ADRENAL GLAND - PhysiologyDr. Gafate- OngAnatomy-pyramidal structure- 2cm wide, 5cm long, and 1cm thick lying immediately above the kidney on its posteromedial surface.- wt. of each gland = 4g

2 distinct parts: Adrenal Medulla central 20% Related to its sympathetic NS Epinephrine and Norepinephrine

Adrenal Cortex Corticosteroids Mineralocorticoids (ex. Aldosterone) Glucocorticoids (ex. Cortisol) Sex hormones (androgenic hormones)

A. Adrenal CORTEX

Outer Zona Glomerulosa 15% of the adrenal cortex Site of mineralocorticoid production (aldosterone)

Central Zona Fasciculata Responsible mainly for glucocorticoid synthesis (cortisol & cortisone) and adrenal androgens and estrogens 75% middle and widest layer

Inner Zona Reticularis Site of adrenal androgen (dehydroepiandrostenedione [DHEA] , DHEA sulfate, androstenedione)

Mineralocorticoids Aldosterone Very potent, 90% of all mineralocorticoid activity 150-250 mg/day ave. secretory rate 6 nanograms/100ml- normal concentration in the blood

Deoxycortisone 1/30 as potent as aldosterone; secreted in small amounts

Corticosterone Sli. Mineralocorticoid activity

9 - Flurocortisol Slightly more potent than aldosterone

Cortisol Very sli. Mineralocorticoid activity; secreted in large quantities

Cortisone Sli. Mineralocorticoid activity

Cellular Mechanism of Aldosterone Action Diffuses readily to the interior of the tubular epithelial cells (lipid soluble) Combines with a highly specific cytoplasmic receptor protein Aldosterone-receptor complex or a product of this complex diffuses into the nucleus inducing specific portions of the DNA to form mRNA related to the process of Na and K transport mRNA diffuses back into the cytoplasm causing protein formation (enzyme/membrane transport proteins) Na-K ATPase- principal part of the pump for Na and K exchange (basolateral membrane of renal tubular cells)

FUNCTIONS of Mineralocorticoids RENAL and CIRCULAR effects Renal tubular reabsorption of Na and secretion of K ECF volume and arterial pressure Pressure natriuresis and diuresis Excretion of salt and water secondary to rise in arterial pressure as a result of aldosterone mediated increase in ECF Aldosterone Escape Return to normal salt and water excretion by the kidneys as a result of pressure natriuresis and diuresis excess aldosterone

Excess aldosterone Hypokalemia and muscle weakness Loss of K from the ECF into the urine and transport to most cells of the body decrease plasma K conc.

Alteration of electrical excitability of the nerve and muscle fiber membranes prevent transmission of normal action potential Severe muscle weakness

Increased Tubular Hydrogen Ion Secretion with Mild Alkalosis Decreased ECF hydrogen ion concentration due to secretion of hydrogen ions in exchange for Na in the intercalated cells of the cortical collecting tubules.

Na and K transport in Sweat/ Salivary glands and intestinal Epithelial cells Increased reabsorption and secretion of K by ducts Regulation of Aldosterone Secretion Increased K ion conc. In the ECF Increased activity of RAS Increased Na ion conc. In the ECF ACTH

GLUCOCORTICOIDS Cortisol Very potent , 95% of all glucocorticoids activity 15-20mg/day ave. secretory rate 12mg/ 100ml ave. concentration in the blood Corticosterone 4% of total glucocorticoid activity; less potent than cortisol Cortisone Almost as potent as cortisol Prednisone 4x as potent as cortisol Methylprednisone 5x as potent as cortisol Dexamethasone 30x as potent as cortisol

Regulation Of Cortisol Secretion ACTH activates adrenocortical cells to produce steroids by: Activating adenylyl cyclase In the cell membrane - formation of cAMP activates intracellular enzymes formation of cortisol Activation of Protein kinase A initial conversion of cholesterol to pregnenolone (rate Limiting step)Cellular Mechanism of Cortisol Action Diffuses through the cell membrane (lipid soluble) Combines with a receptor protein in the cytoplasm Hormone-receptor complex inducing specific regulatory DNA sequences (Glucocorticoid response elements) to induce or repress gene transcription Transcription of many genes to alter synthesis of mRNA for the proteins that mediate their multiple physiologic effects.Functions of GLUCOCORTICOIDS Effects of Cortisol on Carbohydrate metabolism Stimulation of Gluconeogenesis (6-10 fold) Cortisol increase the enzymes required to convert AA into glucose in the liver cells Cortisol causes mobilization of AA from extrahepatic tissues (muscle) Decreased glucose utilization by the cells ADRENAL DIABETES

Effects of Cortisol on Protein Metabolism Reduction in cellular protein Decreased protein synthesis Increased protein catabolism Increase Liver and plasma proteins Enhanced AA transport into liver cells and enhanced liver enzymes for protein synthesis Increase blood AA, diminished transport of AA into the extrahepatic cells and enhanced transport into hepatic cells.

Effects of Cortisol on Fat Metabolism Mobilization of Fatty acids Increased conc. Of fatty acids in the plasma increasing their utilization for energy Enhanced oxidation of fatty acids in the cells

Anti-inflammatory Effects Block the early stages of the inflammatory process Stabilizes the lysosomal membranes Decrease permeability of the capillaries Decrease both migration of WBC into the inflamed area and phagocytosis of the damaged cells Suppress the immune system (decrease in lymphocyte reproduction) Reduce the release of IL-1 from the WBC Rapid resolution of the inflammation and increase rapidity of healing

Other Effects: Blocks the inflammatory response to allergic reactions Decrease eosinophils and lymphocytes in the blood

Transport of Adrenal Hormones Cortisol Binding Globulin or Transcortin Binds 90-95% of the cortisol in the plasma 60-90 min. - half-life of cortisol

Aldosterone- 60% combines with plasma proteins 40% are in free form Half-life of 20mins.*** In BOTH the bound and free forms, they are transported throughout the ECF

Metabolism of Adrenal Hormones Adrenal Steroids Degraded mainly in the LIVER Conjugated to glucuronic acid and sulfates Remaining conjugates are filtered by the kidneys and excreted in the urine

Circadian Rhythm of Glucocorticoid Secretion Secretory rates of CRF, ACTH and Cortisol: HIGH in early AM and LOW in the late evening Plasma Cortisol Level 20ug/dl AM (an hour before arising) 5ug/dl- MidnightAbnormalities of Adrenocortical Secretions ADDISONs disease Mineralocortiocoid deficiency Decreased renal tubular Na reabsorption Decreased ECF volume Hyponatremia, hyperkalemia and mild acidosis (failure of K and hydrogen ions to be secreted in exchange for Na reabsorption) Depletion of ECF, fall in plasma vol., rise in RBC conc., decreased cardiac output, shock and death in 4days to 2 weeks after cessation of mineralocorticoid secretion

Glucocorticoid deficiency Failure to maintain normal blood glucose levels Absence of gluconeogenesis Reduced mobilization of proteins and fats from the tissues Depression of the immune system

Melanin Pigmentation Mucous membranes and skin. Deposited in blotches Due to stimulation of ACTH and concomitant stimulation of MSH

Treatment Mineralocorticoid and glucocorticoid replacement

ADDISONIAN CRISIS Occurs in individuals with Addisons dse who are exposed to stress (surgical procedures) who may acutely need excessive amounts of glucocorticoids (10 or more times the normal)

Hyperadrenalism ( CUSHINGs Syndrome ) Hypersecretion of cortisol by the adrenal cortex

Causes: ACTH Dependent Ant. Pituitary adenomas- secrete ACTH (cushings dse) Abnormal function of the Hypothalamus- secrete CRH Ectopic secretion of ACTH- Tumor (abdominal CA)

ACTH Independent Adenomas of the adrenal cortex

Clinical Features Hypertension most common (in endogenous hypercortisolism) Obesity Glucose intolerance Gonadal dysfunction Moon facies, plethora Violaceous striae, hirsutism

Treatment Surgery (adrenalectomy) Medical inhibit cortisol secretion Ketoconazole Metyrapone Aminoglutethimide Mitotane

Primary Aldosteronism CONNS SYNDROME Small tumor in the zona glomerulosa Excessive aldosterone secretion Hypokalemia, increase ECF and blood vol. and hypertension Dx: decreased plasma renin conc. Tx: surgical removal of the tumor

ADRENAL ANDROGENS DHEA active male hormone secreted by the Adrenal CORTEX Converted to testosterone Progesterone and Estrogen female sex hormones secreted in minute quantities

Adrenogenital Syndrome Tumor secreting large quantities of androgens Intense masculinizing effects In Females- growth of beard, deeper voice, baldness, growth of clitoris resembling a penis and masculine distribution of body hairs and muscles Dx: elevated 17-Ketosteroids in the urine (10-15x)

B. ADRENAL MEDULLA Central 20% Related to the sympathetic NS Epinephrine and NorepinephrineFunctions of Adrenal Medulla Hormones produced: Norepinephrine- 20% Vasoconstriction of ALL blood vessels in the body Increase activity of the heart Inhibits GIT Dilatation of the pupils

Epinephrine 80% Greater effect on cardiac stimulation (beta receptor stimulation) Weak constrictions of the Blood vessels in the muscles Raises arterial pressure and increase cardiac output 5-10x greater metabolic effect than NE (glycogenolysis)

Abnormalities in the Adrenal Medulla PHEOCHROMOCYTOMA Tumor usually located in the adrenals Usually unilateral (right adrenal > left adrenal) Encapsulated (true or pseudocapsule) Firm in texture, size range from microscopic to 3600g (ave. 100g and 4.5 cm in diameter) Symptoms: Hypertension- BP >140/90 Palpitations/ tachycardia Headache Episodic sweating Anxiety / fear of impending death Tremor Fatigue / exhaustion N/V Abdominal/ Chest pain Visual disturbances/ dyspnea

Dx: Urine fractionated catecholamines and metanephrines Plasma fractionated catecholamines and metanephrines MIBG CT scan/ PET scan

Treatment: Surgery with adequate pre-op medical management of hypertension