PGY452 552 Human Physiology Endocrinology 11 Cortisol the slow stress response A Adrenal anatomy cortisol biosynthesis B Signaling mechanism C Role in stress metabolism D Regulation E Role as a drug pathophysiology Let s talk stress Adrenal hormones respond to stress What is stress A state of real or perceived threat to homeostasis Physiologic responses Metabolic Immune CNS integration Can be harmful 2 Humans are exposed to many stresses Studying for Endocrinology exams Often 1 stress Neurogenic Systemic Integrated response Endocrine system maintains homeostasis Often down regulates stress response Homeostasis Emotional depression Fear Thirst Hypothermia Starvation hypoglycemia Physical exertion exertion Infection Injury Injury 3 Adrenal hormones Cortisol Steroid Glucocorticoid Regulates metabolism Aldosterone Steroid Mineralocorticoid Regulates blood ion balance Androgens Epinephrine HN CH3 CH2 HO CH OH OH 4 Anatomy of the adrenal gland Capsular artery Adrenal gland capsule Cortisol Zona glomerulosa kidney Z fasciculata Z reticularis Androgens Medulla The adrenal cortex is the Zonas glomerulosa fasciculata and reticularis STEROIDS made in CORTEX Aldosterone Epinephrine Medullary vein 5 Cortisol synthesis signaling Stepwise synthesis Modifies transcription 6 Steroid synthesis starts with cholesterol LDL mobilization LDL receptor Cholesterol ester in lipid droplets Pregnenolone StAR Steroid acute regulatory protein Cytochrome P450SCC Side Chain Cleavage 7 Cortisol synthesis by multiple pathways in the Zona fasciculata Progesterone Pregnenolone 21 hydroxylase 3 hydroxysteroid dehydrogenase 17 hydroxylase 11 deoxycorticosterone corticosterone inactive Cortisol 11 hydroxylase 17 hydroxypregnenolone 17 hydroxyprogesterone 11 deoxycortisol 8 Cortisol is a steroid therefore we know something about it Passes through membranes Not soluble Secretion not necessary Sequestration not possible Transport protein Transcortin Clearance requires chemical modification Long half life 90 min High concentration 0 7 M many targets Type I nuclear receptor inside cells 9 Cortisol signaling Type I nuclear hormone receptor Transcortin Cortisol Conformational change nuclear localization Transcriptional regulation GGTACANNNTGTTCT Glucocorticoid response element 4000 in the human genome Classical mechanism what the text book shows 10 Cortisol activation of transcription Coactivator proteins Histone acetyl transferase HAT Heterochromatin transcriptionally silent Histones DNA Euchromatin transcriptionally active GRE HAT Pol II General transcription factors RNA polymerase 2 11 Cortisol repression of transcription Critical mechanism Key effect of cortisol inhibit transcription of inflammatory genes corepress or HAT T HA II HDAC Po l 12 Glucocorticoid receptors remodel chromatin Transcriptional viability is determined by histone acetylation state Activation vs GCR Cortisol complex repression HATs HDACs Other transcription factors Full story very complex Large scale transcriptional modulation Long term Outlive cells Lifetime 13 Now are you stressed and you don t even know what cortisol does 14 Cortisol mediates the slow stress response Metabolic Cardiovascular Cardiac output Red blood cell production LH FSH reproduction GH TSH ECF Calcium Excretion in kidney GI uptake Bone resorption Kidney Conserves water Anterior Pituitary Psychological Fast response by epinephrine 15 Best known response Homeostasis of inflammatory immune response Immune system responses to injury stress First line of defense inflammation Synthesis of prostaglandins Local defense response clotting swelling pain Inhibits infection or bleeding Can result in runaway immune response out of proportion to insult Cortisol inhibits response homeostasis Cortisol slow inflammation fast 16 Cortisol ensures glucose for the CNS Amino Acids Liver is key gluconeogenesis glycogenesis I ATP os ph ox Metabolic state not important Often opposes insulin EXCEPT in glycogenesis 2 Glycogen I Citric acid cycle CoA O Pyruvate 17 Supports liver glucose synthesis protein catabolism amino acids for GNG HSL NEFA for energy GNG GLUT4 glucose use Insulin transcription secretion NEFA Amino Acids 4 Insulin 4 HSL Pol II TA G Proteins Muscle Lipid Droplet Adipose Pancreas 18 Regulation through HPA Corticotropin releasing hormone CRH 41 amino acid peptide Stimulated by stress sensors in the CNS G s coupled cAMP PKA Hypothalamus CRH Adrenocorticotropin ACTH Corticotrophs 39 amino acid peptide From 241 amino acid proopiomelanocortin POMC G s coupled ACTH Anterior Pituitary 19 CRH ACTH increase cortisol synthesis Ca2 CRH s AC LDLR LDL receptor Z Fasciculata adrenal cortex ACTH s AC cAMP cAMP PKAii P cAMP Size number of adrenal cortex cells cAMP PKA cAMP PKAii cAMP Ca2 cAMP cAMP cAMP cAMP PKAii PKA PKAii StAR ACTH P Pol II Corticotroph SCC 20 CRH ACTH increase cortisol synthesis ACTH has multiple effects in the adrenal cortex all activated by PKA o It phosphorylates P450SCC and StAR to increase their activity directly o It also induces a transcriptional program that Increases transcription of StAR P450SCC the other steroidogenic enzymes to increase cortisol synthesis Increases LDL receptor transcription allowing more uptake of cholesterol precursor Increase the size hypertrophy and number of adrenal cortex cells 21 Circadian Neurogenic e gativ p ne t loo back Shor feed CRH thirst Antidiuretic hormone posterior pituitary CRH stress inputs are very strong can overcome ACTH and cortisol negative feedback during extreme stress Inputs HPA feedback Systemic ADH ACTH long loop negative feedback ACTH Adrenal Gland 22 its own circadian system on no t gh ni id m on no Circadian Rhythms are an important regulator of cortisol Cortisol peaks at 8 AM Reason not understood ACTH is pulsatile Pulses are ahead of cortisol peaks CRH lowest at 3 PM 6 PM 9 PM 3 AM 6 AM 9 AM night High stress can Cortisol ACTH overcome The adrenal gland has circadian effects 23 Cortisol in medicine As a drug corticosteroids or glucocorticoids Disease states 24 You have to get this right cortisol ACTH CRH cortisol ACTH CRH Unless pathophysiology either Defeats feedback Is outside of the feedback Or else 1 You will never understand endocrine disease 2 You will miss the 2 4 questions on the test that I can ask many ways 25 Corticosteroids as drugs Effective anti inflammatory Control swelling pain caused by runaway inflammation Treat allergies and autoimmune diseases 0 5 of US population on chronic corticosteroid therapy That