Thyroid Introduction to the thyroid: anatomy, histology, hierarchy, feed-back regulation, effect of T3- T4 on Na/K ATPase and uncoupling proteins 07 of T3-T4: thyroglobulin, iodide pump, iodination and coupling res, lysosomes T3-T4 effects: metabolism, T C/F control, growth / development, reproduction, tertiary hypometabolism (starvation, hibernation) : T4 to T3, T3 receptor, nuclear / mitochondrial sites, increase enzymes, Na/K ATPase, uncoupling proteins Pathology: goitrogens, hypo and hyperthyroidism, thyroid hormone resistance Introduction Thyroid & its story lines Page 1
Introduction I I I I I I I The human thyroid is located at the base of the neck wraped around the traquea Introduction TRH TSH T3 T4 The thyroid is controlled by feedback systems that include the hypothalamus and the AP gland Page 2
Introduction Half-life T4 = 6 days Metabolism of T4 T3 = 1 day The half - life of the thyroid hormones T3 and T4 is different Introduction 3V 3V TRH TSH secretion is controlled by TRH, whose cell bodies are located in the PVN Page 3
Introduction 3V 3V TRH TSH secretion is controlled by TRH, whose cell bodies are located in the PVN Introduction 3V 3V TRH TSH secretion is controlled by TRH, whose neuronal terminals are located in the ME Page 4
Introduction left PVN right PVN TRH 3V The left & right PVN in a control. TRH-mRNA labeled by hybridization. TSH paraventricular nucleus (PVN) contains the cell bodies of TRH neurons ending in the ME Introduction left PVN right PVN TRH 3V T3 implanted unilateral in left PVN TSH secretion is controlled mainly by a negative feedback of T3 - T4 Page 5
Introduction TRH TSH TSH secretion is controlled mainly by a negative feedback of T3 - T4 Introduction Hormones in AP and hypothalamus Normal and abnormal response to TRH TSH Effect of TRH on Prl and GH Prl GH T3 TRH stimulates the secretion of TSH and of Prl from the AP Page 6
Introduction The hypothalamic-pituitary-thyroid axis The hypothalamic - pituitary - thyroid axis is controlled by negative feedbacks Biosynthesis of T3 - T4 Thyroid hormones and related compounds tyrosine 3,5 D-I-tyrosine 3 M-I-tyrosine Tetra iodo tyronine (T4) 3,5 D-I-tyrosine 3,5,3 tri iodo tyronine (T3) 3,3,5 tri iodo tyronine (reverse T3) Thyroid hormones (T3 - T4) derived from the aminoacid tyrosine Page 7
Biosynthesis of T3 - T4 TSH R pump A C camp I 2 I - I - I 2 TBG TBP albumin A T3 T4 protease lysosome (tyrosin) T MIT (tyronine) DIT colloid droplet T3 T4 t h y r o g l o b u l i n Thyroid hormones (T3 - T4) derived from the aminoacid tyrosine Biosynthesis of T3 - T4 Thyroid hormones (T3 - T4) derived from the aminoacid tyrosine Page 8
Biosynthesis of T3 - T4 Thyroid hormones (T3 - T4) derived from the aminoacid tyrosine Biosynthesis of T3 - T4 Thyroid hormones (T3 - T4) derived from the aminoacid tyrosine Page 9
Physiological effects of thyroid T3 - T4 have multiple physiological effects Physiological effects of thyroid 500 metabolism (ml O2 / 100g/h) 300 100 T3 T4 0 100 200 dose of thyroid hormone 500 body weight (g) 300 100 pituitary extract + T4 pituitary extract normal Tx + T4 thyoidectomy (Tx) 0 100 200 time in days T3 - T4 increases oxygen consumption and body weight, two metabolic indices Page 10
Physiological effects of thyroid Oxygen consumption as % of hypothyroid control hours after T4 days after T4 animal, heart gastric mucosa liver, smooth muscle diaphragm, kidney skeletal muscle animal spleen brain testis T3 - T4 increases oxygen consumption and body weight, two metabolic indices Physiological effects of thyroid Developmental age T3 - T4 increases bone age, hight age and mental age in a child with no thyroid tissue Page 11
Physiological effects of thyroid e.g. fasting, hibernation Hypothalamic or tertiary hypometabolic states: fasting and hibernation A change in the set-point alters the level at which the whole system operates variable under control set point or CS feedback detector comparator common language error signal amplifier feedback detector Long negative feedback loop A tertiary hypometabolic state is useful to understand various of the thyroid functions Set point C S comparator TRH AP thyroid Thyroid hormones Physiological effects of thyroid e.g. fasting, hibernation PVN, link to ME and ANS POA, t C/F Integration site ANS, neuronal link to thyroid Thyroid, control of Na/K ATPase and uncoupling proteins ME, link to AP A tertiary hypometabolic state is useful to understand various of the thyroid functions Page 12
Physiological effects of thyroid e.g. fasting, hibernation T3-T4 (low) TSH (low / normal) TRH mrna (low) UC proteins (low) TRH-induced TSH release (high) TRH release (low) SS inhibits TSH release Insulin (low) Glucagon (high) Cortisol (high) Epinephrine (high) LH/FSH (low) Leptin (low) Cas, NPY, amsh, arcuate thermogenesis (low) energy expenditure (low) Thyroid hormones control the expression of the Na/K ATPase and uncoupling proteins Physiological effects of thyroid e.g. fasting, hibernation Thyroid hormones control the expression of the Na/K ATPase and uncoupling proteins Page 13
TRH / TSH mechanism of TRH and TSH mechanism of are associated with a GCPR TRH mechanism of (-) (+) TRH mechanism of is associated with a GCPR linked to PLC Page 14
TSH mechanism of TSH mechanism of is associated with a GCPR linked to AC TSH mechanism of TSH hormone signal can be increased by rising camp or by decreasing phosphodiesterase TSH mechanism of is associated with a GCPR linked to AC Page 15
TSH mechanism of amplification cascade TSH mechanism of is associated with a GCPR linked to AC T3-T4 mechanism of T3 - T4 mechanism of is associated with intracellular receptors (genomic effect) Page 16
T3-T4 mechanism of inactive T3R D N A empty binding site H R E T3R co-repressor NH2 COOH TFIIB TATA box RNA -Pol II active T3R D N A T3 H R E T3R co-repressor COOH NH2 TFIIB TATA box RNA -Pol II T3 - T4 mechanism of is associated with intracellular receptors (genomic effect) T3-T4 mechanism of In its free state T3R binds to its HRE as homodimer, or as a heterodimer with retinoid-x. The carboxy-terminus of T3R interacts with TFIIB preventing the formation of a stable preinitiation complex and, together with a co-repressor, silences transcription. Upon T3 binding, its receptor undergoes a conformational change, dissociation of the co-repressor, a decreased inter of the T3R with the carboxy-terminus TFIIB and an increase inter of the T3R amino-terminus with TFIIB. These changes facilitate TFIIB binding an assembly of a stable preinitiation complex, the binding of RNA polymerase II and the activation of transcription initiation. T3 - T4 mechanism of is associated with intracellular receptors (genomic effect) Page 17
T3-T4 have permissive effects R Na / K pump camp ----> PKA ----> channel / enzyme AC Protein synthesis XX1 HRE 5 3 E1 mrna SR Steroid S + R ----> SR DNA additional transcription factor T3 - T4 mechanism of is associated with intracellular receptors (genomic effect) Diseases of the thyroid axis TSH high normal low primary failure target organ trophic hormone deficiency normal range autonomous trophic secretion or resistance to target hormone FB autonomous target secretion low normal high T3 - T4 Some endocrine pathologies can be visualized in a tropic / target diagram Page 18
Diseases of the thyroid axis What went wrong with this person??? Some endocrine pathologies can be visualized in a tropic / target diagram or in a photography Diseases of the thyroid axis twin sisters, one has hypo and the other hyperthyroidism hyperthyroidism, nervousness, irritability, emotional instability, pounding heart, fatigue, heat intolerance, weight loss despite normal or increased food intake, tachycardia, atrial arrhythmia, even congestive heart adult hypothyroidism, slow onset, tiredness, lethargy, constipation, slow mental and motor function, cold intolerance, menstrual abnormalities, infertility, sc accumulation of mucopoly-sacharides (mixedema) Characteristic symptomatology of adult hyper and hypothyroidism Page 19
Diseases of the thyroid axis congenital hypothyroid before / after T4 Hypothyroidism in infancy leads to cretinism. Severe T3/ T4 deficiency cause mental and growth retardation Infancy hypothyroidism leads to cretinism if it is not treated Diseases of the thyroid axis Hyper-thyroidism Hypo-thyroidism Characteristic symptomatology of adult hyper and hypothyroidism Page 20
Diseases of the thyroid axis Pathophysiology of the human thyroid Page 21