ADRENAL CORTEX

AND MEDULLA

ADRENAL MEDULLA AND CORTEX

• The adrenal glands are located in the retroperitoneal cavity above each kidney The adrenal glands are two separate glands, the adrenal medulla and the cortex whose secretions are essential for life.

• The adrenal medulla (inner) is approximately 20% of the tissue. The adrenal medulla is of neuroectodermal origin and secretes the catecholamines epinephrine and norepinephrine .

Adrenal cortex

Adrenal Steroid Hormones

The adrenal cortex secretes three classes of steroid hormones: glucocorticoids, mineralocorticoids, and androgens.

Each layer of the adrenal cortex synthesizes one of the three types of hormones.

The innermost zone of the cortex called the zona reticularis, secretes mainly adrenal androgens.

The middle (and biggest zone), called the zona fasciculata, secretes glucocorticoids.

The outermost zone, called the zona glomerulosa, secretes mineralocorticoids.

Structures of adrenal steroids

• The structures of the major adrenal steroids are shown in the next slides.

• The critical aspect of adrenal steroid synthesis is a hydroxylation step at C-21, catalyzed by a C-21 hydroxylase enzyme.

• This step directs synthesis towards cortisol and aldosterone

•The structures of the major adrenocortical steroids. All of the steroids are chemical modifications of a basic structure. •The basic nucleus is a carbon skeleton, with carbons numbered from 1 through 21 and four rings A, B, C and D. •The glucocorticoids, represented by cortisol, have a ketone group at carbon 3 (C3) and hydroxyl groups at C11 and C21. •The mineralocorticoids, represented aldosterone, have a double-bond oxygen at CI8. •The androgens represented in the adrenal cortex by dehydroepiandrosterone (DHEA) and androstenedione have a double-bond oxygen at C17.

Regulation of adrenal steroids

• Synthesis and secretion of steroid hormones by the adrenal cortex depends on the stimulation of cholesterol desmolase (the first step) by ACTH.

• In the absence of ACTH, biosynthesis of adrenocortical steroid hormones ceases.

Regulation of adrenal steroids

• The zona fasciculata, which secretes glucocorticoids, is under the exclusive control of the hypothalamic-pituitary axis. The hypothalamic hormone is corticotropin-releasing hormone (CRH), and the anterior pituitary hormone is ACTH.

• The zona reticularis, which secretes adrenal androgens, is also under the control of the same hypothalamic-pituitary axis.

• The zona glomerulosa, which secretes mineralocorticoids, depends on ACTH for the first step in steroid biosynthesis, but IN ADDITION, it is controlled separately via the renin-angiotensin system.

REGULATION OF GLUCOCORTICOIDS

• Cortisol exhibits pulsatile and diurnal patterns. The daily profile of blood cortisol levels is characterized by an average of 10 secretory bursts during a 24-hour period.

• The lowest secretion is during the evening hours and after falling asleep, and the highest secretory rates occur just before awakening in the morning (e.g., 8 AM).

• The major burst of cortisol secretion before awakening accounts for one half of the total daily cortisol secretion.

• ACTH has a pulsatile and diurnal secretory pattern that drives a parallel pattern of cortisol secretion.

• The early morning peak of ACTH is driven by a burst of CRH secretion. The "internal clock" that drives the diurnal pattern can be shifted by alternating the sleep-wake cycle (e.g., varying the time of going to sleep and awakening). The diurnal pattern is abolished by coma, blindness, or constant exposure to either light or dark.

Diurnal pattern of cortisol

Summary of actions of adrenal steroids

• Actions of Glucocorticoids: Increase proteolysis (catabolic) Increase lipolysis; Decrease glucose utilization; Decrease insulin sensitivity; Anti-inflammatory; Immunosuppression; Maintain vascular responsiveness to catecholamines; Inhibit bone formation; Increase GFR; Decrease REM sleep.

• Actions of Mineralocorticoids: Increase gluconeogenesis: Increase Na+ reabsorption; Increase K+ secretion; Increase H+ secretion

• Actions of Adrenal Androgens: Females: presence of pubic and axillary hair; libido

• Males: same as testosterone

Actions of Glucocorticoids

• Glucocorticoids are essential for life. • The actions of glucocorticoids (e.g., cortisol)

are essential for: • Gluconeogenesis (hence the name)• for vascular responsiveness to catecholamines, • suppression of inflammatory and immune

responses, modulation of CNS function.

Metabolic effects of cortisol

• Stimulation of gluconeogenesis. A major action of cortisol is to promote gluconeogenesis and storage of glycogen. Overall, the effects of cortisol are catabolic and diabetogenic. Cortisol affects protein, fat, and carbohydrate metabolism to increase glucose synthesis as follows.

• Cortisol increases protein catabolism in muscle and decreases new protein synthesis, thereby providing additional amino acids to the liver for gluconeogenesis.

• Cortisol increases lipolysis, which provides additional glycerol to the liver for gluconeogenesis.

• Finally, cortisol decreases glucose utilization by tissues and decreases the insulin sensitivity of adipose tissue. Glucocorticoids are essential for survival during fasting, because they stimulate these gluconeogenic routes.

• In hypocortisolism (e.g., primary adrenal insufficiency, Addison's disease), there is hypoglycemia.

• In hypercortisolism (e.g., Cushing's syndrome), there is hyperglycemia.

Anti-inflammatory and –immune effects of cortisol

• 1) Cortisol induces the synthesis of lipocortin, an inhibitor of the enzyme phospholipase A2. Phospholipase A2 liberates arachidonic acid from membrane phospholipids and provides the precursor for the prostaglandins and leukotrienes that mediate the inflammatory response. Therefore, this component of the anti-inflammatory effect of cortisol is based on inhibiting the synthesis of the precursor to prostaglandins and leukotrienes.

• (2) Cortisol inhibits the production of interleukin-2 (IL-2) and the proliferation of T lymphocytes.

• (3) Cortisol inhibits the release of histamine and serotonin from mast cells and platelets.

• Cortisol inhibits the production of IL-2 and the proliferation of T lymphocytes, which also are critical for cellular immunity. Exogenous glucocorticoids can be administered therapeutically to suppress the immune response and prevent the rejection of transplanted organs

More actions of cortisol• Cortisol is necessary for the maintenance of normal blood

pressure and plays a permissive role in the arterioles by up-regulating alpha-adrenergic receptors. In this way, cortisol is required for the vasoconstrictive response of the arterioles to catecholamines. In hypocortisolism, there is hypotension; in hypercortisolism, there is hypertension.

• Inhibition of bone formation. Cortisol inhibits bone formation by decreasing the synthesis of type I collagen, the major component of bone matrix; by decreasing osteoblast production; and by decreasing intestinal Ca2+ absorption.

• Increases glomerular filtration rate (GFR). Cortisol increases GFR by causing vasodilation of afferent arterioles, thereby increasing renal blood flow and GFR.

• Glucocorticoid receptors are found in the brain, particularly in the limbic system. Cortisol decreases REM sleep, increases slow-wave sleep, and increases wake time.

Relative potencies of drugs and dangers

• There is overlap of activity between the classes of steroids, i.e. cortisol has a weak mineralocorticoid action.

• Therefore, all synthetic steroids used as drugs have mixed actions.

• Dexamethasone (30X more potent than a cortisol) also has an aldosterone-like effect, but is 15X weaker.

• Give enough dexamethasone, will see fluid retention (moon-face).

• Dexamethasone suppresses ACTH secretion – withdraw slowly.

Actions of aldosterone

• Aldosterone has three actions on the kidney distal tubule and collecting ducts of the kidney: it increases Na+ reabsorption into blood, it increases K+ and H+ secretion into urine. Aldosterone is the most important means of retaining Na+, and thereby maintaining fluid and electrolyte balance.

• Aldosterone also increases Na+ reabsorption and K+ secretion in salivary and sweat glands.

Action of aldosterone on kidney

Regulation of aldosterone Secretion

• The regulation of aldosterone secretion by the zona glomerulosa is different from the regulation of cortisol. ACTH remains essential in this process because it stimulates cholesterol desmolase, the first step in the biosynthetic pathway.

• However, the primary regulation of aldosterone secretion occurs not by ACTH, but through:

• (1) changes in ECF volume via the renin-angiotensin system

• (2) changes in serum potassium levels

Zona Glomerulosa: Disorders

Aldosteronism = hypersecretion (adrenal tumor)

→increased water and Na+ reabsorption --> hypertension, edema;

→loss of K+ --> disruption of neural and muscle function

Disorders

• Addison’s Disease = Hyposecretion of glucocorticoids and mineralocorticoids

• Causes : Auto Immune disorders, Carcinoma,Tuberculosis.– decreased aldosterone

• results in decreased Na+ and water reabsorption, increased blood K+ --> low blood volume --> hypotension, dehydration

• altered K+ results in changes in membrane potentials --> disruption in neural and muscular function

– cortisol secretion by zona fasciculata also decreased --> decreased blood glucose levels (hypoglycemia; especially during prolonged stress)

Hyperadrenalism: Cushing’s Syndrome

Hyper secretion of cortisol1.Independent of ACTH i.e GC excess with low ACTH Causes :Treatment with Gcs Tumor of Ad cortex 2. ACTH dependent ( Cushing Disease ) GC excess with increased ACTH Causes :- Tumor in Pituitary, lungs, kidneys, or pancreas Treatment with ACTH

Cushing’s Disease

• suppresses glucose metabolism resulting in– hyperglycemia (elevated glucose= steroid diabetes), – stimulates lipid metabolism (weight loss), – loss of muscle and bone mass,– water and salt retention (effect of aldosterone

hypersecretion --> water retention --> hypertension) – “buffalo neck” and “moon face” (fat redistribution)– Fat deposition between shoulders or in face – anti-inflammatory effects (mask infection).– Treatment : Removal of adrenal tumor /pituitary tumor or

decrease the secretion of ACTH .– Drugs that inhibit ACTH secretion : Serotonin antagonists .

• Adrenogenital syndrome (AGS)– adrenal androgen hypersecretion,

commonly accompanies Cushing syndrome

– causes enlargement of external sexual organs in children & early onset of puberty

– masculinizing effects on women (deeper voice & beard growth)

Adrenal medulla

Adrenal medulla• Acts functionally to amplify the autonomic sympathetic

nervous system• Sympathetic ganglion innervated by sympathetic

preganglionic fibers – consists of modified neurons called chromaffin cells

• Releases epinephrine and norepinephrine (catecholamines) into blood. Target tissues contain alpha and beta type receptors.

• Tonic secretion, increased when stimulated by increased sympathetic activity

• Output is increased by stress, fear, cold, hypoglycemia, blood loss.

• Major actions: increase blood glucose levels, maintain cardiovascular functions

Adrenal medulla

Stress

Types of Stress• physical stress• psychological stress

Responses to Stress• hypothalamus triggers sympathetic impulses to various organs• epinephrine is released• cortisol is released to promote longer-term responses

Responses to Stress

Life-Span Changes

• endocrine glands shrink• GH levels even out, muscular strength decreases• ADH levels increase due to slow break down• calcitonin levels decrease• PTH increases, osteoporosis risk increases• insulin resistance may develop• changes in melatonin secretion affect the body clock• thymosin production declines increasing risk of infections

Phaeochromocytoma

• Tumor of Adrenal medulla • Hyper secretion of catecholamines

PANCREAS

Pancreas

• Endocrine and exocrine functions• Exocrine pancreas: acinar cells and

duct cells that secrete enzymes and fluid into the digestive tract

• Endocrine pancreas: islets of Langerhans cells secrete insulin cells secrete glucagon cells secrete somatostatinF cells secrete pancreatic polypeptide

Hormones of the pancreas

• INSULIN• GLUCAGON• SOMATOSTATIN• PANCREATIC POLYPEPTIDE

INSULIN

Actions of Insulin

• Insulin is known as the hormone of "abundance" or plenty. When the availability of nutrients exceeds the demands of the body, insulin ensures that excess nutrients are stored as glycogen in the liver, as fat in adipose tissue, and as protein in muscle. These stored nutrients are then available during subsequent periods of fasting to maintain glucose delivery to the brain, muscle, and other organs.

• Insulin has the following actions on liver, muscle, and adipose tissue.

• Decreases blood glucose concentration. The hypoglycemic action of insulin can be described in two ways: Insulin causes a decrease in blood glucose concentration by increasing peripheral uptake, and insulin limits the rise in blood glucose that occurs after ingestion of carbohydrates.

Insulin decreases blood fatty acid and ketoacid concentrations.

• The overall effect of insulin on fat metabolism is to inhibit the mobilization and oxidation of fatty acids and, simultaneously, to increase the storage of fatty acids.

• As a result, insulin decreases the circulating levels of fatty acids and ketoacids. In adipose tissue, insulin stimulates fat deposition and inhibits lipolysis.

• Simultaneously, insulin inhibits ketoacid formation in liver because decreased fatty acid degradation means that less acetyl coenzyme A (acetyl CoA) substrate will be available for the formation of ketoacids.

Insulin decreases blood amino acid concentration

• The overall effect of insulin on protein metabolism is anabolic.

• Insulin increases amino acid and protein uptake by tissues, thereby decreasing blood levels of amino acids. Insulin stimulates amino acid uptake into target cells (e.g., muscle), increases protein synthesis, and inhibits protein degradation.

Other actions of insulin• In addition to major actions on carbohydrate, fat, and

protein metabolism, insulin has several additional effects.

• Insulin promotes K+ uptake into cells (at the same time that it promotes glucose uptake) by increasing the activity of the Na+/K+ ATPase. This action of insulin can be viewed as "protecting" against an increase in serum K+ concentration. When K+ is ingested in the diet, insulin ensures that ingested K+ will be taken into the cells with glucose and other nutrients.

• Insulin also appears to have a direct effect on the hypothalamic satiety center independent of the changes it produces in blood glucose concentration.

Summary of major actions of insulin: ANABOLIC

• Increases glucose uptake into cells by directing the insertion of glucose transporters into the cell membranes.

• Increases glycogen formation• Decreases glycogenolysis• Decreases gluconeogenesis• Increases protein synthesis (anabolic)• Increases fat deposition• Decreases lipolysis• Increases K+ uptake into cells• Decreases blood [glucose]• Decreases blood [amino acid]• Decreases blood [fatty acid]• Decreases blood [ketoacid]• Decreases blood [K+]

Insulin control

Stimulated by: • increased blood glucose• increased blood amino acid and fatty acid

levels• parasympathetic impulses• hyperglycemic hormones (GH, glucagon,

epinephrine, thyroxine, glucocorticoids) indirectly result in insulin secretion by increasing blood glucose levels Inhibited by:

• low blood glucose and by somatostatin• sympathetic impulses

Insulin Disorders: Diabetes Mellitus

• A chronic condition associated with abnormally high blood sugar

• Results from either deficiency of or a resistance to insulin- a hormone produced by the pancreas whose function is to lower blood sugar.

Signs and symptoms

• Hyperglycemia (excess blood glucose)

– not all sugar reabsorbed from urine glucose lost in urine (glucosuria) increased water loss

excessive urine production (polyuria) and

excessive thirst (polydipsia)

Continued …..

• Cells use fats as energy source (due to poor glucose uptake).Hyperglycemic hormones stimulate fat mobilization fats in blood (lipidemia) increase in lipid metabolites in blood (ketone bodies, which are strong organic acids) decrease blood pH (ketoacidosis) and ketone bodies in urine (ketonuria)– decreased blood pH (acidemia) severe

depression of nervous system deep breathing diabetic coma death

• Polyphagia (excessive hunger) – final sign, due to use of fats and proteins as energy sources

Diagnostic criteria

Fasting Glucose

Random OGTT (2 hr)

Normal <110 mg/dl (5.5 mM)

<140 mg/dl (7.7 mM)

IGT 111-125 mg/dl 140-200 mg/dl

Diabetes >126 mg/dl (7.0 mM)

>200 mg/dl (11.1 mM)

>200 mg/dl (11.1 mM)

Type I Diabetes Mellitus

• Insulin-dependent diabetes formerly juvenile onset diabetes.

• onset is sudden, usually before age 15.• May be due to autoimmune attack of proteins

in beta cells result is lack of insulin activity. • Lipidemia (high blood lipid content) and

increased cholesterol lead to long-term vascular problems (arteriosclerosis, strokes, heart attacks, renal shutdown, gangrene, blindness)

• Treatment with insulin injections or pancreatic islet transplant (newer technique).

Type II Diabetes Mellitus• Non-insulin-dependent (NIDDM; formerly mature-onset

diabetes)• Usually starts after age 40• insulin levels are normal or elevated, but peripheral

tissue become less sensitive to it .• 25-30% of Americans carry gene that predisposes them

to NIDDM, more likely in over-weight people (~90% of cases)– adipose cells secrete tumor necrosis factor alpha that

depresses production of protein needed for glucose uptake• Often controllable with diet and exercise• Drugs : Metformin & Sulfonylureas – increase insulin

sensitivity

Risk Factors for Type 2 Diabetes

Age > 40Age > 40Family history of diabetesFamily history of diabetesEthnicity Ethnicity Obesity; abdominal fat distributionObesity; abdominal fat distributionGDM, or infant > 9 lbsGDM, or infant > 9 lbsHypertension, hyperlipidemiaHypertension, hyperlipidemiaPrevious Impaired Glucose TolerancePrevious Impaired Glucose Tolerance

GLUCAGON

Glucagon

• Glucagon is synthesized and secreted by the cells of the islets of Langerhans. In most respects (i.e., regulation of secretion, actions, and effect on blood levels), glucagon is the mirror image of insulin.

• While insulin is the hormone of "abundance," glucagon is the hormone of "starvation." In contrast to insulin, which promotes storage of metabolic fuels, glucagon promotes their mobilization and utilization.

Regulation of Glucagon Secretion

• The actions of glucagon are coordinated to increase and to maintain the blood glucose concentration. Thus, the factors that cause stimulation of glucagon secretion are those that inform the cells that a decrease in blood glucose has occurred.

• The major factor stimulating the secretion of glucagon is decreased blood glucose concentration.

Effects of glucagon

Factors Affecting Glucagon Secretion

• Stimulatory Factors: Fasting; Decreased glucose concentration; Increased amino acid concentration (especially arginine); Cholecystokinin (CCK); Adrenergic agonists; Acetylcholine

• Inhibitory Factors: Insulin; Somatostatin; Increased fatty acid and ketoacid concentration

Major actions of glucagon

• Increases glycogenolysis• Increases gluconeogenesis• Increases lipolysis• Increases ketoacid formation• Increases blood [glucose]• Increases blood [fatty acid]• Increases blood [ketoacid]

Pancreatic somatostati

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Pancreatic somatostatin• A polypeptide (same as in brain) secreted by the delta cells

of the islets of Langerhans. Serves to inhibit pancreatic hormone secretion.

• Secretion of pancreatic somatostatin is stimulated by the ingestion of all forms of nutrients (i.e., glucose, amino acids, and fatty acids), by several gastrointestinal hormones, by glucagon, and by -adrenergic agonists.

• Secretion of somatostatin is inhibited by insulin via an intra-islet paracrine mechanism.

• Pancreatic somatostatin inhibits secretion of insulin and glucagon via paracrine actions on the alpha and beta cells. Thus, somatostatin is secreted by the delta cells in response to a meal, diffuses to the nearby alpha and beta, and inhibits secretion of their respective hormones.

• May circulate in blood to reduce motility and secretion of gut

Paracrine interactions

Pancreatic polypeptide

Pancreatic polypeptide

• A 36-aa peptide produced by F cells of pancreas

• Acts on the GI tract to inhibit secretion of pancreatic enzymes, inhibit contraction of gallbladder, increase gut motility and gastric empting

• Stimulated by ingested proteins, CCK, secretin, gastrin, and vagal input

• Inhibited by somatostatin• Overall importance is unclear?

“Secondary” Endocrine Organs

Pineal: Melatonin, light/dark cyclesBrain: encephalins, endorphins ?Heart: Atrial natriuretic peptide (ANP) which regulates sodium

reabsorptionKidneys: Erythropoietin which stimulates red blood cell

production, renin, vitamin DDigestive organs: Secrete several hormones important in

digestive and absorptive processesLiver: insulin-like growth factors which promote tissue growthSkin: calcitrol (vitamin D3) which regulates blood calcium levelsThymus: Thymic peptides, role in maturation of immune systemPlacenta: GH and PRL-like hormones. LH like hormones. Steroids

like progesteroneAll tissues (??): products of arachidonic acid (prostaglandins,

thromboxane, prostcyclin).