Adrenal

Adrenal gland

Dr (Mrs.)Geeta Arvind Kurhade, B. Sc., M.B.B.S., D.G.O., M.D.Senior Lecturer, Physiology Unit, Department of Basic Sciences, EWMSC,Mt.Hope

John F. Kennedy's Addison's Disease

• Addison's disease- a disorder of the adrenal system affecting digestion and causes a brownish coloration to the skin.

• Although it isn't fatal, it is uncomfortable.

Left untreated, an Addison's Crisis can be fatal.

• Symptoms of an Adrenal Crisis include:

• sudden penetrating pain in the lower back, abdomen, or legs

• severe vomiting and diarrhea

• dehydration• low blood pressure• loss of consciousness

Moon face

Cushing’s syndrome-parched skin and Buffalo hump

Some features of Cushing’s syndrome:

Adrenal gland

• Complex• Multifunctional endocrine organs.• Essential for life. • Severe illness results from their atrophy.• Death follows their complete removal, unless

life-essential hormones are replaced

Introduction• Adrenal cortex surrounds adrenal medulla.

• Adrenal Medulla- sympathetic ganglion in which neurones have lost the axons to become secretory cells) - not essential for life.

• It has two types of cells which secrete catecholamines

a) 90% large cells with dense granules → Epinephrine

b) 10% small cells with very dense granules → Norepinephrine.

Dopamine

Adrenal cortex-Salt, sugar, and sex: the deeper you go, the sweeter it gets.

• secretes steroids- essential for life

• Zona glomerulosa ( whorls of cells) → mineralocorticoids (for Na balance & ECF )

aldosteronedeoxycorticosterone

• Zona fasciculata (columns of cells)→ glucocorticoids (for metabolic effect on CHO & proteins)

cortisolcorticosterone

Zona Reticularis ( network of cells) → sex hormones(minor effect on reproductive function )

Dehydroepiandrosterone (DHEA)Androstenedione↓(produces) estrogen)

Adrenal medulla – acts as sympathetic ganglion

• Postganglionic neurons have lost their axons & became secretory cells.

• Adrenal cortical hormones are controlled by ACTH from anterior pituitary.

• Mineralocorticoids are ALSO independently controlled by circulating factors like Angiotensin II

Each adrenal gland 4 gm.

Permissive action of glucocorticoids• After removal of both adrenals humans will not survive for

long without glucocorticoid replacement.

• Cortisol has a wide range of actions, many of which are considered ‘permissive’.

• This is because it does not always initiate processes but allows them to occur by

• increasing the activity of enzymes, • inducing enzymes or• augmenting/ inhibiting the action of other hormones.

Foetal adrenal• Large & under pituitary control• 20% of foetal gland →permanent cortex• 80% foetal adrenal cortex → degenerates at birth.• The foetal adrenal cortex synthesizes & secretes conjugated

androgens which are converted to estrogens in placenta.• Zona glomerulosa secrets aldosterone & also forms new

cortical cells.• Adrenal medulla does not regenerate.• What will happen immediately to Zona glomerulosa,Zona

fasciculata and zona reticularis after hypophysectomy and why? (HW)

Actions of catecholamines (half life 2 min in circulation)Norepinephrine Epinephrine Dopamine

Formed by hydroxylation &decarboxylation of tyrosine

Formed by methylation of NE

70% of NE is conjugated & inactive

70% of E is conjugated & inactive

95% conjugated

Normal plasma level in recumbent human:Free NE= 300pg/ml↑ up to 50-100% on standing

Free E=30 pg/ml Plasma free dopamine level=35pg/ml

Other substances secreted by adrenal medulla:• Opioid peptide• Metenkephalin• Adrenomedullin (vasopressor)

Effects of epinephrine & norepinephrine• Glycogenolysis in liver & SKM• Mobilization of FFA• ↑ plasma lactate• Stimulates metabolic rate • ↑ force & rate of contraction of isolated heart.• ↑ myocardial excitability→ causes extra systole & serious

cardiac arrhythmia.• NE acts on α1 receptors → causes vasoconstriction• E acts on β2 receptors → vasodilation which overbalances

vasoconstriction & total PR ↑.

Effects of E & NE contd...• ↑ alertness.

• ↑ secretion of insulin & glucagon via β adrenergic mechanism.

• ↑ metabolic rate: Prompt & delayed rise

a) prompt rise due to cutaneous vasoconstriction → ↓heat loss → ↑ in body temperature.

b) delayed rise ↑ due to oxidation of lactate in liver.

Pheochromocytoma-adrenal medullary tumors

• Secrete NE & E or both → sustained hypertension.

• Sometimes episodic secretions → Pt gets bouts of palpitations, head ache, glycosuria & extreme systemic HT.

Dopamine

• Physiological fn unknown.

• ↑ systolic BP & no change in diastolic BP.

• Useful in traumatic & cardiogenic shock.

Regulation of medullary secretions

• Physiologic stimuli affect medullary secretions through nervous system.

• Catecholamine levels are low & are further low during sleep.

• Diffuse sympathetic discharge →↑ adrenal medullary secretions.

• NE →↑ secretions by emotional stress.• E →↑ secretions when the individual doesn‘t know what to

expect.

•Adrenal cortical hormones

Average daily secretions & Plasma concentrations (free & bound) of various cortical hormones• Mineralocorticoids: aldosterone-Daily secretion= .15 mg/day. Plasma concentration= .006µg/dl

deoxycorticosterone=Daily secretion= .20 mg/day. plasma concentration = .006µg/dl (3% of aldosterone activity)

• Glucocorticoids:cortisol – Daily secretion= 10 mg /day.

plasma concentration= 13.9µg/dl corticosterone – Daily secretion= 3 mg/day.

plasma concentration= .4µg/dl• Androgens:

Dehydroepiandrosterone (DHEA) - daily secretion =20 mg/dayPlasma concentration =175µg/dlAndrostenedione -daily secretion 2-3 mg/dayPlasma concentrationforms estrogens that are not formed in the ovary.

Relative potencies of corticosteroids as compared to cortisolSteroid Glucocorticoid activity Mineralocorticoid activity

Cortisol 1 1

Corticosterone .3 15

Aldosterone .3 3000

Deoxycorticosterone .2 100

Corticosterone .7 .8

Prednisolone 4 .8

Dexamethasone 25 -0

Measure of glucocorticoid activity in this table was i) liver glycogen deposition 2) anti-inflammatory assay

Measure of mineralocorticoid activity was1) Effect on urinary Na+/K+

Cholesterol desmolase X1

3β hydroxysteroid dehydrogenase X2

21 β hydroxylase X3

21 β hydroxylase X4

17 α hydroxylase 17 ,20 lyase

x2

Enzyme deficiencies• X1- Deficiency in cholesterol desmolase-fatal (why?)• X2- deficiency of 3β hydroxysteroid dehydrogenase deficiency-

causes masculinisation in female.In genetic male-not adequate to produce full masculinisation→ hypospadias

• X3- 21 β hydroxylase deficiency → causes virilization (Why?)• What does it cause in females??( AGS)• What is salt losing form of congenital virilising adrenal

hyperplasia? [21 β hydroxylase deficiency-underlying mechanism] • X4- What is hypertensive form of virilising adrenal hyperplasia? [11 β hydroxylase deficiency-underlying mechanism]

Transport, Metabolism & Excretion of Adrenocortical Hormones• Glucocorticoid- cortisol bound to α globulin k/as transcortin or

corticosteroid-binding globulin (CBG). • Half life of cortisol is longer (60-90 min) as compared to

corticosterone (50 min)as it binds to a lesser degree.• Bound form is physiologically inactive acts as reservoir of Hr to

keeps supply available to tissues.• Normal level of cortisol are 13.5 µg/dl• Corticosteroid binding globulin is produced in liver & its

production ↑ es by estrogen.• Level of CBG ↑ es in pregnancy (implications?) & decrease in

liver cirrhosis, nephrosis, multiple myeloma.• Cortisol is metabolized in liver where it is conjugated to glucoronic

acid.

Metabolism and excretion of aldosterone

• Binds to protein to slight extent.• Half time is 20 min.• Total plasma level =.006µg/dl.

Adrenal androgens

1) 17-ketosteroids dehydroepiandrosterone (DHEA)

2) Testosterone –also converted to 17 ketosteroids.

2/3rd of urinary ketosteroids in male secreted by adrenal or formed from cortisol in liver.

1/3rd are formed testicular in origin

• Notes on physiological action of adrenal cortical hormones.

• Page:35 of notes.

MCQs

Q. Which of the following are functions of glucocorticoids in normal individuals? Key: DI. protein catabolismII. gluconeogenesisIII. ketone body formationIV. hepatic glycogenolysisA. I onlyB. II and III onlyC. I and IV onlyD. I, II, and IV only

explanation

• Because glucocorticoids plasma lipid levels and ketone body formation in diabetics. In the normal individual this does not happen since insulin secretion es in response to blood sugar levels.

MCQs

Q4. Patients with obstructive jaundice have pale-colored stools because in obstructive jaundice, urobilinogens are absent from the stool. (Key: B)A. The assertion and the reason are both correct, and the reason is valid.B. The assertion and the reason are both correct, but the reason is invalid.C. The assertion is correct but the reason is incorrect.D. The assertion is incorrect but the reason is correct.E. Both the assertion and the reason are incorrect.

MCQ

• Q4. The glucocorticoids the lymphocytes in circulation because they stimulate the lymphocytic mitotic activity. (Key: E)

• A. The assertion and the reason are both correct, and the reason is valid.

• B. The assertion and the reason are both correct, but the reason is invalid.

• C. The assertion is correct but the reason is incorrect.• D. The assertion is incorrect but the reason is correct.• E. Both the assertion and the reason are incorrect.

Etiocholanolone fever ?

Plasma cortisol levels are increased by

• Stress of surgery• Burns• Infection• Fever• Psychosis• Electroconvulsive therapy• Acute anxiety• Prolonged and strenuous exercise• Hypoglycaemia.

Z. Glomerulosa (15%) ECF conc of AgII & [K+]

• Aldosterone (very potent 90% of all mineralocorticoid activity) (Aldosterone synthetase)

• Desoxycorticosterone (1/30th as potent as alodsterone) secreted in very small quantity)

• Corticosterone slight moneralocorticoid activity)

• 9α Fluorocortisol (synthetic and slightly more potent than aldosterone.

• Cortisol & Cortisone –very slight mineralocorticoid activity of both.

Z. Fasciculata(75%)- ACTH regulation

• Glucocorticoids:Cortisol-very potent 95% activity

• Corticosterone 4% activity- less potent than cortisol.

• Cortisone –synthetic activity as much as cortisol.

• Methylprednisone- (synthetic-5 times potent than cortisol.

• Dexamethasone-synthetic 30 times more potent than cortisol- no mineralocorticoid activity

• Some have both glucocorticoid & mineralocorticoid activities.

• Small amount of androgens

• Estrogens

Z.ReticularisDeeper layer of cortex

• Adrenal androgens• Dehydroepiandrosterone

(DHEA)• Androstenedione• Small amounts of

estrogens• Some amount of

glucocrticoids• Controlled by ACTH

Quiz: If the cells show following signs; then what’s up

• ↑ in the size and number of cells in the fasciculata and reticularis.

• Their mitochondria become larger and more numerous, • They develop central ribosomes and vesicular cristae.• The mitochondria also develop polylamellar membranes that

extend to nearby cholesterol-containing vacuoles. • The endoplasmic reticulum also increases. • These changes relate to ACTH stimulation and its effects on

steroid hormone synthesis.

Regulation of Zona Glomerulosa Function:

• Aldosterone- the major mineralocorticoid.• Sustain ECF volume by conserving body

sodium. • Hence, aldosterone is largely secreted in

response to signals that arise from the kidney in response to reduction in circulating fluid.

Regulation of aldosterone secretion.

• Body Na+ depletion -↓ECF & hypovolemia.

• Activation of the renin-angiotensin - the predominant stimulus to aldosterone production.

• Elevation of plasma potassium is the other major stimulus.

• ACTH has a minor tonic stimulatory role.

Sodium sparing action of aldosterone• Aldosterone controls body fluids and electrolytes balance by acting on

renal epithelium.

• Whenever blood pressure falls below a certain threshold, the renin-angiotensin-aldosterone system (RAAS) is activated and more salt and water are reabsorbed in the kidney.

• Vascular endothelium is another target for mineralocorticoids. Probably endothelium and kidney join forces in the regulation of body fluids.

• Adosterone acts not only on epithelial cells of kidney and colon but also at nonepithelial sites in brain, heart, and vasculature.

• ↑ Na + absorption in sweat glands, colon.

Source: News in Physiological Sciences, Vol. 19, No. 2, 51-54, April 2004 © 2004 Int. Union Physiol. Sci./Am. Physiol. Soc

Functions of mineralocorticoid

• Acute life saving

• Aldosterone deficiency causes severe renal NaCl wasting and hyperkalemia.

• The person will soon develop ↓ECF volume and ↓ blood volume- ↓ COP-shock like state.

• Total loss of adrenocortical secretion may cayse death within 3 days to 2 weeks unless person receives extensive salt therapy or mineralocorticoids.

Aldosterone- negative feedback relationship with potassium

• K+ acts to stimulate aldosterone secretion which facilitates the clearance of K+ from the ECF.

• Conversely, K+ depletion lowers aldosterone secretion.

Excess aldosterone-hypokalemia (implications?)

• From normal value of 4.5 mEq/L to low as 2 mEq/L.

• If [K+] ↓ to < half of normal →severe muscle weakness because alteration of the electrical excitability of the nerve and muscle fibre membrane preventing the transmission of normal action potential.

Deficiency of aldosterone: [K+] in ECF ↑ (if > 60-100%- serious cardiac toxicity, weakness of heart contraction, arrhythmia and heart failure.

Excess aldosterone ↑ tubular H+ secretion & causes mild alkalosis

• H+ are exchanged for Na+ which are excreted.• [Na+ ] in ECF ↓ causing mild alkalosis.

Regulation of aldosterone secretion

• Regulation of aldosterone by Z glomerulosa cells is independent of the regulation of corisol by Z fasciculata and androgens by Z reticularis.

• FOUR factors in order of their importance are: i) ↑ [K+] in ECF → ↑ aldosterone secretion ii) ↑ Renin Ag II activity ↑ aldosterone secretion iii) ↑ [Na+] in ECF very slightly ↓ aldosterone secretion iv) ACTH is necessary but has little effect in controlling the

rate of aldosterone secretion.• Aldosterone acts on kidney to excrete excess K+ and ↑ the

blood volume and arterial pressure thus returning renin – AgII system towards normal level of activity.

• OK

Glucocorticoids

• Cortisol-very potent 95% activity• Corticosterone 4% activity-much less potent than cortisol.• Cortisone –synthetic activity as much as cortisol.• Methylprednisone- (synthetic-5 times potent than cortisol.• Dexamethasone-synthetic 30 times more potent than cortisol-

has no mineralocorticoid activity• Some of these hormones have both glucocorticoid and

mineralocorticoid activities.

Effects on Carbohydrate metabolism-Diabetogenic

• Cortisol stimulates the release of amino acids from muscle. These are taken up by the liver and converted to glucose.

• The increased circulating concentration of glucose stimulates insulin release. Cortisol inhibits the insulin-stimulated uptake of glucose in muscle via the GLUT4 transporter.

• Cortisol has mild lipolytic effects. These are overpowered by the lipogenic action of insulin secreted in response to the diabetogenic action of cortisol.

• Cortisol also has varied actions on a wide range of other tissues

• Gluconeogenesis

Pulsatile and diurnal nature of cortisol secretion. (From Weitzman ED et al: J Clin Endocrinol Metab 33:14, 1971.)

• The plasma peaks of cortisol are determined by the frequency and duration of secretory bursts, rather than by gradual changes within a range of cortisol secretion rates.

• Thus, the basal unstimulated rate of secretion is actually near zero, and acute ACTH pulses produce essentially all-or-none adrenal responses.

• The reason for each of the daytime bursts of cortisol is unknown

Functions of glucocorticoids• Although cortisol has some minor lipolytic activity, this effect is overshadowed in a patient

with Cushing's syndrome by the increased insulin secretion in response to the diabetogenic actions of cortisol.

• Insulin has a strong lipogenic action- excess glucocorticoids and increased fat deposition. • The reason for the centripetal distribution of fat is not fully explained but probably results

from metabolic differences between adipocytes in the omentum and those situated in subcutaneous tissues.

• Bruising, scarring and purple striae around the abdomen are other classical signs of Cushing's syndrome . Cortisol inhibits fibroblast proliferation and also the formation of interstitial materials such as collagen. Excess glucocorticoids result in a thinning of the skin and the loss of connective tissue support of capillaries. This makes them more susceptible to injury and leads to bruising. Bones are also affected by excess glucocorticoids.

• Cortisol decreases osteoblast function and decreases new bone formation; osteoclast numbers increase and measures of their activity increase. Furthermore, glucocorticoids decrease gut calcium absorption and decrease renal calcium reabsorption, thus adversely affecting calcium balance. Overall excess glucocorticoids cause osteoporosis.

• Glucocorticoids have other diverse actions including those on the cardiovascular system, central nervous system, kidney and the fetus.

• In the cardiovascular system, it is required for sustaining normal blood pressure by maintaining normal myocardial function and the responsiveness of arterioles to catecholamines and angiotensin II.

• In the CNS, cortisol can alter the excitability of neurons, induce neuronal death (particularly in the hippocampus) and can affect the mood and behavior of individuals. Depression may be a feature of glucocorticoid therapy. Furthermore, depressed patients may show increased cortisol secretion with alteration in the circadian rhythm of cortisol secretion.

• In the kidney, cortisol increases glomerular filtration rate by increasing glomerular blood flow and increases phosphate excretion by decreasing its reabsorption in the proximal tubules.

• In excess, cortisol has aldosterone-like effects in the kidney causing salt and water retention. This is because the capacity of 11β-hydroxysteroid dehydrogenase type 1 enzyme that converts active cortisol to inactive cortisone in the kidney tubule is overwhelmed.

• Cortisol is then available to interact with the aldosterone receptor for which it has equal affinity .

• This may be a factor in the hypertension seen in patients with Cushing's syndrome.

• Cortisol also facilitates fetal maturation of the central nervous system, retina, skin, gastrointestinal tract and lungs.

• It is particularly important in the synthesis of alveolar surfactant which occurs during the last weeks of gestation. Babies born prematurely may suffer respiratory distress syndrome and mothers with pre-term labor may be treated with glucocorticoids to stimulate fetal synthesis of surfactant.

• One of the most important actions of glucocorticoids is on inflammatory and immune responses .

• Inflammation (increased capillary permeability, attraction of leukocytes etc.) results from injury and these effects are mediated by several factors the production of which is inhibited by cortisol.

Corticosteroids & organ transplant:

• After an organ transplant- immunosuppressant.• Because immune system will try to destroy the new

organ.• Corticosteroids e.g.prednisone or methylprednisolone is

given right before transplant, to decrease immune system's activity, reduce inflammation, and prevent rejection.

• Why?

High doses of corticosteroids• Corticosteroids are usually continued for a few days after your surgery and

then tapered to the lowest dose that helps prevent rejection. • Taking high doses of corticosteroids for just a few days : causes temporary

side effects such as high BP, high cholesterol, weight gain, sleep problems, and anxiety.

• High doses can sometimes cause more severe side effects, such as extreme agitation, paranoia, and psychosis (trouble telling the difference between what is real and what is not real) or have hallucinations.

• • Prolonged use of corticosteroids :cause glaucoma, steroid-induced

diabetes, ↑ risk of getting an opportunistic infection (such as pneumocystic pneumonia),due to weakened immune systems.

• Glucocorticoids inhibit the conversion of phosphatidyl choline to arachidonic acid by inducing the production of lipocortin which inhibits phospholipase-A2 (PL-A2).

• They inhibit the production of inflammatory prostaglandins and thromboxanes by inhibiting cycloxygenase (COX).

• They inhibit the production and action of leukotrienes which are also formed from arachidonic acid by lipo-oxygenase (L-O).

• They block cytokine (IL-1β) production, reduce the number of circulating T cells and so reduce antibody production.

• x = inhibitory effects of glucocorticoids

• Some of these factors are synthesized from arachidonic acid and cortisol inhibits the synthesis and release of arachidonic acid by inducing lipocortin which inhibits phospholipase A2.

• This enzyme releases arachidonic acid from phosphatidyl choline and, thus, the availability of arachidonic acid for the synthesis of inflammatory mediators is reduced.

• In addition glucocorticoids stabilize lysosomes, preventing the release of proteolytic enzymes.

• They inhibit the proliferation of mast cells, production of cytokines and also the recruitment of leukocytes to the site of infection or trauma.

• They also affect the numbers and functions of circulating neutrophils, eosinophils and fibroblasts.

• In addition, glucorticocoids reduce the number of circulating thymus derived lymphocytes (T- cells) and as a result the recruitment of B lymphocytes.

• The net result is to reduce both cellular and humoral immunity

Effects of cortisol on circulating leukocytes. Note the increase in neutrophils and decrease in monocytes and lymphocytes of all types. T4 helper lymphocytes were disproportionately reduced.

Eosinophils (not shown) also decrease. (From Calvano SE et al: Surg Gynecol Obstet 164:509, 1987.)

Adrenal cortical androgens• DHEA and its sulfate have an ill-defined role in normal physiology. • Together with androstenedione, they are generally termed ‘weak

androgens’ and have a much lower affinity for the androgen receptor than testosterone.

• These adrenal androgens are, however, converted peripherally to the more active testosterone .

• In males, the amount released from the adrenal glands and converted to testosterone is physiologically insignificant compared to the amount secreted by the testes.

• but, in females, adrenal-derived testosterone is important in maintaining normal pubic and axillary hair.

• After the menopause, adrenal androgens may also be an important source of estradiol, again due to peripheral conversion. Adrenal androgen hypersecretion does not cause any clinical signs in adult males but is detectable in females by signs of hirsutism and masculinization.

• Symptoms of Adrenal Insufficiency (AI)

• In patients with secondary AI, these symptoms often occur immediately. In people with primary insufficiency the symptoms of adrenal insufficiency usually begin gradually.

• In either case the characteristics of AI are:• chronic, worsening fatigue• muscle weakness• loss of appetite• weight loss • headache• slow, sluggish, lethargic movement• dehydration• high fever• chills, shaking• confusion or coma

• rapid heart rate• joint pain• abdominal pain• unintentional weight loss• rapid respiratory rate• unusual and excessive sweating on face and/or palms• possible skin rash or lesion• flank pain• irritability and depression• a craving for salty foods due to salt loss• Hypoglycemia, or low blood glucose, is more severe in children than in

adults

Addison’s Disease• About 50 percent of the time, one will notice:• nausea• vomiting• diarrhea• Other symptoms may include:• low blood pressure that falls further when standing, causing dizziness or

fainting• skin changes in Addison's disease, with areas of hyper pigmentation, or dark

tanning, covering exposed and nonexposed parts of the body.

This darkening of the skin is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes.

• menstrual periods may become irregular or stop