Thyroid & Growth Axes - Student Copy PDF

Endocrine:Thyroid and Growth Axes and Integration across Axes Annie Newell-Fugate, DVM, MS, PhD  Learning Objectives – Thyroid Identify the steps in the biosynthesis, storage, and secretion of tri- iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the a...

Endocrine:Thyroid and Growth Axes and Integration across Axes Annie Newell-Fugate, DVM, MS, PhD  Learning Objectives – Thyroid Identify the steps in the biosynthesis, storage, and secretion of tri- iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the absorption, uptake, distribution, and excretion of iodide. Explain the importance of thyroid hormone binding in blood on free and total thyroid hormone levels. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in extra-thyroidal tissues. Describe the physiologic effects and mechanisms of action of thyroid hormones. Understand the causes and consequences of a) over- secretion and b) under-secretion of thyroid hormones. Explain what conditions can cause an enlargement of the thyroid gland. The Thyroid is a Lobed Gland Below the Larynx that Regulates Metabolism Fig. 19-1, p. 666 Fig. 19-3, p. 669 Table 18-3 p668 8th ed. GPCR 7-transmembrane receptor signaling TRH binds to this sort of receptor on the pituitary to stimulate release of TSH Fig. 4-26, p. 126 7-transmembrane receptor signaling TSH binds to this sort of receptor on the thyroid to stimulate the release of T3/T4 Fig. 4-25, p. 125  Thyroid Follicular Cells Surround A Colloid- Filled Lumen C cells produce Calcitonin, involved in Follicular cells calcium balance produce T3 and T4 thyroid hormones Colloid= extracellular storage site for Thyroid Hormone Fig. 19-1, p. 666  Follicular cells produce 2 iodine-containing thyroid hormones derived from tyrosine: T4 (Thyroxine) and T3 (Tri-iodothyronine) (Tetra-iodothyronine) Synthesis, storage, and secretion of thyroid hormone into circulation Fig. 19-2, p. 667 Synthesis, storage, and secretion of thyroid hormone into circulation Fig. 19-2, p. 667  Learning Objectives – Thyroid Identify the steps in the biosynthesis, storage, and secretion of tri- iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the absorption, uptake, distribution, and excretion of iodide. Explain the importance of thyroid hormone binding in blood on free and total thyroid hormone levels. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in extra-thyroidal tissues. Describe the physiologic effects and mechanisms of action of thyroid hormones. Understand the causes and consequences of a) over- secretion and b) under-secretion of thyroid hormones. Explain what conditions can cause an enlargement of the thyroid gland. Iodide is Sequestered by the Follicular Cells Through Active Transport Via NIS (Na-Iodine-Symporter) Follicular Cells Synthesize Thyroglobulin & Secrete It Into the Lumen Thyroid Hormones (T3 & T4) are Synthesized on Thyroglobulin and Stored Within the Colloid TSH Stimulates Follicular Cell Uptake of Colloid and Subsequent Thyroid Hormone Release  Learning Objectives – Thyroid Identify the steps in the biosynthesis, storage, and secretion of tri- iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the absorption, uptake, distribution, and excretion of iodide. Explain the importance of thyroid hormone binding in blood on free and total thyroid hormone levels. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in extra-thyroidal tissues. Describe the physiologic effects and mechanisms of action of thyroid hormones. Understand the causes and consequences of a) over- secretion and b) under-secretion of thyroid hormones. Explain what conditions can cause an enlargement of the thyroid gland. T3 & T4 (Lipophilic) bind to thyroid binding globulin Extra-thyroidal Conversion of T4 to T3 is Critical to Affect Target Tissues  Learning Objectives – Thyroid Identify the steps in the biosynthesis, storage, and secretion of tri- iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the absorption, uptake, distribution, and excretion of iodide. Explain the importance of thyroid hormone binding in blood on free and total thyroid hormone levels. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in extra-thyroidal tissues. Describe the physiologic effects and mechanisms of action of thyroid hormones. Understand the causes and consequences of a) over- secretion and b) under-secretion of thyroid hormones. Explain what conditions can cause an enlargement of the thyroid gland.  T3 and T4 are important regulators of basal metabolic rate Increase the basal metabolic rate Regulates the body’s use of oxygen Energy expenditure Calorigenic (heat-producing) Modulate the rates of many specific reactions Synthesis and degradation of carbohydrate, fat, and protein Sympathomimetic Effects of Thyroid Hormone Similar to the effects produced by the SNS Increases target cell responsiveness to epinephrine and norepinephrine (catecholamines) Causes proliferation of catecholamine receptors in target cells Permissive effect  Increased ⍺ and β Adrenergic Receptor Synthesis Increases Responsiveness to Catecholamines  Stimulating Metabolism  Cardiovascular Effects of Thyroid Hormone Increases heart rate and the force of heart contraction Increases blood pressure Increases body heat Peripheral vasodilation Carry heat to the surface for elimination Razvi et. al. 2018  Effects of Thyroid Hormone on Growth Stimulates GH secretion Promotes the effect of this hormone on increased protein synthesis and skeletal growth Synergistic effect Thyroid-deficient children have stunted growth Excess thyroid hormone does not lead to excess growth Thyroid hormone triggers differentiation of tissues  Learning Objectives – Thyroid Identify the steps in the biosynthesis, storage, and secretion of tri- iodothyronine (T3) and thyroxine (T4) and their regulation. Describe the absorption, uptake, distribution, and excretion of iodide. Explain the importance of thyroid hormone binding in blood on free and total thyroid hormone levels. Understand the significance of the conversion of T4 to T3 and reverse T3 (rT3) in extra-thyroidal tissues. Describe the physiologic effects and mechanisms of action of thyroid hormones. Understand the causes and consequences of a) over- secretion and b) under-secretion of thyroid hormones. Explain what conditions can cause an enlargement of the thyroid gland.  Cretinism: Congenital Hypothyroidism Cretinism Patient 3 mos. post-thyroid gland 7 mos. post-thyroid gland 12 mos. post-thyroid gla Pretreatment extract injection extract injection extract injection Age 18y 8mo Age 18y 11mo Age 19y 3mo Age 19y 8mo Dec 25, 1892 Mar 22, 1893 July 17, 1893 Dec 20, 1893 Height 33.5 in Height 35.5 in Height 37 in Height 37.5 in Cretinism: Global Incidence Causes of Goiter Formation Iodine deficiency Autoimmune disease that stimulates the thyroid gland (Graves Disease) Eating large amounts of soy, brassica vegetables, or peanuts which have antithyroidal compounds in them Smoking causes goiter because compounds in cigarettes decrease iodine uptake Pennmedicine.org  HPT Axis Dysfunction Can Occur In Various Ways Table 19-1, p. 670 Graves Disease: Hyperthyroidism SYMPTOMS due to increased BMR: Exophthalmos Goiter Sweating and poor tolerance to heat Tachycardia Nausea/Diarrhea Weight loss Anxiety/Nervousness Tremor Muscle fatigue  Thyroid Storm: Massive Release of T4 Thyroxine increases catecholamine receptors in tissues Increases cardiac muscle sensitivity to epinephrine Increases tissue metabolic activity Increases cardiac muscle’s metabolic demands which can result in myocardial ischemia Cleveland Clinic  HPT Axis Dysfunction Can Occur In Various Ways Table 19-1, p. 670  Hashimotos Disease: Hypothyroidism SYMPTOMS due to decreased BMR: Weight gain Poor tolerance to cold Fatigues easily Slow, weak pulse Slow reflexes Depression Memory difficulties Ralli et. al. 2020  Euthyroid Sick The patient appears to be hypothyroid but instead has some other underlying illness that is driving the thyroid hormones down Concomitant disease alters T4  T3 conversion rT3 formed The ratio of T3 to rT3 must be determined to diagnose this condition accurately  Learning Objectives – Growth Axis Describe the relationship between growth hormone and the insulin-like growth factors and their binding proteins in regulating growth. Understand the regulation of growth hormone secretion. Identify the roles of hypothalamic factors, glucose, and IGF-I. Identify the target organs or cell types for insulin-like growth factors that account for longitudinal growth. Describe the metabolic and growth-promoting actions of growth hormone. Understand the role of somatostatin in inhibition of both growth hormone and TSH to regulate growth and metabolism Understand the cell signaling defects that lead to specific endocrine diseases in the thyroid and growth axes.  The Hypothalamic (SST) Pituitary Growth (HPG) axis has many inputs and regulators Fig. 18-10, p. 676 Table 18-3 p668  GH Releasing Hormone GPCR 7-Transmembrane Receptor GHRH binds to this receptor to stimulate the release of Growth Hormone from the somatotropes Fig. 4-25, p. 125 GHRH and Somatostatin Regulate GH Production By Stimulating & Inhibiting Adenylyl Cyclase via Gs or Gi to alter cAMP levels SS T Growth hormone signals via the JAK-STAT pathway Growth Hormon One Ligand Molecule e Per Dimeric Receptor IGF-1 and others  IGF- IGF-1 signals via Receptor I= Tyrosine Kinases Fig. 4-21, p. 117 Cross-Phosphorylation Of Non-Receptor Tyrosine Kinases by Growth Hormone Growth Hormo ne Receptor Tyrosine Kinase Dimerization and Cross-Phosphorylation Stimulated by IGF-1 IGF-1 IGF-1  Learning Objectives – Growth Axis Describe the relationship between growth hormone and the insulin-like growth factors and their binding proteins in regulating growth. Understand the regulation of growth hormone secretion. Identify the roles of hypothalamic factors, glucose, and IGF-I. Identify the target organs or cell types for insulin-like growth factors that account for longitudinal growth. Describe the metabolic and growth-promoting actions of growth hormone. Understand the role of somatostatin in inhibition of both growth hormone and TSH to regulate growth and metabolism Understand the cell signaling defects that lead to specific endocrine diseases in the thyroid and growth axes. Fig. 18-10, p. 676 Growth Hormone is Essential for Growth, But Also Impacts Other Metabolic Functions Fig. 18-10, p. 656 IGFs Stimulate Hypertrophy AND Hyperplasia in several tissues IGF-I Stimulates Chondrocyte Proliferation In the Epiphyseal Plate Fig. 18-9, p. 655 Growth Spurts During Childhood – Some Sex Steroid Dependent Males: Testicular Androgen-Dependent Females: Adrenal Androgen-Dependent, Ovarian Estrogen-Dependent - dependent ot gender N Girls Boys Age 11 Age 13 Fig. 18-8, p. 653  Factors Regulating Growth Genetics Fetal: Maternal/Fetal/Placental factors, not including GH (IGFII) Postnatally: Normal levels of growth-influencing hormones (GHRH, GH) Adequate diet (protein, essential amino acids in food intake) Malnourished diets decrease maximum growth potential Excess food intake  obesity, not growth Freedom from chronic disease and environmental stress  Learning Objectives – Growth Axis Describe the relationship between growth hormone and the insulin-like growth factors and their binding proteins in regulating growth. Understand the regulation of growth hormone secretion. Identify the roles of hypothalamic factors, glucose, and IGF-I. Identify the target organs or cell types for insulin-like growth factors that account for longitudinal growth. Describe the metabolic and growth-promoting actions of growth hormone. Understand the role of somatostatin in inhibition of both growth hormone and TSH to regulate growth and metabolism Understand the cell signaling defects that lead to specific endocrine diseases in the thyroid and growth axes.  HPG axis abnormalities manifest differently depending on the age of presentation and axis location affected (GH) GHRH (IGF-1) Fig. 18-11, p. 677 8th ed Progressive development of acromegaly Fig. 18-12, p. 659