Serum TSH is usually regarded as a marker of thyroid function on the basis of a simple feedback model.
TSH is released from the anterior pituitary gland in response to thyroid releasing hormone from the hypothalamus and causes the synthesis and secretion of thyroxine (T4) and triiodothyronine (T3) by the thyroid gland. T4 may be converted peripherally to T3. T3 and T4 exert negative feedback on both the pituitary production of TSH and the hypothalamic production of TRH.
The basic assumption are:
- Euthyroidism is present when the value of
TSH is within the normal range. (ca 0.2 mIU/L/4.0 mIU/L)
- Hyperthyroidism is diagnosed if serum TSH
- Hypothyroidism is diagnosed if serum TSH
the term "TSH Reflex" is that the lab will test the TSH and if it's abnormal, the Free T4 will be taken as well. However, if the TSH is normal, only the TSH will be done.
The University of Virginia Laboratory Utilization Committee and the Division of Endocrinology and Metabolism recommend that for most ambulatory patients, TSH alone should be used as the initial test to exclude hypothyroidism and hyperthyroidism. If TSH is abnormal, free T4 should be run on the same sample. Beginning November 1, 2000 these tests can be ordered as "TSH Reflex". It is important to point out, that TSH reflex testing may be misleading with the diagnosis of secondary or tertiary thyroid disease (<5% of patients with thyroid disorders). Therefore, if pituitary or hypothalamic disease is clinically suggested, both TSH and free T4 should be ordered.
A Fusco opinion 2005 TSH algorithm
Regione Lazio Bullettin 2005
Linee Guida Verona 2004
TSH riflesso - Regione Piemonte 2009 pag. 11-15
a deeper insight
A causal view
Factors affecting Thyroid function
Factors affecting Hypothalamus and Hypophysis function
Other factors affecting release of TRH from the hypothalamus include
- blood levels glucose
- the body's metabolic rate.
Somatostatin inhibits TSH secretion
Oestrogen has been shown, in rats, to reverse the negative feedback affect of T3 and T4 on the TSH response to TRH.
Stefano Mariotti 2006
J Investig Med. 2000 Mar;48(2):133-6.
Dopaminergic and cholinergic involvement in the inhibitory effect of dexamethasone on the TSH response to TRH.
Coiro V, Volpi R, Cataldo S, Capretti L, Caffarri G, Pilla S, Chiodera P.
Department of Internal Medicine and Biomedical Sciences, University of Parma, Italy. email@example.com
BACKGROUND: Glucocorticoid administration is associated with reduced basal thyroid-stimulating hormone (TSH) levels and a blunted TSH response to thyrotropin-releasing hormone (TRH), despite thyroid hormone levels within the normal range. In light of the inhibitory effect of somatostatin and dopamine on TSH secretion, we examined whether this condition is caused by glucocorticoids through an increased hypothalamic somatostatinergic and/or dopaminergic inhibitory control of TSH. We measured the TSH response to TRH and serum-free T4 and T3 levels. The study group comprised 18 normal men (age 24-35) within 10% of the ideal body weight, randomly divided into 3 groups of six. METHODS: We used the antidopaminergic agent metoclopramide (MCP) and the acetylcholinesterase inhibitor pyridostigmine, which enhances acetylcholine and thus inhibits hypothalamic somatostatin release. Subjects from group 1 were tested with TRH (20 micrograms in an intravenous bolus) after placebo, dexamethasone (dex) (2 mg/day in 4 divided doses for 3 days before the experimental day), or dex plus pyridostigmine (120 mg p.o.). Subjects from group 2 were tested with TRH after placebo, dex, or dex plus MCP (2.5 mg in an i.v. bolus injection). Subjects from group 3 were tested with TRH after placebo, dex, or dex plus pyridostigmine plus MCP. RESULTS: In all subjects from groups 1, 2, and 3, TRH-induced TSH rise was significantly lower after dex than after placebo treatment. Neither pyridostigmine nor MCP, given alone, changed the TSH response to TRH after dex treatment. In contrast, the concomitant administration of MCP and pyridostigmine significantly enhanced the TRH-induced TSH rise in dex-treated subjects and made the TSH response to TRH similar to that observed in the TRH plus placebo test. CONCLUSIONS: These data indicate that enhanced-hypothalamic somatostatinergic and dopaminergic inhibitory activities are involved in the mechanism underlying the reduced TSH response to TRH induced by glucocorticoid treatment.
Endocrine changes in patients with acute organophosphate poisoning. 1999
Fundam Clin Pharmacol. 2004 Oct;18(5):513-23.
CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement.
Cavun S, Savci V.
Department of Pharmacology and Clinical Pharmacology, Uludag University Medical Faculty, 16059 Bursa, Turkey.
In the present study, we investigated the effect of intracerebroventricular (i.c.v.) administration of cytidine-5'
diphosphate (CDP) choline on plasma adrenocorticotropin (ACTH), serum growth hormone (GH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in conscious rats. The involvement of cholinergic mechanisms in these effects was also determined. In basal conditions, CDP-choline (0.5, 1.0 and 2.0 micromol, i.c.v.) increased plasma ACTH levels dose and time-dependently, but it did not affect the TSH, GH, FSH and LH levels. In stimulated conditions, i.c.v. administration of CDP-choline (1 micromol, i.c.v.) produced an increase in clonidine-stimulated GH, thyrotyropin-releasing hormone (TRH)-stimulated TSH, LH-releasing hormone (LHRH)-stimulated LH, but not FSH levels. Injection of equimolar dose of choline (1 micromol, i.c.v.) produced similar effects on hormone levels, but cytidine (1 micromol, i.c.v.) failed to alter plasma levels of these hormones. Pretreatment with hemicholinium-3, a neuronal high affinity choline uptake inhibitor, (20 microg, i.c.v.) completely blocked the observed hormone responses to CDP-choline. The increase in plasma ACTH levels induced by CDP-choline (1 micromol, i.c.v.) was abolished by pretreatment with mecamylamine, a nicotinic receptor antagonist, (50 microg, i.c.v.) but not atropine, a muscarinic receptor antagonist, (10 microg, i.c.v.). The increase in stimulated levels of serum TSH by CDP-choline (1 micromol, i.c.v.) was blocked by atropine but not by mecamylamine pretreatment. However, CDP-choline induced increases in serum GH and LH levels were greatly attenuated by both atropine and mecamylamine pretreatments. The results show that CDP-choline can increase plasma ACTH and produce additional increases in serum levels of TSH, GH and LH stimulated by TRH, clonidine and LHRH, respectively. The activation of central cholinergic system, mainly through the presynaptic mechanisms, was involved in these effects. Central nicotinic receptors solely mediated the increase in plasma ACTH levels while the activation of central muscarinic receptors was involved in the increase in TSH levels. Both muscarinic and nicotinic receptor activations, separately, mediated the increases in serum GH and LH levels after CDP-choline.
J Clin Endocrinol Metab. 2009 Mar;94(3):1012-6. Epub 2008 Dec 23.
Recombinant human thyrotropin enhances endothelial-mediated vasodilation of conduit arteries.
Napoli R, Apuzzi V, Bosso G, D'Anna C, De Sena A, Pirozzi C, Marano A, Lupoli GA, Cudemo G, Oliviero U, Matarazzo M, Lupoli G, Sacca' L.
Department of Internal Medicine and Cardiovascular Sciences, University Federico II, 80131 Naples, Italy. firstname.lastname@example.org.
CONTEXT: Endothelial cells possess receptors to TSH. Their role is largely unknown. OBJECTIVES: The objective of the study was to determine whether elevated serum TSH levels, as occur in hypothyroidism, affect endothelial function of large arteries and vascular risk biomarkers. SUBJECTS AND METHODS: Thirty-four consecutively recruited patients, who had undergone thyroidectomy for thyroid carcinoma, were studied in connection with one of the monitoring procedures based on recombinant human (rh) TSH administration. Flow-mediated dilation (FMD) of the brachial artery and serum vascular risk markers were measured at baseline and for 5 d after the administration of rhTSH (0.9 mg im on d 1 and 2). Holter electrocardiogram and echocardiography were performed on d 2. RESULTS: rhTSH caused a rapid increase in flow-mediated dilation from the basal value of 10.2 to 15.6% at 6 h (P < 0.0000001), to 16.1% on d 2 (P < 0.0000001), and to 14.9% on d 6 (P = 0.0015). The results were identical when the analysis was made in a subgroup of 19 patients free of vascular risk conditions. Vascular cell adhesion molecule-1, TNFalpha, IL-6, and high sensitive C-reactive protein were unaffected by rhTSH, whereas homocysteine was decreased . Arterial blood pressure, mean 24-h heart rate, and left ventricular function were unaffected by rhTSH. CONCLUSIONS: rhTSH causes marked and persistent activation of the endothelial mediated vasodilation, independent of systemic hemodynamic changes.
Ann Saudi Med. 2008 Mar-Apr;28(2):96-101.
Plasma homocysteine concentrations and serum lipid profile as atherosclerotic risk factors in subclinical hypothyroidism.
Turhan S, Sezer S, Erden G, Guctekin A, Ucar F, Ginis Z, Ozturk O, Bingol S.
Department of Clinical Biochemistry, Ankara Numune Education and Research Hospital, Ankara, Turkey.
BACKGROUND AND OBJECTIVES: Because subclinical thyroid dysfunction may be a risk factor for cardiovascular disease, we evaluated the atherosclerosis tendency in subclinical hypothyroid (SCH) patients. PATIENTS AND METHODS: Fifty-three subclinical hypothyroid patients (serum thyrotropin [TSH] concentrations >4.12 mU/L) were compared with a control group of 50 euthyroid subjects whose age, sex and body mass indices were similar to the patient group. We tested whether serum TSH concentrations were correlated with plasma total homocysteine concentration (tHcy), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides (TG). RESULTS: There was a significant statistical difference between the patient and control groups for normal free T4 (1.02+/-0.17 vs. 0.86+/-0.13, P<.001), TSH (1.64+/-1.02 vs. 6.62+/-2.61, P<.001), TC (185+/-39 vs. 206 /-54 vs. 132+/-85, P=.04), LDL-C (114+/-33 vs. 127+/-36, P=.04), and TC/HDL-C (3.81+/-106 vs. 4.19+/-1.02, P=.04), respectively. No statistically significant difference was found between the two groups for HDL-C, VLDLC, LDL-C/HDL-C, and tHcy. Serum TSH was significantly correlated with plasma tHcy (r=0.55; P=.001) , TC (r=0.52; P=.001), LDL-C (r=0.49; P=.001), TC/HDL-C (r=0.38; P=.002) and LDL-C/HDL-C (r=0.36; P=.004) across all participants. CONCLUSION: Our study suggests that the atherogenicity of SCH is not mediated by hyperhomocysteinemia. Associated hyperlipidemia may explain the observed increased risk of coronary artery disease in patients with SCH.
Clin Biochem. 2006 Mar;39(3):282-6. Epub 2006 Feb 8.
Thyroid function during B-vitamin supplementation of patients on antiepileptic drugs.
Apeland T, Kristensen O, Strandjord RE, Mansoor MA.
Department of Medicine, Stavanger University Hospital, Postbox 8100, 4068 Stavanger, Norway. email@example.com
OBJECTIVES: Patients on antiepileptic drugs (AEDs) may have low serum concentrations of thyroxine, with or without a compensatory increment in thyroid-stimulating hormone (TSH). Furthermore, patients on AEDs often have hyperhomocysteinemia and low concentrations of vitamins B(6), B(2) and folate. Previously, an inverse relationship between thyroxine and homocysteine concentrations has been observed. In animals, deficiency of vitamin B(6) has been found to impair the hypophyseal release of TRH. We have studied the effect of B-vitamin supplements on thyroid function in patients on AEDs. DESIGN AND METHODS: Thirty-two patients on AEDs were identified with hyperhomocysteinemia and low folate, B(6) and B(2). They were supplemented with pyridoxine, riboflavin and folic acid for 30 days. RESULTS: At baseline, the patients had low serum concentrations of free thyroxin and slightly elevated TSH. On day 30 of the B-vitamin supplements, homocysteine had decreased, however, the thyroid parameters remained unchanged. CONCLUSIONS: Hyperhomocysteinemic patients on AEDs have indications of hypothyroidism, however, supplementation with B-vitamins does not improve their thyroid function.
An Unusual Case Of Hyperthyroxinemia
Can impairments of thyroid function test affect prognosis in patients with respiratory failure? 2007
Thyroid function test (TFT) impairments can be detected in extrathyroidal dysfunction, primarily in chronic obstructive pulmonary disease (COPD) with acute respiratory failure (RF). The aims of this study were to: (i) evaluate TFT impairments in patients with RF, (ii) compare TFT results to a control group without RF and (iii) assess the effects of thyroid dysfunction on clinical outcome and prognosis of RF.
Role of cAMP on TSH
J Biol Chem. 2000 Oct 27;275(43):33365-72.
cAMP response element-binding protein-binding protein mediates thyrotropin-releasing hormone signaling on thyrotropin subunit genes. 2000
Hashimoto K, Zanger K, Hollenberg AN, Cohen LE, Radovick S, Wondisford FE.
Thyroid Unit, Division of Endocrinology, Beth Israel Deaconess Medical Center and Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). Since cAMP response element-binding protein (CREB)-binding protein (CBP) integrates a number of cell signaling pathways, we investigated whether CBP is important for TRH stimulation of the TSH subunit genes. Cotransfection of E1A in GH cells completely blocked TRH stimulation of the TSH subunit genes, suggesting that CBP is a key factor for TRH signaling in the pituitary. CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-beta promoter, and amino acids 1-450 of CBP were sufficient for the TRH effect. In contrast, on the human alpha-GSU promoter, CREB and P-Lim mediated TRH signaling. Intriguingly, CREB was phosphorylated upon TRH stimulation, leading to CBP recruitment to the alpha-GSU promoter. CBP also interacted with P-Lim in a TRH-dependent manner, suggesting that P-Lim is an important factor for non-cAMP response element-mediated TRH stimulation of this promoter. Distinct domains of CBP were required for TRH signaling by CREB and P-Lim on the alpha-GSU promoter, amino acids 450-700 and 1-450, respectively. Thus, the amino terminus of CBP plays a critical role in TRH signaling in the anterior pituitary via both Pit-1-dependent and -independent pathways, yielding differential regulation of pituitary gene products.
Inhibited hypothalamic-pituitary-thyroid axis in type I pseudohypoparathyroidism. 1999
The responses of pituitary thyrotrophs to TRH and the thyroid gland to TSH were both considerably inhibited in the patients with type I pseudohypoparathyroidism in comparison with normal control subjects. This finding may be yet another evidence of the lack of adequate generation of cAMP, an important second messenger needed for normal functioning of most polypeptide hormones, including TRH and TSH, in this syndrome.
Mechanisms of action of somatostatin on human TSH-secreting adenoma cells. 1995
The mechanisms of somatostatin (SRIH) action on thyroid-stimulating hormone (TSH) secretion were examined using human TSH-secreting adenoma cells. SRIH (10(-7) M) inhibited TSH secretion through a pertussis toxin-sensitive G protein. SRIH also inhibited forskolin- and 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP)-induced TSH secretion.
SRIH hyperpolarized the membrane and arrested Ca(2+)-dependent action potentials, which accounted for the SRIH-induced decrease in [Ca2+]i. Voltage clamp experiments revealed that this membrane hyperpolarization resulted from the activation of an inward-rectifying K+ current through a pertussis toxin-sensitive G protein.
Application of thyrotropin-releasing hormone (TRH; 10(-7) M) caused an increase in the [Ca2+]i, composed of an initial transient increase followed by a sustained increase. SRIH inhibited the sustained increase in [Ca2+]i. SRIH also inhibited the TRH-induced decrease in the membrane conductance
TSH and hypertension
Recently, the fact whether the reference range of serum TSH (0.3-4.8mIU) is a safe range was doubted. When TSH was in the reference range, there was a linear increase in SBP and DBP with the increasing serum TSH levels, and the prevalence of hypertension also increased:
- Hak AE, Visser TJ, Drexhage HA. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med 2002; 132: 270-278.
- Saltiki K, Voidonikola P, Stamatelopoulos K, Mantzou E, Papamichael C, Alevizaki M. Association of thyroid function with arterial pressure in normotensive and hypertensive euthyroid individuals: a cross-sectional study. Thyroid Res 2008;
- Iqbal A, Figenschau Y, Jorde R. Blood pressure in relation to serum thyrotropin: the Tromso, study. J Hum Hypertens 2006
Adv Biochem Psychopharmacol. 1977;16:331-41.
Dynamic changes in the activities and amounts of neurotransmitter-synthesizing enzymes in mesolimbic and other central catecholamine neurons in response to axonal injury and during collateral sprouting.
Reis DJ, Gilad GM, Pickel VM, Ross RA, Joh TH.
PMID: 18886 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Su
SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kγ Activity through Deacetylation of Specific Lysine Residues in Mammals, 2010
SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Kγ and enhanced PIP5Kγ enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kγ knockdown
GH and TSH
GH and TSH