Functions of Adrenocortical Hormones - Gulf Medical University PDF

Functions of Adrenocortical hormones Dr. Sovan Bagchi Professor of Physiology * www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives Define cortisol and kn...

Functions of Adrenocortical hormones Dr. Sovan Bagchi Professor of Physiology * www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives Define cortisol and know where it is produced Explain the process of cortisol synthesis Identify the cellular binding and major physiological actions of cortisol Describe the regulation of cortisol release by the adrenal gland Define mineralocorticoids and specify their site of production Explain aldosterone synthesis and transport Identify the cellular binding and major physiological actions of aldosterone Describe how the adrenal glands regulate the release of aldosterone Case In school, you have been learning about cortisol and its effects, including its suppression of the immune system. This seems confusing when you think back to your college roommate, AS, who took corticosteroid medication (prednisone) to prevent rejection of her transplanted kidney. You recall that in the emergency department, AS was given additional corticosteroids when she had to have emergency surgery for an ovarian cyst. Wouldn’t that make healing more difficult? Why did AS need extra steroids at a time of stress? What Is Cortisol? Cortisol is a steroid hormone Produced in the adrenal gland (zona fasciculata) Cortisol is an example of a glucocorticoid (involved in glucose metabolism) Also called a corticosteroid How Is Cortisol Synthesized? Cortisol production is dependent on by the adrenocorticotropic hormone (ACTH) Steps of Cortisol production Synthesis of Cholesterol Mitochondrial Conversion Smooth Endoplasmic Reticulum How Does Cortisol Act on Tissues Cortisol affects many functions in the body, since most of our cells have glucocorticoid receptors (GRs) to which cortisol binds Transport and Receptor Binding About 90% of cortisol binds to a corticosteroid-binding globulin (CBG), also called transcortin It is made in the liver, prolongs the half-life of cortisol Only 3% travels free in the plasma Only the free cortisol—unbound to a CBG—can enter cells and activate the receptor Clinical correlation Levels of both total cortisol level and CBG increase during pregnancy. However, the free cortisol is usually normal, and the patient will not have symptoms of high cortisol.  Diverse Effects Cortisol is a hormone critical for life, and deficiencies may be fatal. The hormone affects glucose and overall metabolism, the immune system, cognition, bone formation, and fetal development, etc.  Metabolism It increases energy-generating substrates like glucose, glycerol, and amino acids for use in times of stress. Glucose Cortisol increases the serum glucose by Gluconeogenesis and decreases glycogen formation (Liver). Reduces glucose uptake by decreasing GLUT4 transporters (skeletal muscle and white adipose tissue) This decreased glucose uptake is a form of insulin resistance Decrease insulin and increase glucagon secretion (Pancreas) These effects increases the serum glucose concentration. Fats and Proteins. Increases lipolysis to generate glycerol, which can be used for energy in times of stress Increases proteolysis into amino acids, which can also be used for energy, or sometimes be converted to glucose Inhibits protein synthesis and decreases peripheral amino acid uptake in muscles * Muscle wasting seen in patients who have too much cortisol CLINICAL CORRELATION High cortisol levels (Cushing syndrome) can cause a person to develop insulin-resistant diabetes, making hypercortisolism a cause of secondary diabetes mellitus.  Maintaining Blood Pressure Cortisol maintains normal blood pressure by upregulating the number of vasoconstricting α1 receptors on arterioles High cortisol concentrations activate mineralocorticoid receptors (MRs) increasing renal sodium reabsorption and blood volume, and increasing blood pressure The MR has similar affinity for cortisol and aldosterone Why doesn’t cortisol normally have a strong mineralocorticoid effect? This is because the MR is “protected” from cortisol by an enzyme called corticosteroid 11β-dehydrogenase isozyme 2. This enzyme metabolizes cortisol to an inactive form when it tries to bind the MR. This type of regulation is crucial; otherwise, cortisol would dominate MR signaling.  Immunity and Wound Healing Cortisol inhibits wound healing and immunity Decreasing Inflammation and Immune Responses CLINICAL CORRELATION Cortisol acts as an anti-inflammatory molecule by Cortisol can be used as a drug to reduce decreasing inflammation and immune responses inflammation in chronic inflammatory conditions like skin rashes and some inflammatory kidney Overall, this causes immune suppression and poor wound diseases healing in patients with high cortisol levels Additional Cortisol Functions Decreasing bone formation CLINICAL CORRELATION Modulation of fetal lung development: *Glucocorticoids are given to mothers who go into labor (or are suspected of going into labor) Production of surfactant* prematurely. Steroids freely cross the placenta Stimulating cognition and memory and make it to the fetus, so giving the mother glucocorticoids can help to hasten the fetus’ Terminal maturation and axon lung development in case the baby is born remodeling before their lungs are ready. Cortisol decreases osteoblast activity **Patients taking chronic glucocorticoid drugs are (high levels of cortisol can weaken bones)** at risk for osteoporosis Increases Memory and Cognition Cortisol stimulates the formation of memories associated with strong emotions, both good and bad Development of alertness and cognition follows a similar pattern Largely due to effects on the hippocampus, amygdala, and frontal lobes Cortisol is a BIG FIB: Blood pressure, Insulin resistance, Gluconeogenesis, lipolysis, and proteolysis. Cortisol decreases Fibroblast activity, Inflammation and immune response, Bone production. How Is Cortisol Secretion Regulated? Role of Cortisol in Stress Stress Paraventricular nucleus of the hypothalamus Limbic system Hypothalamus (CRH) ACTH (anterior pituitary) Cortisol Mineralocorticoids Learning objectives Define mineralocorticoids Identify the cellular Describe how the and specify their site binding and major adrenal glands of production. Explain physiological actions regulate the release of aldosterone synthesis of aldosterone. aldosterone and transport. Mineralocorticoids Mineralocorticoids (aldosterone) that are critical for maintaining our blood volume They cause sodium reabsorption and water reabsorption (secondary effect) from the kidney Increase blood volume. Important for potassium regulation (excrete extra potassium) These steroid hormones are produced in the adrenal gland; specifically, in the zona glomerulosa, the outermost layer of the adrenal cortex How Is Aldosterone Synthesized? Steroidogenic acute regulatory protein (StAR) Rate limiting enzyme Transport 50% of aldosterone binds to serum albumin 17% binds to the corticosteroid-binding globulin (CBG), also called transcortin (binds to cortisol and progesterone). 30% of aldosterone circulates freely in the blood Receptor Binding Aldosterone binds to the mineralocorticoid receptor (MR; intracellular) MR equal affinity for mineralocorticoids and for cortisol Cortisol can sometimes stimulate the same actions The aldosterone-MR complex then enters the nucleus Binds to hormone response elements on the nucleus Modulating multiple genes expressions (repressing or enhancing their transcription)  What Does Aldosterone Do? Mineralocorticoid receptor (MR), acts as a ligand- dependent transcription factor (TF), when aldosterone binds the receptor, it acts as a TF. CLINICAL CORRELATION TF alters cell signaling in a variety of tissues in order Inhibition of the enzyme corticosteroid 11β- produce proteins that regulate water and ion transport dehydrogenase isozyme 2 by chemicals found in genuine licorice can cause pseudohyperaldosteronism. MR has similar affinity for cortisol and aldosterone It is so named because the mineralocorticoid effects are But is “protected” from cortisol by an enzyme called not caused by aldosterone, but instead by circulating corticosteroid 11β-dehydrogenase isozyme 2 cortisol that can now bind and activate the MR This enzyme metabolizes cortisol to an inactive form when it tries to bind the MR This regulation is crucial as circulating cortisol concentrations are 100 times greater than circulating aldosterone concentrations Otherwise, cortisol would dominate MR signaling Actions in the Kidney Sodium reabsorption and potassium excretion Increasing the sodium channels on the lumen side of the cell Na+/K+-ATPase pump activity on the blood (basolateral) side of the cell Increasing the number of potassium channels then allows potassium to exit the cell and be secreted into the urine. This is how aldosterone increases urinary potassium excretion One more effect Stimulates the H+-ATPase (sometimes referred to as the proton pump) on the ɑ-intercalated cells in the collecting duct to secrete H+ directly into the tubular fluid. CLINICAL CORRELATION Hypertension can be caused by primary hyperaldosteronism. In this disorder, the adrenal glands continuously secrete aldosterone without regulation. The result is sustained activation of the aldosterone-dependent pathways, causing sodium and water retention, hypertension, and profound hypokalemia caused by urinary potassium wasting. Actions Outside the Kidney While the kidney is the main target of aldosterone, the hormone also stimulates sodium reabsorption through its actions on receptors in the colon, salivary, and sweat glands, assisting the kidney with expansion of plasma volume How Is Aldosterone Secretion Regulated? Angiotensin II Activation of the renin-angiotensin-aldosterone system (RAAS) occurs when there is a drop in blood pressure or blood volume. RAAS activation generates angiotensin II, which directly stimulates aldosterone secretion. Increased Serum Potassium Concentration When serum potassium rises, the adrenal cortex is stimulated to secrete aldosterone. This increases renal potassium excretion, just what we need to rid the body of the excess potassium. Circulating Adrenocorticotropic Hormone Besides RAAS activation and hyperkalemia, the presence of ACTH is also required for aldosterone synthesis, as the hormone is needed to form the aldosterone precursors. ACTH doesn’t stimulate release but is needed for aldosterone synthesis Test your Knowledge Which of the following describes the mechanism by which aldosterone increases sodium reabsorption at the collecting ducts? Stimulates insertion of H+-ATPase in ɑ-intercalated cells Stimulates insertion of H+-ATPase in principal cells Stimulates insertion of Na+/K+-ATPase in ɑ-intercalated cells Stimulates insertion of Na+/K+-ATPase in principal cells Which of the following is the most potent stimulant of CRH release? Blood pressure of 120/80 mm Hg Drinking water Eating food Sleep Stress Learning Resources Textbook: John E. Hall and Michael E. Hall. Textbook of Medical Physiology. 14th ed. Elsevier. 2021. ISBN: 978-0-323-59712-8. Chapter 78, Page no. 955-972 Power-point presentation in the moodle