Adrenal cortex makes hormones from cholesterol (a precursor for steroids) The committed step (side chain cleavage

rx) is done by desmolase: Cholesterol pregnenolone (intermediate) Now pregnenolone is commited to becoming anyone of these 4 steroid hormones: Androgen (i.e. DHEA) Glucocorticoid (cortisol) Mineralcorticoid (Aldosterone) Testosterone (most testosterone is produced in testes not adrenal cortex) Next slide Adrenal cortex is under control of (produced by the) Stress and circadian rhythm (greater activity during waking hours) stimulate hypothalamus hypothalamus secretes corticotropin release hormones (CRH) CRH causes Corticotrophic cells anterior pituitary secrete ACTH ACTH controls Adrenal cortex (trigger 3 responses) increase growth of adrenal cortex AND increase # of enzymes such as cholesterol esterase & cholesterol esterase synthesase to secrete hormones Next slide ACTH stimulates growth of adrenal gland growth!! High ACTH Increase size of adrenal gland and release of hormones No ACTH decrease size of adrenal gland and low cortisol Next slide Cortisol functions in nutrient mobilization: 1. gluconeogenesis in Liver (increases size of liver due to increase in glucose) a. Noncarb precursors are used: i. Cortisol breaks down muscle and fat (lipolytic) 2. Stimulates appetite for more nutrients

Next slide

Cortisol Causes: Glucorticoids decrease in sensitivity to insulin (insulin resistance, antagonizing actions of insulin) = diabeticgenic

In a graph - glucose production suppression of insulin is pushed to right (insulin is less effective) In a graph glucose utilization by insulin is pushed to the right (insulin is less effective) Next slide Cortisol suppress immune and inflammatory response by: 1. blocking enzymes needed for synthesis of prostaglandins, leukotrienes and thromboxanes 2. decreasing production of lymphocytes as well as prod of antibodies. Next slide Cortisol on body tissues Muscle: protein release from muscle for gluconeogenesis Bone: increases breakdown of protein in bone especially the osteoid which results in ca release Decreases connective tissue by enhancing protein breakdown Just described the inhibition of immune and inflammatory response Tremendous influence on cardiovasc system bcuz of importance of cortisol in maintenance of endonergic receptors and therefore controls/enhancing sensitivity of catecholamines Kidneys: increases filtration Brain: enhances activity of catecholamines and therefore influences emotional state as wakefulness Maturation: cortisol enhances or increase rate of maturation of fetus and sometimes used clinically for that purpose

CUSHINGS DISEASES TOO MUCH CORTISOL Appearance Gen characteristics obestity hypertension. Skin red - because skin is thin and you can see vasculature) Hirsitisum=increase in hair. Straie= Skin thins and connective tissue that holds it together break downs and striae marks are seen due to stress

Gonatal dysfunction (no sex hormones are produced) Metabolic Kidney stones are due to increase calcium mobilization moon face (round face) Net lypolitic Increase in depositions of fat pads around trunk of body(increased sensitivity to insulin here causes a lipogenic response resulting in deposition effect) great reduction of fat on extrementies.

pendulous abdomen cuz of fatty deposition as well as tearing or scarring associated with striae. Cortisol causes catabolic breakdown of protein resulting in (3) - Poor wound healing, straie, poor m. development (weak muscles) Buffalo Hump - Fat deposition around the scapula Bone Acne Osteopenia in bone Mental problems (emotional and psycho)

Acne brusing Overall in cushing u have a lipolitic activity and an increase in fatty acids in circulation

Next slide High levels of glucocorticoids bone demineralization increase fractures (expecially in weight bearing bones like spinal column)

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Four causes of cushings

Cause Pituitary dependent Pituitary tumor (secretes POMC, which becomes alpha-MSH and ACTH)

Cortisol HIGH

ACTH HIGH

Symptoms Pigmentation even after adrenal gland is removed (both alpha-MSH and ACTH bind to melanocortin receptors and increase melanin production

Adrenal dependent

Adrenal Adenoma or carcinoma

HIGH

LOW (suppressed via feedback from cortisol) LOW (suppressed via feedback from cortisol) LOW Large Adrenal Gland

Non-pituitary or atropic tumor producing ACTH Exogenous Cushings (glucocorticoid injection for decreasing inflammation: immune suppression) Injection of Lots of Cortisol

HIGH

HIGH

Small Adrenal Gland (takes a while for it to regain function when injections are stopped, thefore you must wean the pt. off)

Note: If given numbers for Cortisol and ACTH (then HIGH use LOW as relatives; i.e. for Exogenous Cushings

 Cortosol levels >ACTH)

Next slide Cushings can increase action of 3 hormones (may not see all 3): Increased Glucocorticoids steroid diabetes (decrease in insulin sensitivity causing impaired glucose tolerance or hyperglycemia) Increased Aldosterone NA reabbsorption and K excretion retention of these leads to metabolic alkalosis. Increased androgens or estrogens Changes in the oligio or ammenerrhea or male sex dysfunction Next slide PMNT enzyme in the adrenal medulla converts norepinephrine to epinephrine increase in epinephrine production increase in cardiovascular response hypertension. High Cortisol levels cortisol binds to mineralcorticoid receptor activitysodium retentionextracellular fluid volume change. Note: Under normal circumstances the cortisol is blocked from binding to the mineralcorticoid receptor because of the enzyme that converts cortisol to cortisone, when u have high levels of cortisol like in cushings then it can still bind and once it binds to the receptor u can have a mineralcorticoid effect.

ADDISIONS DISESASE TO LITTLE GLUCOCORTICOIDS

ALL ADDISIONS PATIENTS SUFFER FROM: Weakness Fatigue Loss of appetite Weight loss (due to decrease in capacity to mobilize nutrients) anorexia ( high alpha-MSH, which decrease appetite so in absence of cortisol, alpha msh goes up)

MOST PATIENTS HAVE: Hyperpigmentation:92%, Hypotension: discussed hypotension, lack of influence on blood pressure due to cardiovascular mechanisms as well as neuromechanisms. 88%, gastrointensinal disturbances: secretion goes down. 56%, salt craving: increases 19%, postural hypotension (aka orthostatic hypotension) 12%

How to diagnose TYPES OF ADDISIONS Cause Cortisol Response to CRH injection Increase ACTH NO CHANGE

Adrenal insufficiency Pituitary insufficiency

LOW LOW

Next slide: Cause of Addisions can be deficiencies in adrenal enzymes like 11- and 21-hydroxylases and dehydrogenases that make coritsol

TX

Normal Cortisol

Cushings (HIGH CORTISOL)

Addisons (LOW CORTISOL) Decreased Enzyme activity (even if epinephrine or glucogon are present to stimulate gluconeogenesis) Decrease lipolysis and decreased adiposity Decreased adiposity is due to: decreased appetite and gi function decrease in nutrient intake Decrease in adiposity hypoinsulinemia with relative hyperinsulinemia (due to increased sensitivity to insulin) which lowers glucose levels Low response to SS increased insulin sensitivity (hypoglycemia)

Liver

gluconeogenic enzymes depend on cortisol for activity (cortisol is permissive)

Increases gluconeogenic enzyme activity Increased gluconeogenesis

Adipose

Generally Lipolytic (depends on where fat deposition is)

Lipolytic but together w. insulin can be lypolytic (moon face and buffalo hump, and trunk have increased insulin sensitivity)

Pancreas

Hyperinsulinemia with relative hypoinsulinemia (due to insulin resistance) which decrease glucose levels High Response to SS increase and maintain plasma glucose. impaired glucose tolerance (insulin resistance hyperglycemia) Metabolic Alkalosis

Adrenal Plasma Glucose

Kidney

Retention of Na and bases

Hyponatremia (loss of sodium) and Acidosis

Excrete of water

Poor water excretion

Decrease Ca reabsorption

Hypercalciuria (loss of ca via urine) Excessive formation of bone

No Change

Bone

Inhibits bone deposition and collagen production Increase Bone turnover

No change

Excessive matrix turnover Muscle weakness

Muscle

muscle break down (protein in muscle) Stimulate Appetite Stimulate reabsorption (i.e. ca and mg)

GI

appetite goes up gastric secretions increase

Decreased Appetite Decreased GI secretions

Skin Heart Hypertension (high BP) - increase in fluid retention and increased endonergeic receptors. More blood cells (increased hemoglobin) Immune system Suppressed (decreased monocytes) Orthostatic hypotension (low BP)

Anemia (especially women) Stimulated (increased monocytes)

Inflammatory response

surpressed

Note: Glucocorticoids (cortisol) decrease Carrier/Binding Proteins (i.e. anything that BG at the end of it: CBG, SHBG, TBG and IGFBPs) increasing levels of ALL FREE HORMONES for ALL HORMONES which will negatively feedback to DECREASE TOTAL HORMONE LEVELS!!!