7 Introduction to Endocrine System

• Endocrine System


  A collection of glands whose function is to regulate multiple organs within the body to: 1. meet the growth & reproductive needs of the organism 2. respond to fluctuations within the internal environment, including various types of stress
• Endocrine Glands


  • Glands that are solely dedicated to an endocrine function, involving synthesis & secretion of bioactive hormones
• Partly Endocrine Structures of the Body


  • Nerve endings- Ach, EP
  • GIT- Gastrin, CCK, Secretin
  • Kidneys- Erythropoietin, Vit. D
  • Placenta- HCG
  • Heart- ANP
  • Skin- Melanin
  • Liver- IGF or Somatomedin, Vit. D
  • Pineal gland- Melatonin
  • Hypothalamus- thirst center, satiety center (main ganglion of autonomics) & temperature regulation

  
• Hormones


  Maintain homeostasis by regulating processes such as development, metabolism, & reproduction. Maintain homeostasis through feedback loops. Act slowly relative to the nervous system.
• Hormonal Regulation System


  1. Biosynthesis

  2. Transport

  3. Metabolism

  4. Excretion

  5. Effector

  
• Endocrine


  Hormones transported in the blood
• Paracrine


  Tissue hormones, target cells are in the immediate vicinity of the glandular cells that produce them, e.g. GI hormones, Insulin

  
• Autocrine


  Signal substances also pass effects back to the cells that synthesize them, e.g. tumor cells
• Hormonal Dynamics


  Hormones circulate in the blood at very low concentration (10-12 to 10-7 mol/L), but these change periodically
• Event-regulated


  Increase in hormone as a response to an increase in another chemical, e.g. glucose-mediated increase in insulin

  
• Closed-loop Feedback Control


  Depends on the number of occupied receptors on the responsive cell, when cells are continually occupied, they reduce the number of receptors to avoid having the metabolic effects overstimulated (down-regulation)
• General Classes of Hormones


  • Proteins and Polypeptides
  • Derivatives of the Amino Acid Tyrosine/Biogenic Amine
  • Steroids
• Protein Hormones


  Receptor: membrane receptors, soluble in body fluids (exception IGFs and growth hormone), unbound form, short biological half-lives, excretion: blood primarily by endocytosis and lysosomal degradation of hormone-receptor complexes
• Peptide Hormone Synthesis


  1. In the nucleus, primary gene transcript, a messenger RNA precursor molecule, undergoes excision of introns, splicing of exons, capping of the 5' end, & addition of poly-a tail

  2. Resultant mature messenger RNA enters the cytoplasm, where it directs the synthesis of a preprohormone peptide sequence on ribosomes

  3. N-terminus signal is removed, resultant prohormone is transferred vectorially into the endoplasmic reticulum

  4. The prohormone undergoes further processing & packaging in the Golgi apparatus

  5. After final cleavage of the prohormone within the granules, they contain the hormone & copeptides ready for secretion by exocytosis

  
• Polypeptide Hormones


  • Hypothalamic releasing & inhibiting hormones (EXCEPT for dopamine or the prolactin inhibitory hormone)
  • Posterior pituitary & Anterior pituitary hormones
  • Parathyroid hormone (PTH)
  • Calcitonin
  • Insulin
  • Glucagon

  
• Biogenic Amine Hormones


  • T3 & T4 from thyroid gland
  • Catecholamine (Epi, NE)
  • Prolactin Inhibitory Factor (Dopamine)
• Steroid Hormone Categories


  • Progestins
  • Mineralocorticoids
  • Glucocorticoids
  • Androgens
  • Estrogens
• Steroid Hormones


  Synthesized by a series of enzymatic modifications of cholesterol, and a cyclopentanoperhydrophenanthrene ring (ora derivative thereof) serves as their core. Hydrophobic (nonpolar), receptor: intracellular (cytoplasm), bound to albumin or specific transport proteins (SHBG, CBG), excretion: liver (glucuronide & sulfate conjugation) the biliary excretion

  
• Peripheral Conversion (of active steroid hormones)

  1. A more active but similar class of hormone 2. A less active hormone that can be reversibly activated by another tissue 3. A different class of hormone
• Steroid Hormones


  • Sex hormones (Estrogen, Progesterone, & Testosterone)
  • Adrenal Cortical Hormones (Cortisol, Aldosterone, Androgens)
  • Different forms of VITAMIN D
• Hormone Receptor Types


  • Cell membrane receptors (Ion channel linked receptors & G-protein coupled receptors)
  • Intracellular receptors (Cytoplasmic receptors- Steroid, Nuclear receptors- T3 & T4)
• Hormones that use Adenylyl Cyclase cAMP System


  • CRH, GHIH
  • ACTH, FSH, LH, TSH
  • HCG, PTH, Calcitonin
  • ADH (V2 receptors in the DCT)
  • Catecholamines ( receptors)
  • Angiotensin II (epithelial cells in renal tubules)
  • Glucagon

  
• Hormones that use Phospholipase C as the 2nd messenger system


  • GnRH, GHRH, TRH
  • Oxytocin
  • ADH (V1 receptor in the vascular smooth muscle)
  • Catecholamines (α receptor)
  • Angiotensin II (vascular smooth muscle)

  
• Calcium-Calmodulin 2nd Messenger System


  Present in the visceral smooth muscle
• Nuclear Thyroid Hormone Receptor
• Example of Membrane Receptor
• Second Messenger


  Intracellular chemical signals, concentration is regulated by hormones, NTA's, & other extracellular signals, has short half-life, Examples: cAMP, cGMP, Ca++, IP3, DAG, and Nitrogen monoxide

  
• cAMP


  Metabolism: adenylate cyclase activity is regulated by G proteins (Gs and Gi), which in turn are controlled by extracellular signals via 7-helix receptors (Ca+-calmodulin also activates specific adenylate cyclses). Action: cAMP is an allosteric effector of protein kinase A (PK-A)

  
• Inositol 1,4,5-triphosphate and DAG


  Gq G proteins activate phospholipase C. This enzyme creates two second messengers from the double-phosphorylated membrane phospholipid phosphatidylinositol bisphosphate (PlnsP2): 1. Inositol 1,4,5-triphosphate (InsP3), which is hydrophilic, and 2. Diacylglycerol (DAG), which is lipophilic. IP3 migrates to the endoplasmic reticulum (ER), where it opens Ca2+ channels that allow Ca2+ t flow into the cytoplasm. By contrast, DAG, which is lipophilic, remains in the membrane, where it activates protein kinase C, which phosphorylates proteins in the presence of Ca2+ ions and thereby pass the signal on.
• Nitrogen Oxide (NO)


  Toxic, short live gas molecule, found as a signaling molecule in the CVs, binding of Ach to the G protein causes the release of NO in the vascular endothelial cells that causes relaxation of the BV smooth muscle (vasodilation)
• Mechanism of Action of Hormones


  1. Hormone-Receptor Interaction

  2. Up-regulation

  3. Down-regulation

  4. Negative Feedback

  5. Positive Feedback

  6. Hormone-binding proteins
• Plasma Protein Hormone Binding


  • Albumin- Multiple lipophilic hormones
  • Transthyretin- Thyroxine (T4)
  • Transcortin- Cortisol, aldosterone
  • Thyroxine-binding globulin- Triiodothyronine (T3), T4
  • Sex hormone-binding globulin- Testosterone, Estrogen
• Pregnancy (Euthyroid or normol cortisol)
• Protein-bound hormone


  Extends half-life of bound hormone, levels often increases in pregnancy
• Plasma Protein Hormone Binders


  • Albumin
  • Transthyretin
  • Transcortin
  • Thyroxine-binding globulin
  • Sex hormone-binding globulin
• Albumin


  Binds multiple lipophilic hormones
• Transthyretin


  Binds thyroxine (T4)
• Transcortin


  Binds cortisol, aldosterone
• Thyroxine-binding globulin


  Binds triiodothyronine (T3), T4
• Sex hormone-binding globulin


  Binds testosterone, estrogen