Adrenal Cortex - Hormones & Physiology - Student Copy.pptx

Adrenal Cortex: Hormones & Physiology BSMS203: Theme 1, Lecture 10 Oliver G. Steele [email protected] Join at slido.com #1859472 Lecture in Context This lecture will build on … • Steroid hormone mechanism of action • The previous introduction to Cushing Syndrome … by introducing and covering...

Adrenal Cortex: Hormones & Physiology BSMS203: Theme 1, Lecture 10 Oliver G. Steele [email protected] Join at slido.com #1859472 Lecture in Context This lecture will build on … • Steroid hormone mechanism of action • The previous introduction to Cushing Syndrome … by introducing and covering … Introduction to Endocrinolog y • Structure and Series of function of the Endocrin adrenal gland e • Action of Physiolo mineralocorticoid gy You are s and Lectures glucocorticoids here! • Adrenal pharmacology 2 Intended Learning Outcomes To understand adrenal cortical hormone physiology, with special reference to glucocorticoids (cortisol) physiology 3 Outline 1. Structure and Function • Structure, blood supply and region specific functions 2. Glucocorticoid Physiology • Synthesis and mechanism of cortisol • Cortical physiology across health, disease and stress 3. Mineralocorticoid Physiology • Aldosterone synthesis and mechanism of action • Renin-angiotensin-aldosterone system (RAAS) introduction 4. Pathophysiology & Pharmacology • Addison’s Disease, Cushing Syndrome and Addisonian Crisis 4 Structure and function of the Adrenal Gland Section 1 of 4 Blood supply to the adrenal gland Superior adrenal artery Superior adrenal artery arises from the inferior phrenic artery Inferior phrenic artery R L Middle adrenal artery arises from the abdominal aorta. Middle adrenal artery Inferior adrenal artery arises from the renal arteries. Inferior adrenal artery Abdominal aorta 6 Veinous drainage from the adrenal gland Single central vein draining from each adrenal gland Proximity to the renal vein determines drainage R Inferior cava vena Right vein adrenal L Right adrenal vein drains into the posterior of the vena cava Left vein Left adrenal vein enters the left renal vein adrenal Renal vein 7 Different regions of the adrenal gland Capsule – outer connective tissue, no endocrine function Zona glomerulosa – mineralocorticoid production Zona fasciculata – glucocorticoid and androgen production Cortex Zona reticularis – glucocorticoid and androgen production Medulla – epinephrine production Capsule Zona glomerulosa Zona fasciculata Cortex Mineralocortico ids Glucocorticoids Zona reticularis Cortex Medulla Medulla 8 Epinephrine Mineralo- or gluco-corticoid? Both mineralocorticoids and glucocorticoids are derived from cholesterol Presence or absence of the enzyme 17α-hydroxylase determines which is the end-product If absent, processing stops prematurely and only mineralocorticoids can be produced If present, processing continues and favours glucocorticoid production Cortex Zona glomerulosa Zona fasciculata Zona reticularis 9 Mineralocortico ids 17αhydroxylase Glucocorticoids 17αhydroxylase Which layer of the adrenal gland produces mineralocorticoids? A. Zona glomerulosa B. Zona fasiculata C. Sona reticularis D. Medulla Correct Answer: A – Zona Glomerulosa Move to reveal answer 10 Mineralo- or gluco-corticoid? Both mineralocorticoids and glucocorticoids are derived from cholesterol Presence or absence of the enzyme 17α-hydroxylase determines which is the end-product If absent, processing stops prematurely and only mineralocorticoids can be produced If present, processing continues and favours glucocorticoid production Cortex Zona glomerulosa Zona fasciculata Zona reticularis 11 Mineralocortico ids 17αhydroxylase Glucocorticoids 17αhydroxylase Glucocorticoids: Synthesis, Transport & Function Section 2 of 4 Synthesis of Glucocorticoids Presence of 17α-hydroxylase enables the glucocorticoid pathways and androgenic pathways Context & Interest I do not expect you to memorise this entire pathway IMPORTANT: I do not expect you to learn this pathway in its entirety! 13 Diurnal secretion of cortisol Cortisol secretion is pulsatile in nature, and follows a diurnal rhythm • Peak is in the early hours of the morning • Nadir is during the middle of the night Cortisol levels follow ACTH levels by ~2 hours Cortisol secretion sensitive to … • Manipulations of the circadian rhythm (ie, snacking, light, activity etc) • Physical stress • Negative feedback Context & Interest 14 I do not need you to memorise this graph and ACTH - Regulation Hypothalamus Releasing Hormone CRH Pituitary (Anterior) Trophic Hormone - Longloop Inhibitio n ACTH Adrenal Glands Short-loop Inhibition Target Tissue Cortisol 15 Corticotrophin releasing hormone (CRH) is secreted from the hypothalamus The anterior pituitary gland then secretes adrenocorticotrophic hormone (ACTH) ACTH enters circulation then promotes Cortisol secretion from the adrenal cortex Circulating cortisol then prevents it’s own secretion via negative feedback Glucocorticoid Transport Cortisol is a steroid hormone, therefore has a very low water solubility Only 10% of cortisol is actually free - 75% bound to corticosteroid binding globulin - 15% bound to albumin Plasma protein-bound cortisol is considered inactive, only becoming active when free 16 Protein bound Free 90% 10% Inert Active Bound Status Proportion Activity Status Mechanism Cortisol is steroid hormone, so can pass through cell membrane Most abundant intracellular receptor is the heatshock protein 90 (hsp90) Cortisol-hsp90 hormone-receptor complex then enters the nucleus and acts as a transcription factor driving altered gene expression Response to cortisol is cell and tissue specific, but mechanism is largely consistent 17 Physiology of Cortisol – Normal Circumstances Cortisol Liv er expression of gluconeogenic enzymes Skele tal Muscl e uptake of amino acids 18 protein synthesis Blood Vesse ls catecholamine sensitivity Brain & Cogniti on Feelings of elation vasoconstrictio Glucose usage Physiology of Cortisol – Heightened Stress/Injury Cortisol Immun e syste ms antibody production Inflammatory Pain respo nse Pain awareness 19 Woun d heali ng Dampened prostaglandin activity Physiology of Cortisol – Heightened Stress/Injury During injury … • Pain alerts the sufferer to damage Cortisol • Inflammation dilutes toxic substances and immobilises damaged joints • Immune response destroys invading pathogens Pain respo nse Pain awareness Immun e syste ms antibody production Inflammatory Woun d heali ng Dampened prostaglandin activity 20 • Tissue repair is enhanced by prostaglandins Glucocorticoids therefore appear to act against a persons best interests … WHY?! Stress response and cortisol During the fight or flight response, adrenaline manages the immediate effects whilst cortisol prolongs these effects as needed • Decreased inflammatory response results in decreased pain and immobilisation • Steroid induced sedation/elation lowers awareness of the severity of the situation NET EFFECT: Cortisol enables an individual to Short term benefit perform despite presence of extreme physical or Long term emotional stressors detriment Danger/Stress/Harm 21 Fight or Flight What type of mechanism of action does cortisol have? A. Receptor tyrosine kinase B. G-Protein coupled receptor C. Steroidal intracellular receptor D. Membrane bound transporters Correct Answer: C –to Steroidal Intracellular Move reveal answer Receptors 22 Answer Cortisol is steroid hormone, so can pass through cell membrane Most abundant intracellular receptor is the heatshock protein 90 (hsp90) Cortisol-hsp90 hormone-receptor complex then enters the nucleus and acts as a transcription factor driving altered gene expression Response to cortisol is cell and tissue specific, but mechanism is largely consistent 23 Mineralocorticoids Section 3 of 4 Synthesis of mineralocorticoids Absence of 17α-hydroxylase prevents the glucocorticoid pathways and androgenic pathways IMPORTANT: I do not expect you to learn this pathway in its entirety! 25 Renin-angiotensin-aldosterone system (RAAS) Aldosterone plays a key role in the renin-angiotensin-aldosterone system (RAAS) Angiotensin II drives aldosterone production from the adrenal cortex Aldosterone promotes sodium retention in the kidney, increasing blood pressure through increased water retention Overarching aim of the RAAS is to increase blood pressure 26 Aldosterone Mechanism of Action Angiotensin II triggers secretion of aldosterone from the zona glomerulosa of the adrenal cortex Aldosterone binds to mineralocorticoid receptors (MCRs) in the cytosol of renal collecting duct epithelial cells Aldosterone-MCR complexes promote transcription of an enzyme which prevents the breakdown of sodium channels, Sgk1 Subsequently, more sodium channels are found on the cell surface enabling increased sodium retention 27 Mineralocorticoid action of glucocorticoids Glucocorticoids can stimulate mineralocorticoid receptors (MCRs) Aldosterone sensitive tissues have an enzyme, 11β-hydroxysteroid dehydrogenase (HSD), which converts cortisol to inactive cortisone C HSD Mineralocorticoid action of glucocorticoids only apparent at higher concentrations 28 Production of aldosterone is stimulated by which component of the renin-angiotensin-aldosterone system (RAAS)? A. Renin B. Angiotensinogen C. Angiotensin I D. Angiotensin II Correct Answer: D – Angiotensin II Move to reveal answer 29 Answer Slide Aldosterone plays a key role in the renin-angiotensin-aldosterone system (RAAS) Angiotensin II drives aldosterone production from the adrenal cortex Aldosterone promotes sodium retention in the kidney, increasing blood pressure through increased water retention Overarching aim of the RAAS is to increase blood pressure 30 Pathophysiology and Pharmacology Section 4 of 4 Mineralocorticoid replacement therapy Only therapeutic use of mineralocorticoids is in replacement therapies of mineralocorticoid insufficiencies Context & Interest I do not need you to memorise the chemical structure Aldosterone has a very short half life, therefore fludrocortisone is usually the drug of choice Addison’s Disease - Autoimmune destruction of the adrenal cortex - Impaired aldosterone and cortisol production Aldosterone - Hyponatremia (low sodium) specific - Hyperkalaemia (high potassium) impairments 32 Fludrocortisone Low blood pressure, Arrythmia, Seizures Adrenal Cushing Syndrome Presentation - Fat deposition, including novel locations - Elevated blood pressure - Fatigue - Bone density loss Treatment - Radiotherapy - Surgical removal of the adrenal gland (adrenalectomy) Context & Interest I do not need you to memorise the chemical structure Adrenal adenoma with ACTHindependent Cushing syndrome 33 Jordy Cernik – Cushing Syndrome Context & Interest I will not examine you on details relating to Jordy Cernik’s story 34 Adrenal Cushing Syndrome Presentation - Fat deposition, including novel locations - Elevated blood pressure - Fatigue - Bone density loss Treatment - Radiotherapy - Surgical removal of the adrenal gland (adrenalectomy) - Glucocorticoid replacement therapy vital, and life long Adrenal adenoma with ACTHindependent Cushing syndrome Hydrocortisone (Cortisol) - Analog of cortisol - 60-80% oral bioavailability - Acts via steroid receptor pathway to alter gene expression - Approx. 15-20 mg35daily, Context & Interest I do not need you to memorise the chemical structure Hydrocortisone (cortisol) Glucocorticoids – Usage and Adverse Reactions Selection is largely dominated by pharmacokinetics Adverse effects - Suppression of wound healing - Immune suppression Oral – Replacement therapies / immunosuppression Inhaled – Asthma, hayfever, allergies Topical – Eczema, insect bites, stings - Infection exacerbation Novel infections Over-dosing - Diabetes (elevated blood glucose) - Cushing (elevated cortisol levels) Generally, corticosteroids are symptomatic treatments, not addressing underlying disorders 36 Addisonian Crisis Hypothalamus Releasing Hormone CRH Pituitary (Anterior) Trophic Hormone - Longloop Inhibitio n ACTH Adrenal Glands Short-loop Inhibition Target Tissue Cortisol 37 Normal cortisol levels are maintained through negative feedback loops Addisonian Crisis Hypothalamus Releasing Hormone CRH Pituitary (Anterior) Trophic Hormone - Longloop Inhibitio n ACTH Adrenal Glands Short-loop Inhibition Target Tissue Cortisol Cortis 38 Normal cortisol levels are maintained through negative feedback loops Pharmacologically elevated glucocorticoid levels further drive the negative feedback Addisonian Crisis Hypothalamus Releasing Hormone CRH CRH Pituitary (Anterior) Trophic Hormone - Longloop Inhibitio n ACTH ACTH Adrenal Glands Short-loop Inhibition Target Tissue Cortisol Cortis 39 Normal cortisol levels are maintained through negative feedback loops Pharmacologically elevated glucocorticoid levels further drive the negative feedback Levels of CRH and ACTH are suppressed further Addisonian Crisis Hypothalamus Releasing Hormone Normal cortisol levels are maintained through negative feedback loops CRH CRH Pharmacologically elevated glucocorticoid levels further drive the negative feedback Levels of CRH and ACTH are suppressed further Pituitary (Anterior) Trophic Hormone ACTH ACTH Adrenal Glands Target Tissue 40 Normal HPA function will not be able to compensate after sudden withdrawal following prolonged usage Addisonian Crisis Can also be caused by adrenalectomy, Addison's disease and adrenal haemorrhage IMPORTANT: Addisonian crisis can be fatal, and is a serious medical emergency Liv er Blood glucose Cortisol Treatment - Immediate emergency hydrocortisone injection - Hospitalisation and cortisol replacement therapy Blood Vesse ls Skele tal Muscl e Fatigue Muscle weakness Vasoconstricti on Brain & Cogniti on Consciousness Glucose usage 41 Blood What can be the most serious consequence of prolonged glucocorticoid delivery? A. Glucocorticoid toxicity B. Resistance to activity C. Suppression of the hypothalamic-pituitary axis D. Mineralocorticoid activity Correct Answer: C – Suppression of the hypothalamic-pituitary axis Move to reveal answer 42 Answer Can also be caused by adrenalectomy, Addison's disease and adrenal haemorrhage IMPORTANT: Addisonian crisis can be fatal, and is a serious medical emergency Liv er Blood glucose Cortisol Treatment - Immediate emergency hydrocortisone injection - Hospitalisation and cortisol replacement therapy Blood Vesse ls Skele tal Muscl e Fatigue Muscle weakness Vasoconstricti on Brain & Cogniti on Consciousness Glucose usage 43 Blood What you need to know • Structure of, and blood supply to, the adrenal gland • Layer specific functions of the adrenal cortex • The role of 17α-hydroxylase in adrenal hormone synthesis • The function of cortisol in health, disease and stress • Involvement of aldosterone in the Reninangiotensin-aldosterone system (RAAS) • An appreciation of the pathophysiology behind 44 Addison’s Disease, Cushing Syndrome and the Suggested Additional Reading Greenspan’s Basic and Clinical Endocrinology. “Chapter 9 here provides a very in depth discussion of glucocorticoids, whilst Chapter 10 goes into much more detail than you need on mineralocorticoids.” Tenth Edition. Gardner & Shoback. McGraw-Hill Medical; 2018. ISBN: 978-0071622431. “Chapter 10 is a good concise overview of much of the content in this lecture” Integrated Endocrinology First Edition. Laycock & Meeran. Wiley-Blackwell; 2013. ISBN: 978-0470688120. 45 Feedback Opportunity If you have any feedback for me on this lecture, please either scan the QR code or follow the link below Questionnaire is short (~2 mins) and anonymous All feedback helps me to improve, and as a result improve the quality of your teaching. https://universityofsussex.eu.qualtrics.com/jfe/form/SV_3wVeRAhOFt bXjee 46