1. Dr. Ayisha Qureshi Assistant Professor, MBBS, Mphil
THE ADRENAL GLAND
Dr. Ayisha Qureshi
Assistant Professor,
MBBS, Mphil

2. 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.
There are two adrenal glands, one embedded above each kidney in a capsule of fat (ad means “next to”; renal means “kidney”).

3. Epinephrine, norepinephrine,
ADRENAL GLAND
Cortex
Zona Glomerulosa
(15%)
Mineralocorticoids
Zona Fasciculata
(75%)
Glucocorticoids
Zona Reticularis
Androgens
Medulla
Epinephrine, norepinephrine,
dopamine
There are 2 endocrine organs in the adrenal gland, one surrounding the other.

4. The adrenal medulla is in effect a sympathetic ganglion in which the postganglionic neurons have lost their axons and become secretory cells. The cells secrete when stimulated by the preganglionic nerve fibers that reach the gland via the splanchnic nerves. The medulla secretes epinephrine, norepinephrine and dopamine. While the cortex is divided into 3 further zones, which are glomerulosa layer near the surface, fasciculata layer in the midcortex and reticularis near the cortical-medullary junction.

5. 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

6. PROPERTIES
All Adrenocortical Hormones are:
Derivatives of cholesterol 1.
2. Synthesized in the mitochondria & ER of the adrenocortical cells
Degraded in the liver & excreted in the bile, faeces & thru the kidneys. 3.
Lipophilic & so carried bound to plasma proteins 4.
Because the adrenocortical hormones are all lipophilic and immediately diffuse through the plasma membrane of the steroidogenic cell into the blood after being synthesized, the rate of secretion is regulated by controlling the rate of synthesis.
Being lipophilic, the adrenocortical hormones are all carried in the blood extensively bound to plasma proteins.

7. Adrenocortical hormones
(promote salt & water retention by the kidneys)
Mineralocorticoids
ALDOSTERONE
Transported by Albumin
(Increase blood glucose levels)
Glucocorticoids
Corticosterone
CORTISOL
Transported by Transcortin (corticosteroid-binding globulin)
Androgens
(have androgenic effects)
Dehydroepiandro-sterone (DHEA)
Androstenedione
Because the steroid hormones are lipophilic and therefore soluble in blood, thus they are carried in the plasma bound to the plasma proteins. This increases their half-life and also remember, bound hormone is inactive. This is also a way of providing a store of hormones, so that as the requirement increases, more hormone is released from the bound form and made available for use. Bound hormones are physiologically inactive. The relationship is similar to that of T4 and its binding protein.

8. Biosynthesis of adrenocortical hormones

9. Synthesis of cholesterol from acetyl co-A.
The precursor for all steroid hormones is CHOLESTEROL. The sources of cholesterol are:
Import of cholesterol from circulating LDL thru LDL-receptor mediated endocytosis
Synthesis of cholesterol from acetyl co-A.
Cholesterol is synthesized primarily in the liver, is an important component of cell membranes and serves as a precursor for bile acids & steroid hormones.

11. LDL-Receptor Mediated Transport
LDL receptors are especially abundant in adrenocortical cells. The cholesterol is esterified and stored in lipid droplets.

12. What happens if there is deficiency of:
Cholesterol desmolase (here cholesterol cholesterol monoxygenase)
21-hydroxylase deficiency
11-beta-hydroxylase deficiency

13. Side chain cleavage enzyme is also called the cholesterol desmolase
Side chain cleavage enzyme is also called the cholesterol desmolase. If this enzyme is deficient in utero, it proves fatal because it prevents the placenta from making the progesterone necessary for pregnancy to continue. The point to note is the enzymes is blue. Interestingly no adrenocortical hormone will be formed if the enzyme 21-hydroxylase is missing. Similarly, Aldosterone synthase is present only in the zona glomerulosa and so aldosterone is formed only this zone and not in any other…..While 11-beta-hydroxylase is found in both zona fasciculata and reticularis and so corticosterone is formed in both the zones.

15. 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.)

16. MECHANISM OF ACTION

18. Receptor Types & Specificity
Each 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.

19. Relative Potency of Natural & Synthetic steroids Aldosterone'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
CORTICOSTERONE
0.3 15
ALDOSTERONE
3000
PREDNISONE
Synthetic 4
0.8
9α-FLOROCORTISOL 10
125
DEXAMETHASONE 25
aValues are approximations based on liver glycogen deposition or anti-inflammatory assays for glucocorticoid activity, and effect on urinary Na+/K+ or maintenance of adrenalectomized animals for mineralocorticoid activity. Also taken into consideration is the affinity for the GR and MR (receptors).

20. ALDOSTERONE

21. Synthesis:
Derivative of cholesterol in the mitochondria & ER of cells of zona glomerulosa.
Transport:
Bound to ALBUMIN! But only about 60%. About 40% is free.
Half life:
Thus, shorter half life of about 20 minutes!
ALDOSTERONE
Is a mineralocorticoid so called because of its effect on the minerals (Na & K) of the body.

22. ACTIONS OF ALDOSTERONE
SITE OF ACTION: Kidneys+sweat +salivary glands+Intestines
↑ Na Reabsorption
↑ K excretion
↑ Water reabsorption
↑ H ion excretion in exchange for Na
Na in the extracellular space retains water- it is the primary osmotically active particle in the extracellular space- and thus the amount of Na that is present determines the volume of ECF. The extracellular volume is itself a prime determinant of arterial blood pressure. And therefore aldosterone plays an important role in the maintenance of blood pressure.
So, Aldosterone and other steroids with mineralocorticoid activity increase the reabsorption of Na from the Urine, sweat, saliva, and the contents of colon. In the kidneys they act primarily on the principal (P) cells of the collecting ducts.

23. ↑ Hydrogen excreted in exchange for Na
↑ Na Reabsorbed +
↑ Potassium excretion
↑ Water Reabsorbed
↑ Hydrogen excreted in exchange for Na
↑ Plasma vol.
↑ Blood Pressure
Mild Alkalosis
Hypokalemia
Under the influence of Aldosterone, increased amounts of Na are in effect exchanged for K and H in the renal tubules, producing a K diuresis and an increase in urine acidity.

24. Altered cell function:
In the target organ, when Aldosterone complexes with MR, it causes increased transcription of mRNAs. This increases protein synthesis which alters cell function.
Altered cell function:
↑ synthesis and activity of epithelial Sodium channels (ENaCs)
This increases Na reabsorption & K excretion.
↑ activity of Na-K exchangers
MR: Mineralocorticoid Receptor

25. Regulation of Aldosterone Secretion:
1. ↑ACTH secretion from PITUITARY
↑Aldosterone
An extremely mild effect!
2. ↑ Activity of Renin- Angiotensin system
↑ Aldosterone
A very potent effect!!
3. ↑ K and Na plasma conc.
↑ K has a more potent effect while ↓ Na has a mild effect.
Interestingly, the most potent effect is of renin and increased plasma potassium conc. Na plasma levels will have to decrease by about 20mEq/L to stimulate Aldosterone but changes of this magnitude are rare. While increase in K levels by only 1 mEq/L stimulates the K secretion and transient increases of this magnitude occur even after a K- rich meal.

26. POINT TO REMEMBER:
ACTH from the Anterior pituitary is necessary for Aldosterone secretion but has little effect in controlling the rate of secretion!

27. Increased blood pressure stimulates secretion of ANP (atrial natriuretic peptide) from the atrial muscles of the heart. ANP causes excretion of Na in spite of increase in aldosterone secretion. It also causes pressure diuresis (excretion of excess salt and water after high blood pressure) through urine. This decreases the salt and water content in ECF, in spite of hypersecretion of aldosterone.
Besides ANP, two more peptides BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide) are also secreted by the cardiac muscle. BNP and CNP also have similar actions as ANP.

29. DOES ANY OTHER ADRENOCORTICAL HORMONE HAVE MINERALOCORTICOID ACTIVITY?
Yes, Cortisol does have MINERALOCORTICOID activity (to the same extent as its glucocorticoid activity) and it also has great affinity for the MR. Corticosterone also has mineralocorticoid activity (15 times its glucocorticoid activity). However, the renal epithelial cells have the enzyme 11-beta-hydroxysteroid dehydrogenase type II. This enzyme converts Cortisol to cortisone. Cortisone does not bind to the MR and does not have mineralocorticoid activity.
IF SO, THEN WHY DO THEY NOT EXERT THEIR EFFECT THROUGH THE MR (MINERALOCORTICOID RECEPTOR)?

30. WHAT WILL HAPPEN IF THERE ARE NO MINERALOCORTICOIDS BEING PRODUCED IN THE BODY?

31. Without mineralocorticoids:
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.

32. WHAT HAPPENS IF THERE IS EXCESS ALDOSTERONE SECRETION?

33. What happens if Excess Aldosterone secretion?
Effect on Sodium conc.
Only a few mEq rise in Sodium ECF levels.
B/c simultaneous osmotic absorption of equivalent amounts of water
Effect on Potassium conc. (normal levels: 4.5mEq/L)
Hypokalemia (2mEq/L)
Severe muscle weakness.
Effect on Hydrogen ion conc.
Hydrogen ion conc. decreased
Mild Alkalosis
Also, Na doesn’t increase for another reason: Small increases in extracellular fluid sodium concentration stimulate thirst and increased water intake, if water is available. Therefore, the extracellular fluid volume increases almost as much as the retained sodium, but without much change in sodium concentration.

34. 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
Figure shows Effect of aldosterone infusion on arterial pressure, extracellular fluid volume, and sodium excretion in dogs. Although aldosterone was infused at a rate that raised plasma concentrations to about 20 times normal, note the "escape" from sodium retention on the second day of infusion as arterial pressure increased and urinary sodium excretion returned to normal.
This return to normal of salt and water excretion by the kidneys as a result of pressure natriuresis and diuresis is called aldosterone escape. Thereafter, the rate of gain of salt and water by the body is zero, and balance is maintained between salt and water intake and output by the kidneys despite continued excess aldosterone. In the meantime, however, the person has developed hypertension, which lasts as long as the person remains exposed to high levels of aldosterone. This aldosterone escape is a work of the ANP as explained in the earlier slides.

35. 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.

36. CORTISOL

37. 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 minutes.

38. BIOSYNTHESIS of CORTISOL
Cholesterol ↓cholesterol desmolase Pregnenolone ↓17-α- hydroxylase 17-hydroxypregnenolone ↓3-β-hydroxydsteroid dehydrogenase Progesterone →17-hydroxyprogesterone ↓21-β-hydroxylase 11- deoxycortisol ↓11-β-hydroxylase cortisol

39. ACTIONS OF CORTISOL 1. METABOLISM STRESS & INFLAMMATION 2.
3. BLOOD CELLS

40. EFFECT ON METABOLISM

41. CHO METABOLISM
1. Increased Gluconeogenesis in Liver
a. Increasing the activity of enzymes needed for gluconeogenesis.
b. Increased mobilization of amino acids from extrahepatic sites mainly muscle.
2.Decreased Utilization of Glucose
Inhibits the uptake and utilization of glucose by peripheral cells
This actions is called ANTI-INSULIN action of glucocorticoids
3. ADRENAL DIABETES
Increased Gluconeogenesis
Decreased Glucose Utilization
Increased blood Glucose levels
It has a permissive effect on Glucagon. Glucagon cannot exert its effect in its absence. Hyposecretion of glucocorticoids causes hypoglycemia and fasting during adrenal insufficiency will be fatal. It decreases blood glucose levels to a great extent, resulting in death.

42. PROTEIN METABOLISM
Decrease in Cellular proteins
↑Catabolism of all cellular proteins except liver.
By ↓AA transport into extrahepatic tissues.
Increases Liver & Plasma Proteins
Paradoxically, there is ↑ AA transport into Liver cells for Gluconeogenesis.
↑ Plasma protein formation in the Liver (for transport of cortisol).
In hypersecretion of glucocorticoids, there is excess catabolism of proteins, resulting in muscular wasting and negative nitrogen balance.

43. FAT METABOLISM ↑ oxidation of Free fatty acids
Conserves Glucose & Glycogen
Shifts the energy metabolism to FAT
Mobilizes the fatty acids from the adipose tissue
Increases the concentration of fatty acids in blood.
↑ oxidation of Free fatty acids
(ketogenic effect of glucocorticoids)

44. FAT METABOLISM
Mobilization of fatty acids from all tissues & redistribution of this fat in an abnormal pattern.
Moon face & Buffalo Hump & around the abdomen
Strange Obesity caused by Excess Cortisol:

45. Effect on STRESS & INFLAMMATION

46. ACTIONS ON STRESS 1.
Exposure to stress increases ACTH secretion which increases the Cortisol secretion 2.
Release of fatty acids from cells for the production of more energy during stress. 3.
Immediate release & transport of amino acids to liver for synthesis of new proteins & other subs. Essential to withstand stress.
They also cause enhancement of vascular response to catecholamines and fatty-acid mobilizing action of catecholamines, which are necessary to withstand the stress. It also prevents severity of other changes in the body caused by stress.

47. The process of Inflammation: Inflammation is defined as a localized protective response induced by injury or destruction of tissues. When the tissue is injured by mechanical or chemical factors, some substances are released from the affected area. These substances evoke a series of reactions in the affected area.
Some of the chemical substances that are secreted and lead to the process of inflammation are: histamine, serotonin, leukotrienes, PG, bradykinin. All these substances cause vasodilatation and erythema in the affected area. These vasodilator substances also increase capillary permeability resulting of oozing out of fluid from blood into interstitial space. Coagulation occurs in interstitial fluid because of fibrinogen and other proteins that have leaked out. All this leads to edema.

48. The Devastating effects of Inflammation

49. 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.
Cortisol stabilizes the lysosomal membranes as a primary effect.
Cortisol decreases the permeability of the capillaries as a secondary effect.
Cortisol decreases both migration of White blood cells & phagocytosis of the damaged cells in the inflamed area.
Cortisol suppresses the immune system, esp. decreasing the lymphocyte reproduction.
Cortisol reduces fever as it decreases the release of interleukin-2.

50. Immunosuppressive Effects: Role in Autoimmune diseases
Certain diseases respond well to cortisol given as “steroids”:
Rheumatoid arthritis
Rheumatic fever
Acute Glomerulonephritis
All 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.
Most of the immune system suppression is brought about by decreasing the number of circulating T lymphocytes and release of IL-2 by T-cells.

51. Effect of Cortisol on: WATER & MINERALS ON BONE
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.
It stimulates the bone resorption (osteoclastic activity) and prevents bone formation (osteoblastic acitivity).
So, in hypersecretion of Cortisol, Osteoporosis occurs.

52. Effect on Blood Cells & Immunity
1. Decreases Eosinophils
2. Decreases Basophils
3. Atrophy of Lymphoid tissues:
T-cells & Ab. ↓
4. Increases RBCs
IMMUNOCOMPROMISED PATIENT
5. Increases Platelets

53. Regulation of cortisol secretion

54. 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:
Maintenance of structural integrity & vascularization of zona fasiculata & reticularis.
Conversion of cholesterol into pregnenolone.
Release of glucocorticoids

55. ACTH & POMC
Anterior 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.

56. Seen above are all the products that Proopiomelanocortin gives rise to….. However, MSH activity is shown by ACTH and other by products as well. Therefore, hypersecretionof ACTH can also cause hyperpigmentation of the skin.

57. Regulation of Cortisol Secretion
Hypothalamus (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.)

58. CRH secretion is induced by several factors as emotion, stress, trauma and circadian rhythm.

59. The Diurnal Rhythm for Cortisol
ACTH follows a circadian rhythm. The rate of secretion of both ACTH and CRF is high in the morning and low in the evening. The highest secretion of the cortisol is between 4 a.m and 10 am in the morning and it has nothing to do with the stress of getting up.

60. Question Scenario 1 Scenario 2
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.
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.