Axis TRH-TSH-T3/T4
TRH, thyrotropin-releasing hormone
Characteristics
- Peptide with central effects – neuromodulation,
thermoregulation
- Peripheral effects
Hypothalamo-hypophyseal axis
- Regulation of TSH and PRL secretion (prolactinemia,
galactorea)
Clinical significance
- In the past – hyperthyroidis diagnosis (hypothalamic X
hypophyseal causes)
- Possible role in depression treatment, spinal muscular
atrophy and amyotrophic lateral sclerosis
- Treatment of some syndromes (West, Lannox-Gastaut,
early infantile epileptic encephalopathy)
Regulation of secretion
- Neural control
- Circadian rhythm (maximum between 21:00 and 5:00 and
between 16:00 and 19:00, peaks in 90–180 min intervals
- Temperature (cold) – higher synthesis among people from
colder regions in winter – together with ANS
(catecholamines)
- Stress – TRH synthesis and secretion inhibition (indirect
negative feedback loop between glucocorticoids and
effect on hippocampus)
- Starvation – TRH secretion decrease („saving“ energy);
effect of leptin
- Body mass - POMC (-) and ARGP (+) system
TSH, thyroid stimulating hormone
Characteristics
- Heterodimer
- Negative feedback T3 – inhibition of a subunit transcription;
dopamine (a and b)
- Positive feedback – TRH
Function
- Stimulation of thyroid hormones synthesis
- „Growth hormone“ for thyroid gland
Clinical significance
- TSH deficiency (mutation in genes coding
TRH and TSH receptors)
- Analogues of somatostatin
- ! (+) cortisol metabolism
TSH
- Half-life ca 30 min
- Pulsatile secretion (2-3 h), circadian rhythms (peak between
23:00 and 5:00)
- Magnitude changes – starvation, disease, surgery
- Leptin, ADH, GLP-1, glucocorticoids, a-adrenergic agonists,
prostaglandins, TRH (+)
- T3/T4, dopamine, gastrin, opioids, glucocorticoids (high
doses), serotonin, CCK, IL-1b a 6, TNF-a, somatostatin (-)
Feedback mechanism!
Thyroid gland
• Glandula thyroidea (15 - 20 g, frontal side of
trachea under thyroid cartilage
• Two lobes connected by thyroidal isthmus,
lobus pyramidalis
• Strong vascularization
• Round follicles (acini) with one layer of
follicular cells (T3/T4)
• Cavity filled with colloid
• Capillaries with fenestrations
• Parafollicular (C-) cells (calcitonin)
• From day 29 of gravidity (Tg), T4 – 11th week
Follicles are the basic functional units of thyroid gland
Dietary iodine
- Bioavailability of organic and inorganic I
- breast milk
- I- filtered with passive reabsorption 60 – 70 %
- loss through stool (10 – 20 mg/day)
- Highest daily intake in Japan (several mg)
- In many countries on decrease – eating habits
Clinical relevance
- Endemic goiter
- Endemic cretinism
Iodine and hormone secretion – general view
• NIS (Na+/I- symporter)
• PDS (pendrin)
• TPO (thyroidal peroxidase)
• TG homodimers and their iodation –
MIT and DIT
• DUOX1 and 2 – together with TPO
oxidation of iodide and
transportation to TG structure
• TPO - connection DIT+DIT (T4) or
DIT+MIT (T3)
• Pinocytosis and phagolysosomes
• Deiodation of MIT and DIT – DEHAL1
(iodotyrosine dehalogenase)
• Other proteins (TSHR)
• Transcriptional factors (TTF-1, TTF-2,
PAX8, HNF-3)
T3 and T4 secretion
- High supply vs low daily turnover (about 1 %)
- Supply ca 5000 mg T4 – euthyroid state for ca 50 days
- Macropinocytosis and micropinocytosis (apical membrane)
- Endocytosis
- Selective proteolysis (cathepsin D and D-like thiol proteases,
active at low pH)
- Release from Tg in lysosomes
- T4 available to deiodases D1 and D2 – modulation of systemic
conversion?
- Inhibition of T4 secretion by iodide
TSH and T3, T4 secretion
- TSHR
- TSH binding
- TRAb (TSHR-stimulating antibody )
- TBAb (thyroid-blocking antibodies )
- LH (+)
- hCG (+)
- PLC + Ca2+
- iodide efflux, peroxide generation,
iodation of Tg
-PKA
- iodide uptake
- Tg transcription
- transcription and generation of TPO
and NIS
T3 and T4 transport
TBG
- Glycoprotein
- One binding site for iodothyronine
- Half-life ca 5 days
Transthyretin
- Binds one T4 molecule, low affinity
- Half-life ca 2 days
- CSF – relevance ?
Albumin
- Low affinity
- Little relevance for T3/T4 transport (max. 10 %)
Low solubility of iodothyronines determines their reversible binding and transport by plasmatic proteins.
Other – lipoproteins (3 – 6 %)
TBG concentration and saturation is the main free-T4 determinant.
Deiodination and (seleno-)deiodinases*
- all deiodinases require thiol presence as cofactor
(glutathione (GSH), thioredoxin (TRX), glutaredoxin (GRX))
- D1 - main source of plasmatic T3
- D3 - most important „deactivating“ enzyme over-expressed
in tumor tissue
Sources of intracellular T3 and T4
D2 as a source of supplementary
nucleic T3
T3 supply critical for tissues:
- cortex
- BAT
- PIT
Physiological relevance:
- Normal development
- Thyroid gland function regulation
- Cold
Preferential plasmatic T3 utilization
Clinical relevance
- Amiodarone (D1/D2 (-))
- Propylthiouracil (D1 (-))
- Glucocorticoids (D3 (+))
Physiological effects of thyroid hormones
- Non-nuclear receptors
- Interactions with adaptor proteins
- Regulation of transcriptional activity
- cAMP
- MAPK
- Ca2+-ATPase (+)
- Na+/H+ antiporter (+)
Cell response
- Normal growth and development
- Regulation of metabolism
Organ-specific effects of thyroid hormones
Bones
- increase of bone turnover
- regulation of activity of osteoblasts/clasts, chondrocytes
- hyperthyroidism – risk of osteoporosis
Cardiovascular system
- Inotropic and chronotropic effect
- (+) cardiac output and IVF
- (-) vascular resistance
- changes in transcriptional activity:
-Ca2+-ATPase
-Phospholamban
-Myosin
−b-AR (upregulation and sensitivity)
-G-proteins, AC
-Na+/Ca2+ exchanger
-Na+/K+-ATPase
-Voltage-gated ion channels
Adipose tissue
- (+) differentiation of adipose tissue, adipocytes proliferation
- (+) lipogenic enzymes
- (+) cell accumulation of lipids
- (+) uncoupling proteins, uncoupling of oxidative phosphorylation
- Hyperthyroidism (+) lipolysis
- (+) b-AR
- (-) phosphodiesterase activity
- (+) cAMP
- Hypothyroidism (-) lipolysis
(+) activity HSL
Liver
- regulation of triglyceride, lipoprotein and cholesterol
metabolism
- (+) fatty acids metabolism
- (+) gluconeogenesis
- (+) mitochondrial respiration
CNS
- expression of genes related myelination, cell differentiation,
migration and signaling
- Axonal growth and further development
GIT
- (+) resorption of monosaccharides
- (+) motility
Metabolic effects of thyroid hormones
Saccharides
- increased glucose resorption
- Increased utilization of Glu in tissues
- Increased liver gluconeogenesis
- Increased glycolysis
- hyperthyroidism = postprandial hyperglycaemia
- hypothyroidism = inbalances in glycaemia
Proteins
- Proteoanabolic effect (mainly during intrauterine
development and the first year after birth – brain)
- hyperthyroidism = protein catabolism!
Lipids
- increased activity of lipoprotein lipase
- Increased synthesis of LDL receptor in hepatocytes
- increased synthesis of fatty acids (nonesterified)
- increased beta-oxidation
- hypothyreosis = proatherogenic changes!
Thyroid hormones and iodide deficit and excess
Deficit
- Rapid T4 decrease, TSH increase
- No change in T3
- Increased synthesis of NIS, TPO, Tg, organification of iodide
and Tg turnover
- Increase D2 in CNS, hypothalamus and hypophysis
- Stimulation of follicular cells (TSH)
- Long-term deficit – decreased D3
- Decrease supplementation under 75 µg/day (China, India,
Indonesia, Africa)
- hypothyroidismus
Excess
- At first increase, then decrease of iodide organification
(Wolff–Chaikoff effect)
- Long-term high iodide supplementation = hypothyroidism
and goitre
- decreased NIS generation
- Immediate inhibition of thyroid hormones secretion
Thyroid gland functions during disease and starvation*
Starvation
- Decreased plasmatic T3, increased rT3,
T4 no change
- Upregulation of D3
- Decreased oxygen consumption
- Slower heart rate
- More positive nitrogen balance
= mechanisms to save energy and proteins
- Chronic malnutrition – decreased
plasmatic T3
Disease
- Changes in T4 to T3 D2) conversion – TSH binding
- IL-6
- Increased intra-/extracellular ROS = changes in deiodinase activity – decreased T4 to T3 conversion
BUT! no change in D3
- potential therapy – infusion of TSH + GHRP2
- Bipolar disorder – (+) TSH, (-) T4
- Severe depression – (-) TSH, (+) T4
Hormones and
thyroid gland
Glucocorticoids
- Decreased pulsatile secretion of TSH and TRH
secretion
- Increased activity (expression) of D3
Sex steroids
- Estrogens
- increased TBG
- TSH (+ 15 – 20 %)
- Androgen
- decreased TBG
GH
- (+) T3, (-) T4
- Deiodinase
Hypothyroidism
Disruptions of HYP-ADH-TG axis including
mutations
Goitrogens and treatment
Primary versus secondary
- Cold sensitivity
- Dry cold skin
- Slower movements
- Slow quiet speech
- Bradycardia
- Water retention
- Psychomotoric retardation (children)
- Myxedema (accumulation of protein
complexes, polysaccharides, hyaluronic
acid and chondroitin sulfuric acid in
skin)
- Hypothyroidism since birth = cretinism
Hyperthyroidism
Graves disease, diffusion toxic goiter,
toxic nodular goiter, inappropriate
pharmacotherapy, excessive iodide intake,
thyroiditidis, follicular carcinoma, tumors
producing TSH
- increased BMR
- Changes in catecholamines reactivity
- Exophthalmos - infiltration of lymphocytes
and periocular fibroblasts into extraocular
muscles and tissue
- unrest
- Tachycardia
- Hyperventilation
Hypo- versus hyperthyroidismus
Parameter Hypothyroidism Hyperthyroidism
BMR (-) (+)
Carbohydrate metabolism Gluconeogenesis (-)
Glycogenolysis (-)
Glycemia (N)
Gluconeogenesis (+)
Glycogenolysis (+)
Glycemia (N)
Protein metabolism Proteosynthesis (-)
Proteolysis (-)
Proteosynthesis (+)
Proteolysis (+)
Muscle mass (-)
Lipid metabolism Lipogenesis (-)
Lipolysis (-)
Serum cholesterol (+)
Lipogenesis (+)
Lipolysis (+)
Serum cholesterol (-)
Thermogenesis (-) (+)
Autonomic nervous system Plasmatic catecholamines (N) Increased reactivity – b-AR (+)
Plasmatic catecholamines (-)