THE ADRENAL GLAND

THE ADRENAL GLANDS

• 2 in number• Each weighs about 4 gms.• They are located above the

upper pole of each kidney in the retroperitoneal space.

• Each adrenal is composed of 2 distinct parts:- Adrenal cortex

- Adrenal medulla• Embryologically, the cortex

is derived from the mesoderm whereas the medulla is derived from the neural crest cells that migrate into the developing cortex.

Each Adrenal Gland consists of a STEROID-SECRETING CORTEX and a CATECHOLAMINE-SECRETING MEDULLA.

On the basis of their primary action, the adrenal steroids (the adrenocortical hormones) can be categorized into: •Mineralocorticoids•Glucocorticoids•Sex Hormones esp. Androgens

PROPERTIES

Adrenocortical hormones

BIOSYNTHESIS OF ADRENOCORTICAL HORMONES

LDL-Receptor Mediated Transport

What happens when there is a deficiency of the enzyme 21 α-Hydroxylase Deficiency?

From the last slide we can predict that deficiency of this enzyme will lead to inadequate production of both glucocorticoid and mineralocorticoid hormones. Affected infants are ill with symptoms of: •Mineralocoroticoid deficiency. •Glucocorticoid deficiency.Congenital defects in the enzymes lead to deficient cortisol secretion and the syndrome of congenital adrenal hyperplasia. The hyperplasia is due to increased ACTH secretion. All the precursor molecules are converted into Androgens which leads to “virilization” of the infant which means more male characteristics which will be more apparent in the female child.

(detail with the pathophysiological disorders.)

MECHANISM OF ACTION

Receptor Types & SpecificityEach of the adrenocortical steroid hormones binds with a receptor specific for it within the cytoplasm of the hormone’s target cells:

•MR- Mineralocorticoid Receptor: binds a mineralocorticoid.•GR- Glucocorticoid Receptor: binds a glucocorticoid. •AR- Androgen Receptor: binds dehydroepiandrosterone.

As is true of all steroid hormones, each hormone-receptor complex moves to the nucleus and binds with a complementary hormone-response element in DNA, namely the mineralocorticoid response element, glucocorticoid response element, and androgen response element. This binding initiates specific gene transcription leading to synthesis of new proteins that carry out the effects of the hormone.

Relative Potency of Natural & Synthetic steroidsAldosterone's mineralocorticoid activity is about 3000 times greater

than that of cortisol, but the plasma concentration of cortisol is nearly 2000 times that of aldosterone.

STEROID ORIGIN Glucocorticoid activity

Mineralocorticoid activity

CORTISOL Natural 1.0 1.0

CORTICOSTERONE Natural 0.3 15

ALDOSTERONE Natural 0.3 3000

PREDNISONE Synthetic 4 0.8

9α-FLOROCORTISOL Synthetic 10 125

DEXAMETHASONE Synthetic 25 0

ALDOSTERONE

ALDOSTERONEIs a mineralocorticoid so called because of its effect on the minerals (Na & K) of the body.

ACTIONS OF ALDOSTERONE

In the target organ, when Aldosterone complexes with MR, it causes increased transcription of mRNAs. This increases

protein synthesis which alters cell function.

Regulation of Aldosterone Secretion:

POINT TO REMEMBER:

ACTH from the Anterior pituitary is necessary for Aldosterone secretion but has little effect in

controlling the rate of secretion!

IF SO, THEN WHY DO THEY NOT EXERT THEIR EFFECT THROUGH THE MR (MINERALOCORTICOID

RECEPTOR)?

DOES ANY OTHER ADRENOCORTICAL HORMONE HAVE MINERALOCORTICOID ACTIVITY?

WHAT WILL HAPPEN IF THERE ARE NO MINERALOCORTICOIDS BEING PRODUCED IN

THE BODY?

Total loss of adrenocortical secretion usually causes death within 3 days to 2 weeks unless the person receives extensive salt therapy or

injections of mineralocorticoids.

Without mineralocorticoids:•Potassium ion concentration of the extracellular fluid rises markedly.•Sodium and chloride are rapidly lost from the body.•Total extracellular fluid volume and blood volume become greatly reduced. •The person soon develops diminished cardiac output, which progresses to a shock like state, followed by death.

This entire sequence can be prevented by the administration of aldosterone or some other mineralocorticoid. Therefore, the mineralocorticoids are said to be the acute "lifesaving" portion of the adrenocortical hormones.

WHAT HAPPENS IF THERE IS EXCESS ALDOSTERONE SECRETION?

What happens if Excess Aldosterone secretion?

Aldosterone Escape

Excess Aldosterone secretion↓

Na & water retention↓

Increased blood volume↓

Pressure Natriuresis & Pressure Diuresis

↓Salt & water excretion returns to

normal↓

This is called Aldosterone Escape

Question:

• What is Pressure Natriuresis & Pressure Diuresis?

• A rise in arterial blood pressure causes increased excretion of both salt (Pressure Natriuresis) and water (Pressure Diuresis). This is due to the secretion of ANP from the atrial muscles of the heart.

CORTISOL

• Cortisol is a Glucocorticoid so called because of its effect on glucose levels in the plasm.

• It is also a derivative of cholesterol.• About 99% cortisol binds to the plasma proteins

esp. a globulin called Cortisol Binding Globulin (CBG) or Transcortin.

• Because most of the cortisol is in bound form, thus, it has a relatively long half-life of 60-90 minutes.

BIOSYNTHESIS of CORTISOLCholesterol

↓cholesterol desmolasePregnenolone

↓17-α- hydroxylase17-hydroxypregnenolone

↓3-β-hydroxydsteroid dehydrogenaseProgesterone →17-hydroxyprogesterone

↓21-β-hydroxylase11- deoxycortisol

↓11-β-hydroxylasecortisol

ACTIONS OF CORTISOL

EFFECT ON METABOLISM

CHO METABOLISM

PROTEIN METABOLISM

FAT METABOLISM

FAT METABOLISM

EFFECT ON STRESS & INFLAMMATION

ACTIONS ON STRESS

The Devastating effects of Inflammation

How does Cortisol help in resolution of healing?

- Blocks early stages of inflammation preventing it from starting

- If inflammation already started then it causes its rapid resolution & hastens healing.

- Blocks the inflammatory response to allergic reactions. 1. Cortisol stabilizes the lysosomal membranes as a primary

effect.2. Cortisol decreases the permeability of the capillaries as a

secondary effect.3. Cortisol decreases both migration of White blood cells &

phagocytosis of the damaged cells in the inflamed area.4. Cortisol suppresses the immune system, esp. decreasing the

lymphocyte reproduction.5. Cortisol reduces fever as it decreases the release of interleukin-

2.

Immunosuppressive Effects: Role in Autoimmune diseases

• Certain diseases respond well to cortisol given as “steroids”:

- Rheumatoid arthritis- Rheumatic fever- Acute GlomerulonephritisAll these diseases are characterized by severe local

inflammation and the harmful effects are caused by the inflammation itself and not by the disease.

When cortisol is given, then the inflammation subsides within 24 hours. This prevention of the damaging effects of the inflammation alone can be a life saving measure.

It is also given in organ transplant to reduce chances of rejection.

Effect of Cortisol on:

WATER & MINERALS• Important role in maintenance

of water balance. • Accelerating excretion of

water. • Adrenal insufficiency causes

water retention & water intoxication after intake of large quantities of water.

• Increases the secretion of Na & excretion of K.

ON BONE • It stimulates the bone

resorption (osteoclastic activity) and prevents bone formation (osteoblastic acitivity).

• So, in hypersecretion of Cortisol, Osteoporosis occurs.

Effect on Blood Cells & Immunity

REGULATION OF CORTISOL SECRETION

ACTH• Major control is brought about by ACTH(Adrenocorticotropic hormone) also called Corticotropin or

Adrenocorticotropin.- Large peptide: 39 aa - secreted by the cells of the anterior pituitary gland.- ACTH secretion is regulated by hypothalamus through the corticotropin-releasing hormone (CRH).

ACTH has the following actions: 1. Maintenance of structural integrity & vascularization of

zona fasiculata & reticularis. 2. Conversion of cholesterol into pregnenolone.3. Release of glucocorticoids

ACTH & POMCAnterior pituitary secretes a large protein as a

Preprohormone called as POMC or Proopiomelanocortin, which when cleaved causes the formation of:

• ACTH• MSH (melanocyte stimulating hormone) which causes

darkening of the skin by stimulating formation of melanin & dispersing it to the epidermis

• Beta Lipoprotein• Beta endorphin & few others

ACTH also has 1/30 as much activity of MSH & so its hypersecretion also causes Hyperpigmentation of the skin.

Regulation of Cortisol SecretionHypothalamus (paraventricular cells)

↓CRH

↓Hypophsyial- Hypothalamic portal system

↓Anterior Pituitary

↓ACTH

↓Adrenocortical cells of the adrenal gland

↓Increased cAMP

↓Activates the intracellular enzymes esp. Protein kinase A

↓Conversion of cholesterol to pregnenolone (rate limiting step for all adrenocortical hormone syn.)

The Diurnal Rhythm for Cortisol

Question

Scenario 1• Make a scenario of an MCQ.

Outline the signs and symptoms that you would expect in a patient with hyposecretion of adrenocortical hormones. Give 4 options for the MCQ question.

Scenario 2• Make a scenario of an MCQ.

Outline the signs and symptoms that you would expect in a patient with hypersecretion of adrenocortical hormones. Give 4 options for the MCQ question.