Endocrine I IntroMelatGCMBS_StudentAnswer_11.11.24 PDF

Dawn Owens, Ph. D. Adapted from Dr. Yuri Zagvazdin lecture Introduction to the Endocrine System Principles of Endocrinology Pineal Gland and Melatonin Cortisol and Adrenal Gland...

Dawn Owens, Ph. D. Adapted from Dr. Yuri Zagvazdin lecture Introduction to the Endocrine System Principles of Endocrinology Pineal Gland and Melatonin Cortisol and Adrenal Gland Lecture highlights: 1. Hormones, general characteristics 2. Melatonin 3. Cortisol as a representative of glucocorticoids (GC) The adrenal peripheral clock: Glucocorticoid and the circadian timing system Son, Gi Hoon, Frontiers in Neuroendocrinology, Volume 32, Issue 4, 451-465 Copyright © 2011 Elsevier Inc. Ch. 7 Silverthorn, D.U. Human Physiology. An integrated Approach. 2015, 8th edition (or older). Pearson Education Inc. OBJECTIVES 1 Explain the criteria that make a chemical signal a hormone and what the cellular mechanism of action it has. 2 List 3 chemical classes of hormones with examples of each. 3 Review endocrine cells’ storage, release, receptor locations, and cellular mechanism of action of peptide and steroid hormones. 4 Describe the role of the nervous system in endocrine reflexes. 5 Compare the structure and function of the anterior and posterior pituitaries 6 List the six anterior pituitary hormones, the hormones that control their release, and their primary targets. 7 Compare long-loop negative feedback signaling for anterior pituitary, insulin, and parathyroid hormones. 8 Name common endocrine pathologies and explain how negative feedback can determine problem location. Endocrinology – study of the production and action of hormones Hormones – molecules that serve as chemical signals which control physiological functions of tissues and homeostasis. Traditional definition of a hormone-chemical secreted by a cell or group of cells into the blood for transport to a distant target, where it exerts its effect at very low concentrations (nanomolar [10-9] to picomolar [10-12] range)  Hormones regulate: - energy utilization and storage - water and electrolyte balance - body temperature - growth, maturation and development  Glands of Endocrine System Anatomy Summary: Hormones Fig. 7.2 – majority Characteristics of hormones: 1. Site of production 2. Target tissue 3. Physiological actions 4. Chemical structure 5. Stimuli for release and regulation 6. Intracellular mechanisms & 2nd messengers 7. Endocrine pathology Types of chemical signaling: Local – autocrine – paracrine Distant Neurons – endocrine GF, growth factor. – neurocrine Development, Molecular Biology, and Physiology of the Prostate Ross, Ashley Evan, MD, PhD, Campbell-Walsh Urology, 102, 2393-2424.e9 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved.  Other signaling molecules: Cytokines – usually local acting peptides released by the cells of immune system; Eicosanoids - lipid-derived locally acting molecules Both are important in growth, development, immune responses  What is the difference between cytokines and hormones? Site of Target Timing of production production Hormones glands or specific cells Produced and specialized stored in cells endocrine cell Cytokines and many cells in broad Made on spectrum of demand Growth Factors the tissue cells Sometimes distinction between hormones and cytokines is blurry (erythropoietin-molecule that controls red blood cell production)  Lipid and Water Soluble Hormones Tyrosine & Proteins and Peptides Steroids Tryptophan (3-200 amino acids) (Cholesterol) Derivatives Catecholamines: ADH Androgens Norepinephrine* Angiotensin Testosterone Epinephrine* Renin Dopamine* Insulin Estrogens Glucagon Estradiol Indolamines: Calcitonin Melatonin** Parathyroid Hormone Glucocorticoids ----------------------- Oxytocin Cortisol Thyroxine (T4)* Somatostatin Mineral - Triiodothyronine Thyrotropin - TSH corticoids (T3)* Adrenocorticotropin - ACTH Aldosterone ----------------- Growth Hormone * - tyrosine Prolactin Vitamin D ** - tryptophan Luteinizing Hormone - LH Progesterone derivatives Follicle stimulating hormone- FSH -------------------- Braun color = lipid soluble hormones; blue color = water soluble hormones  Characteristics of Hormones Characteristics Peptides Catecholamines Thyroid Steroids and Soluble: hormones Vitamin D in plasma Yes Yes No No in lipid no no yes yes Plasma binding no no yes yes proteins *Half - life short very short very long long (hours) (minutes) (seconds) (days) Receptors cell surface cell surface nuclear nuclear/ intracellular/surface Mechanisms second second transcription transcription of action messengers messengers and translation and translation *Half-life (t1⁄2) is the time required for the amount of something to fall to half its initial value.  Fractions of circulating testosterone in the blood Testosterone (T) = steroid = lipophilic hormone The majority of circulating T is The combination of bound to serum proteins: free and weakly about 60% to albumin, and about bound to albumin T 40% to sex hormone–binding is referred to as protein bioavailable (SHBG also known as testosterone testosterone. binding globulin) Only about 2% of circulating T is free of protein binding. Low plasma level of free T is much more Testicular Disorders Matsumoto, Alvin M., Williams Textbook of Endocrinology, Chapter 19, 694-784 likely to be associated with male reproductive Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. problems than low plasma total T.  What hormones stay in the body longer? A) Fat soluble B) Water soluble  Receptors for Hormones: - cell membrane proteins (hydrophilic ligands) - intracellular cytosolic or nuclear (lipophilic ligands) capillary Binding protein peptide catecholamine Steroid or another lipophilic hormone Cell membrane receptor Intracellular receptor  Receptors for Hormones Lipophilic signal molecules diffuse through the cell membrane and bind to cytosolic Extracellular ligands Cell or nuclear receptors (mostly lipophobic) membrane bind to cell membrane receptors and initiate rapid response (seconds – minutes) Slow (hours) response to intracellular receptor binding involves altered gene activity  Slow change in basal metabolic rate caused by a single large dose of thyroxine that binds to intracellular receptors Thyroid Metabolic Hormones ${parentCitation.authFull}, Guyton and Hall Textbook of Medical Physiology, CHAPTER 76, 907-919 Copyright © 2011 Copyright © 2011, 2006, 2000, 1996, 1991, 1986, 1981, 1976, 1966, 1961, 1956 by Saunders, an imprint of Elsevier Inc. Cell membrane receptors Ion channel-linked receptors (ionotropic) G protein coupled or 7 transmembrane spanning helical receptors (e.g. metabotropic for glutamate) Enzyme-linked receptors Signal Transduction, Membrane Receptors, Second Messengers, and Regulation of Gene Expression Koeppen, Bruce M., MD, PhD, Berne & Levy Physiology, CHAPTER 3, 34-49 Copyright © 2010 Garland Science  STRUCTURE AND ACTIVATION OF THE GROWTH HORMONE RECEPTOR Enzyme linked receptor Plasma Membrane Receptors Pollard, Thomas D., MD, Cell Biology, Chapter 24, 411-423 Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved.  Two Major Types of G Protein– Coupled Receptors More than a 1000 different receptors activate membrane-bound G proteins. Upon ligand binding, G proteins subunits (e. g. α) can interact with other membrane-bound proteins (e.g. adenylyl cyclase/phospholipase C) that turn on second messenger systems. The second messengers (e.g. cyclic adenosine monophosphate cAMP) activate the effector proteins (e.g. protein kinase A = PK-A) Membrane Transport Mulroney, Susan E., PhD, Netter's Essential Physiology, Chapter 2, 12-22 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved.  The G protein- coupled 1. Signal adenylyl molecule binds cyclase-c-AMP to G protein– system linked receptor, which activates the G protein. 2. G protein turns on 3. Adenylyl cyclase adenylyl cyclase, an converts ATP to cyclic amplifier enzyme. AMP (second messenger). 4. cAMP activates protein kinase A. 5. Protein kinase A phosphorylates other proteins, leading to a cellular response. The ADP, adenosine diphosphate; ATP, adenosine triphosphate. cAMP, cyclic adenosine monophosphate. Introduction to Endocrinol ogy Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 75, 925-937 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved. The cell membrane phospholipid second messenger system G protein activates phospholipase C, producing two second messengers: diacylglycerol (DAG) that activates protein kinase C and phosphorylation of intracellular proteins, and inositol triphosphate (IP3) that increase intracellular calcium entry. Both are created from the cleaving of PIP2’s lipid tail portion (DAG) from the Phosphate head group (IP3) PIP2 = phosphatidylinositol biphosphate Introduction to Endocrinology Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 75, 925-937 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved.  Amplifier enzymes and second messengers Amplifier Activated by Converts To a second Enzyme messenger Adenylyl G protein ATP cAMP cyclase coupled receptor Guanylyl Nitric oxide GTP cGMP cyclase Phospholipase G protein Membrane DAG and IP3 C coupled phospholipids receptor IP3 = inositol trisphosphate, DAG = diacylglycerol  G protein and second messenger control of cellular effector systems AA = arachidonic acid How drugs act : Molecular aspects Ritter, James M., DPhil FRCP HonFBPhS FMedSci, Rang & Dale's Pharmacology, 3, 23-51 Copyright © 2020 © 2020, Elsevier Ltd. All rights reserved.  Which of the following is NOT true of ANSWER! G-protein coupled receptors? The cell membrane phospholipid second messenger system G protein activates phospholipase C, producing two second messengers: diacylglycerol (DAG) that activates protein kinase C and phosphorylation of intracellular proteins, and inositol triphosphate (IP3) that increase intracellular calcium entry. Both are created from the cleaving of PIP2’s lipid tail portion (DAG) from the Phosphate head group (IP3) PIP2 = phosphatidylinositol biphosphate Introduction to Endocrinology Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 75, 925-937 Copyright © 2016 Copyright © 2016 by Elsevier, Inc. All rights reserved.  Peptide hormones & 2nd messengers* cAMP* IP3* cGMP* ADH (V2 receptors – ADH (V1 receptors- ANP (natriuretic peptide aquaporins) vasoconsriction) receptors - vasodilation) Adrenaline (1,2) Adrenaline (1) Nitric oxide ACTH (pituitary) Angiotensin II MSH (pituitary) Oxytocin TSH (pituitary) TRH (hypothalamic) LH and FSH CRH (hypothalamic) Calcitonin Parathyroid hormone Glucagon  A hormone can exert its action via different receptors and second AVP = arginine AVP messengers AVP vasopressin V1 receptors activation V1 V2 Gq V2-receptor activation via involves Gq protein linked β with phospholipase C α α, β, γ , Gs protein linked to Gs β γ G protein adenylyl cyclase-cyclic α pathway. γ subunits adenosine monophosphate Phospholipase C (cAMP) pathway Adenylyl Cyclase PIP2 DAG + IP3 ATP cAMP Kinase C Kinase A Calcium release Water Channel Ca++ Reabsorption (aquaporin) Vasoconstriction H2 O insertion Ca++  Hormone release can be controlled by… a. Circadian rhythms b. Stage of development c. Physiological and emotional reactions to environment d. Positive feedback - self- reinforcing e. Negative feedback - self-limiting  Melatonin, Hormone of the Pineal Gland Melatonin, a derivative of amino acid tryptophan, has serotonin as an intermediate product CSF generation by pineal gland results in a robust melatonin circadian rhythm in the third ventricle as a unique light/dark signal Tan, Dun-Xian, Medical Hypotheses, Volume 86, 3-9 Copyright © 2015 Elsevier Ltd  DMLO = dim light melatonin onset Plasma melatonin circadian rhythms in humans Plasma level of melatonin, the “hormone of darkness”, is associated with a decrease in body temperature How to assess circadian rhythm in humans: A review of literature Hofstra, Wytske A., Epilepsy and Behavior, Volume 13, Issue 3, 438-444 Copyright © 2008 Elsevier Inc. Pineal gland receives signals from the suprachiasmatic nuclei (SCN) in the hypothalamus via superior cervical ganglion (SCG) Pineal gland or epiphysis Pinealocytes, specialized neurosecretory cells of the gland Melatonin: Protection against age-related cardiac pathology Favero, Gaia, Ageing Research Reviews, Volume 35, 336- 349 Copyright © 2016 Elsevier B.V. Darkness INSOMNIA (NARCOLEPSY)-RELATED DISORDERS Lee-Chiong, Teofilo, Pharmacology and Therapeutics: Principles to Practice, CHAPTER 57, 849-855 Copyright © 2009  Melatonin acts as an endogenous synchronizer Reprinted from Claustrat et al., 1998 ; copyright 1998 with permission from IOS Press. Melatonin: Physiological effects in humans Claustrat, B., Neurochirurgie, Volume 61, Issue 2-3, 77-84 Copyright © 2015 Elsevier Masson SAS Melatonin is involved in or modulates: sleep control circadian rhythms immune system  What is the general relationship between body temperature and melatonin? A) As light increases, melatonin increases, body temp increases B) As light increases, melatonin decreases, body temp decreases C) As light decreases, melatonin increases, body temp increases. D) As light decreases, melatonin increases, body temp decreases E) As light decreases, melatonin decreases, body temp decreases Adrenal Gland and its Hormones Cortisol: its Effects, Regulation and Clinical Correlations Images Addison Disease Copyright © ExitCare® Patient Information ©2015 ExitCare, LLC Ch. 23 Silverthorn, D.U. Human Physiology. An integrated Approach. 2015, 8th edition (or older). Pearson Education Inc. Adrenal Gland Adrenal Glands & Hormones: 1. Mineralcorticoids (aldosterone) 2. Glucocorticoids (cortisol) 3. Weak androgens (DHEA)* 4. Catecholamines (epinephrine, norepinephrine and dopamine) *DHEA = dehydroepiandrosterone The Adrenal Gland ${parentCitation.authFull}, Endocrine and Reproductive Physiology, 7, 147-176 Copyright © 2013 Copyright © 2013 by Mosby, an imprint of Elsevier Inc.  Weak androgens can be converted to main sex steroids Rate limiting step Weak androgen Endocrine physiology Costanzo, Linda S., PhD, Costanzo Physiology, CHAPTER 9, 399-464 Copyright © 2022 Copyright © 2022 by Elsevier Inc. All rights reserved.  Steroid hormones are derivatives of cholesterol Weak androgen Adrenocortical hormones Campbell, Iain, Anaesthesia and Intensive Care Medicine, Volume 12, Issue 10, 461-464 Copyright © 2011  Most molecules of steroid Steroid hormones are hormones are bound to lipophilic! proteins in plasma. Lipophilic ligands diffuse through the cell membrane and bind to intracellular receptors: Slow (hours) response to intracellular receptor cytosolic or nuclear, in binding involves altered gene activity case of cortisol – to glucocorticoid receptor Cortisol – the main glucocorticoid (corticosterone is another one) Main role - response to stress Effects: I. Metabolic - Increase in blood glucose – - gluconeogenesis in the liver - protein catabolism (muscles) - decreased glucose uptake and protein synthesis (suppresses anabolic effect of growth hormone GH); - increased protein breakdown and build up of amino acids in the blood (source for glucose synthesis)  Cortisol II. Anti-inflammatory action - decrease of cytokine, antibody and histamine production, immunosuppressive effect (suppression of synthesis of prostaglandins and other inflammatory substances) Other Effects of Cortisol Negative Ca++ balance:  Ca++ GI absorption &  renal excretion, promotes bone decalcification Has Mineralcorticoid activity (i.e. aldosterone like action-like maintaining salt balance in the body) Cortisol Hypersecretion: effects?  What do you expect if cortisol levels are high in the body? ANSWER! Cortisol – the main glucocorticoid (corticosterone is another one) Main role - response to stress Effects: I. Metabolic - Increase in blood glucose – - gluconeogenesis in the liver - protein catabolism (muscles) - decreased glucose uptake and protein synthesis (suppresses anabolic effect of growth hormone GH); - increased protein breakdown and build up of amino acids in the blood (source for glucose synthesis)  Endocrine Pathology: 1. Hormone excess 2. Hormone deficiency 3. Abnormal hormones 4. Abnormal hormone release, transport or metabolism 5. Resistance to hormone action  Hypercortisolism (Cushing’s syndrome or disease) Symptoms: 1. Hyperglycemia (may promote diabetes) 2. Muscle wasting (thin extremities, protein catabolism, negative protein balance) 3. Osteoporosis (negative Ca++ balance) 4. Na+ retention, hypertension, K+ loss (kidney) 5. Emotional disturbances, depressed mood (psychosis) 6. Deposition of fat (trunk, “moon” face)  Restart Hypothalamus and anterior pituitary Ch. 23 Silverthorn, D.U. Human Physiology. An integrated Approach. 2015, 8th edition (or older). Pearson Education Inc. gland control release of cortisol Midsagittal section of the brain Neurophysiology Costanzo, Linda S., PhD, Costanzo Physiology, CHAPTER 3, 69 -118 Copyright © 2022 Copyright © 2022 by Elsevier Inc. All rights reserved.  Hypothalamic neurons control release of hormones from the anterior pituitary gland via the hypothalamo-hypophyseal portal vascular system Hypothalamic hormones are released in the primary capillary Two capillary plexus of the portal system networks in series: primary and secondary Superior hypophyseal capillary artery plexuses = Hypophyseal portal vein hypophyseal portal system (Modified from Aron DC, Findling JW, Tyrrell JB, et al: Hypothalamus and pituitary. In Greenspan FS, Strewler GJ, editors: Basic and Clinical Endocrinology, 5th ed., Norwalk, CT, 1997, Appleton & Lange.) Hypothalamus-Pituitary Complex White, Bruce A., PhD, Endocrine and Reproductive Physiology, 5, 99-128 Copyright © 2013 Copyright © 2013 by Mosby, an imprint of Elsevier Inc.  supraoptic (SON) and Hypothalamic neurons: paraventricular (PVN) nuclei control release of tropic anterior release ADH and oxytocin pituitary gland hormones Hypothalamic hormones (releasing factors) stimulate various “trophs” or “tropes”, cells of the anterior lobe of the pituitary gland, to produce tropic hormones. Anterior pituitary is also known as ADH or adenohypophysis. (neurohypophysis) AVP and oxytocin (From Carroll RG. Elsevier’s Integrated Physiology. Philadelphia: Elsevier; 2006.)Endocrinology Pedigo, Ryan A., Crush Step 1, 9, 273-317 Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Cortisol secretion depends on stimuli from the hypothalamus and anterior pituitary Hypothalamic neurons release CRH CRH Hypothalamic Hormone: corticotropin + releasing hormone (CRH) Cortico- Anterior Pituitary Cells trophs with receptors for CRH + ACTH = adrenocorticotropic ACTH Released Tropic Hormone hormone + (ACTH) stimulates the cells of the Primary Gland (i.e. Other Endocrine Disorders of Pregnancy Adrenal adrenal gland) to secrete Nader, Shahla, MD, Creasy and Resnik's Maternal-Fetal Medicine: Principles and Gland their hormone (ex: cortisol) Practice, 61, 1038-1058.e4 Copyright © 2014 Cortex Copyright © 2014, 2009, 2004, 1999, 1994, 1989, + 1984 by Saunders, an imprint of Elsevier Inc Cortisol  Circadian rhythm affects cortisol secretion Peak of cortisol secretion = morning Pituitary Tumors : Diagnosis and Management Muh, Carrie R., Principles of Neurological Surgery, Chapter 40, 621-644 Copyright © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. Hypothalamic–Pituitary– Adrenal Axis & Regulation of Cortisol Secretion: Plasma ACTH High blood cortisol 1. Corticotropin releasing hormone (CRH) stimulates secretion of level suppresses adrenocorticotropic hormone CRH and ACTH (ACTH) production (- negative feedback) 2. ACTH is released from the anterior Plasma pituitary gland into the blood and cortisol maintains circulatory level of cortisol Dinsen, Stina, European Journal of Internal Medicine, Volume 24, Issue 8, 714-720 Copyright © 2013 European Federation of Internal Medicine.  Adrenal Gland Atrophy in Addison’s disease Normal gland Hyperplasia in Cushing’s disease The Endocrine System Klatt, Edward C., MD, Robbins and Cotran Atlas of Pathology, Chapter 15, 387-408.e3 Copyright © 2015 Copyright © 2015, 2010, 2006 by Saunders, an imprint of Elsevier Inc. Hypercortisolism: Moon Face & other features Endocrine System Buja, L. Maximilian, MD, Netter's Illustrated Human Pathology, Chapter 12, 411-440 Copyright © 2014 Copyright © 2014, 2005 by Saunders, an Moon face in Cushing's syndrome. imprint of Elsevier Inc. The adrenal glands Aspinall, Sebastian, Endocrine Surgery, 3, 70-97 What structures control cortisol secretion? Copyright © 2014 Fifth edition © 2014 Elsevier Limited. All rights reserved. Pituitary, tumors, adrenal itself  Hypocortisolism! Symptoms: 1. Hypoglycemia 2. Rapid fatigue and inability to withstand stress 3. Na+ loss, hypotension, K+ retention (aldosterone↓) 4. Increased skin and oral mucosa pigmentation NOTE- Addison’s disease is an eponymic name for hypocortisolism.  JFK had this disease Low cortisol Low aldosterone Anorexia, weakness, hypoglycemia & fatigue Gastrointestinal disturbances, vomiting Loss of weight, dehydration Low blood pressure, hypovolemia Hyperkalemia(K+ ) & hyponatremia(Na+ ) By Stoughton, Cecil (Cecil William), 1920-2008, Photographer - U.S. National Archives and Records Administration, Public Domain, https://commons.wikimedia.org/w/index.php?curid=15390965  Addison's disease = damaged adrenal glands: - autoimmune - infections - cancer Chronic adrenal cortical insufficiency, Addison disease, is a clinical syndrome characterized by progressive weakness and fatigue, hypotension, weight loss, skin and mucosal hyperpigmentation, and abdominal problems. Laboratory test results show hyperkalemia, hyponatremia and volume depletion (decrease in mineralocorticoids such as aldosterone). Endocrine System Buja, L. Maximilian, MD, Netter's Illustrated Human Pathology, Chapter 12, 411-440 Copyright © 2014 Copyright © 2014, 2005 by Saunders, an imprint of Elsevier Inc.  Clinical use of glucocorticoids Synthetic forms (dexamethasone, prednisolone) can be used for managing: - allergic reaction; - post operative swelling; - severe muscle inflammation (temporomandibular disorder, facial paralysis) - - oral ulceration and mucosal lesions; - uveitis, tubulointerstitial nephritis, thyroid ophthalmopathy temporal (giant cell) arteritis Side effects: the use of steroids increases risk of bacterial, viral and fungal infection & diabetes  Glucocorticoids Glucose Production Fat redistribution Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor Cohen, Daniel M., Trends in Endocrinology & Metabolism, Volume 28, Issue 7, 531-540 Copyright © 2017 Elsevier Ltd