbook of Experimental Pharmacology, 2017.
doi:10.1007/164_2016_64 PubMed 27878470
Funding and finding
Funding
The authors are funded by grants HL58506 and A110007 (RBP) and MRC grant G1000861 (IPH).
Finding
Beta2 adrenoceptors are expressed on airway smooth muscle and also on airway epithelial cells, submucosal glands, vascular endothelium, vascular smooth muscle, mast cells, macrophages and eosinophils; the main adverse effects of the class, among them anxiety, tachycardia, tremor and sweating, are ascribed to cross-activation of beta1 adrenoceptors, and the accumulated evidence does not indicate anti-inflammatory effects of current therapeutic beta2 agonists. Loss of the bronchoprotective effect with chronic use has been observed in patients, consistent with receptor desensitisation in cell, tissue and mouse models. Salbutamol, the first β2-selective agonist, was synthesised in 1968 at Glaxo. Inhaled doses are 100-200 µg as required up to four times per day, with onset under 5 min, duration of effect 3-6 h and β2/β1 selectivity 27, against 63 for terbutaline, 150 for formoterol and 3000 for salmeterol. The β2 adrenoceptor was the first G-protein-coupled receptor to be cloned, has seven transmembrane domains and couples to Gs; adenylyl cyclase then catalyses formation of cAMP from ATP and cAMP activates protein kinase A, whose substrates in airway smooth muscle include myosin light chain kinase, KCa channels, heat shock protein 20, Gq-coupled receptors, Gq, phospholipase C and IP3 receptors. G-protein-coupled receptor kinases phosphorylate the receptor and promote β-arrestin binding, which uncouples it from Gs and diminishes cAMP production. Of the four coding variants of ADRB2, Arg16Gly and Gln27Glu are common, with allele frequencies between 0.3 and 0.7 and in linkage disequilibrium; Thr164Ile has an allele frequency of about 2% and alters catechol ligand binding and receptor trafficking in transfected cells; Val34Met is very rare and appears not to alter receptor function. Several studies found that frequent or regular administration of short-acting agonists impairs asthma control in Arg16Arg homozygotes, while most larger retrospective and prospective studies did not confirm these results and large genome-wide association studies of asthma identified no signal at the ADRB2 locus. Short-acting agonists are recommended on an as-required rather than a regular basis, and escalation of use should prompt review of management; widespread use of genetic profiles to dictate treatment with this drug class does not seem warranted.
Independent research
Brent GA. Mechanisms of thyroid hormone action Journal of Clinical Investigation, 2012.
doi:10.1172/JCI60047 PubMed 22945636
Funding and finding
Funding
This work was supported by Veterans Affairs Merit Review Funds and NIH grant R01 CA89364.
Finding
Review. Thyroid hormone is synthesised in thyroid follicles by iodination of tyrosine residues in thyroglobulin; TSH, secreted by the anterior pituitary in response to feedback from circulating thyroid hormone, acts on the TSH receptor of follicular cells and regulates iodide uptake by the sodium/iodide symporter. T4 is a prohormone activated to T3; humans derive circulating T3 primarily from type 2 deiodinase and rodents from type 1; type 3 deiodinase inactivates T4 to reverse T3; selenium is required by all three deiodinases. Unliganded thyroid hormone receptor heterodimerises with RXR, binds a thyroid hormone response element and then a corepressor such as NCoR or SMRT; T3 binding disrupts corepressor binding and promotes coactivator binding. TR-beta mediates thyroid hormone feedback to TRH and TSH; resistance to thyroid hormone, caused by TR-beta mutations, features elevated circulating thyroid hormone and nonsuppressed serum TSH.
Independent research
Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease Nature Reviews Endocrinology, 2017.
doi:10.1038/nrendo.2017.80 PubMed 28731034
Funding and finding
Funding
M.C.P. acknowledges grant support from the US National Institutes of Health (NIH; grants F30 DK-104596 and T32 GM-007205). D.F.V. acknowledges grant support from the NIH (grant K23 DK-102874). G.I.S. acknowledges grant support from the NIH (grants R01 DK40936, R01 DK113984 and P30 DK045735).
Finding
Narrative review. Glucagon receptor (GCGR) activation raises cAMP and activates PKA, which inhibits L-type pyruvate kinase, phosphorylates PFK-2/FBPase-2 to favour its phosphatase activity and lower fructose 2,6-bisphosphate, an allosteric inhibitor of FBPase-1 (printed as fructose-2,6-bisphosphatase 1), phosphorylates and inactivates glycogen synthase, and activates phosphorylase kinase, which phosphorylates glycogen phosphorylase at Ser15; PKA also activates the CREB-CBP-CRTC2 complex for gluconeogenic gene transcription. FOXO proteins with PGC1-alpha raise PCK1 and G6PC expression and are excluded from the nucleus after AKT phosphorylation. Glucose enters hepatocytes by facilitated diffusion through GLUT2; glucose allosterically inhibits glycogen phosphorylase; glucose 6-phosphate is the key allosteric activator of GYS2. In overnight-fasted humans under somatostatin, hyperinsulinaemia was required to stimulate hepatic glycogen synthesis and hyperglycaemia to suppress glycogenolysis. Hepatic glucose production and storage are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Metformin is used as first-line therapy for type 2 diabetes and acts primarily through the suppression of hepatic gluconeogenesis, by a molecular mechanism that remains under investigation. Several lines of evidence cast doubt on the necessity of AMPK: metformin continues to inhibit glucose production in Ampk-knockout primary mouse hepatocytes and improves glucose tolerance in Ampk-knockout mice to a similar extent as in wild-type mice. Inhibition of mitochondrial complex I is observed only at suprapharmacological, millimolar concentrations, in contrast to the clinically relevant plasma concentration range of 50 to 100 µM in patients who take 2 g of metformin daily. Metformin non-competitively inhibits mitochondrial glycerol-3-phosphate dehydrogenase in isolated hepatocytes with a clinically relevant Ki of about 50 µM, which predicts impaired gluconeogenesis only from the redox-dependent substrates lactate and glycerol and not from pyruvate, alanine or dihydroxyacetone phosphate; the importance of the glycerol-3-phosphate shuttle in gluconeogenesis in the human liver is unclear, so studies in humans are required.
Independent research
Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for reversible airway disease Cochrane Database of Systematic Reviews, 2002.
doi:10.1002/14651858.CD002992 PubMed 12519582
Funding and finding
Participants
381
Follow-up
single dose, or continued treatment for 3 to 28 days
Funding
Internal sources: Santa Clara Valley Medical Center, USA. External sources: No sources of support supplied.
Finding
Issue 4, 2002, of this Cochrane review: 19 trials of a single dose and 10 of continued treatment, all randomised, blinded and placebo-controlled. A single dose of a cardioselective beta-blocker reduced the forced expiratory volume in one second by 7.46% (95% CI 5.59 to 9.32), while the response to a beta2-agonist given afterwards rose by 4.63% (2.47 to 6.78) against placebo. Treatment lasting 3 to 28 days produced no change in that volume (-0.42% of baseline, 95% CI -3.74 to 2.91), in symptoms or in inhaler use, and a beta2-agonist response of 8.74% (1.96 to 15.52) persisted. In the subgroup with chronic obstructive pulmonary disease the treatment effect on that volume was -5.28% (-10.03 to -0.54) for single doses and 1.07% (-3.30 to 5.44) for continued treatment. The full text in PubMed Central carries the same effect estimates after a search to June 2011 that added no eligible study, and reports 240 patients in the single-dose trials and 141 in the continued-treatment trials, a risk difference for respiratory symptoms of 0.01 (-0.02 to 0.03) and 0.01 (-0.02 to 0.04) respectively, and cardioselectivity of at least 20-fold for beta1 over beta2 receptors.
Independent research
Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta Proceedings of the National Academy of Sciences of the United States of America, 1989.
doi:10.1073/pnas.86.22.8977 PubMed 2510172
Funding and finding
Funding
This research was supported by U.S. Public Health Service Grants DK13377, DK27384, DK00055, DK15070, RR305, and HD04583 and the David Wiener Research Fund.
Finding
Both affected subjects carried, on one of two THRB alleles, a guanine-to-cytosine change that replaces glycine 340 with arginine in the hormone-binding domain; the in vitro translated mutant receptor did not bind triiodothyronine. Serum T4 was 24.7 µg/dl in the son and 17.9 µg/dl in the father (normal 5.0-12.0), serum T3 369 and 240 ng/dl (normal 85-180), and TSH 2.3 and 1.2 µU/ml (normal 0.5-4.0). Triiodothyronine raising serum T3 to 600-1100 ng/dl completely suppressed the TSH response to TRH in a normal subject but only partially in the proband.
Industry-funded
Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes Diabetes, 2000.
doi:10.2337/diabetes.49.12.2063 PubMed 11118008
Funding and finding
Participants
14
Follow-up
3 months of metformin
Funding
This work was supported by grants from the U.S. Public Health Service (R01 DK-49230, P30 DK-45735, R01 DK-14507, and M01 RR-00125), the Endocrine Fellows Foundation, and an unrestricted grant from Bristol-Myers Squibb.
Finding
Uncontrolled before-and-after study with healthy controls. Endogenous glucose production was 0.70 ± 0.05 mmol·m−2·min−1 in the diabetic subjects against 0.36 ± 0.03 in controls; metformin lowered it by 24% to 0.53 ± 0.03 (P = 0.0009) and fasting plasma glucose by 30% to 10.8 ± 0.9 mmol/l. Gluconeogenesis measured with 2H2O fell by 33%, from 0.42 ± 0.04 to 0.28 ± 0.03 mmol·m−2·min−1 (P = 0.0002); gluconeogenesis derived from 13C NMR glycogenolysis fell by 36%, given as 0.59 ± 0.03 to 0.38 ± 0.03 in the abstract and 0.59 ± 0.07 to 0.37 ± 0.03 in Table 4, with NMR data from five of the seven patients. Means ± SE.
Expert consensus
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement Thyroid, 2014.
doi:10.1089/thy.2014.0028 PubMed 25266247
Funding and finding
Funding
The task force members volunteered their time and expertise and did not receive funds from the ATA. No funds were received from commercial sources for the development of this document. J.J. is partially supported by federal funds (Grant no. UL1TR000101) from the National Center for Advancing Translational Science, NIH, through the Clinical and Translational Science Awards Program. A.S. holds a Health Services Research Chair, funded by Cancer Care Ontario.
Finding
Recommendation 1a: levothyroxine is recommended as the preparation of choice for treating hypothyroidism (strong recommendation, moderate-quality evidence); the rationale is peripheral conversion of the prohormone T4 into T3 by type 1 and type 2 deiodinases. Recommendation 1b: the goals include normalisation of serum thyrotropin; the discussion states that TSH is the most reliable marker of adequate replacement and that a value within the reference range (0.4-4.0 mIU/L) should be considered the therapeutic target. Recommendation 4b: the dose is titrated using serum thyrotropin as the goal, with thyrotropin assessment 4-6 weeks after any dosage change (strong recommendation, moderate-quality evidence).

Updated 2026-10-21