Physiology adrenocortical hormones

1. ADRENOCORTICAL
HORMONE (ACTH)
MBBS 2nd PROFESSIONAL
DATED: 14TH JUNE, 2021
BY
DR. HASSAN BIN ASIF
ASSISTANT PROFESSOR
DEPARTMENT OF BIOCHEMISTRY
AL-TIBRI MEDICAL COLLEGE
ISRA UNIVERSITY KARACHI CAMPUS

2. OBJECTIVE:
Introduction about ACTH
Classification of ACTH
Structure and Function Relationship
To Discuss the effects of Glucocorticoids on
Carbohydrate, Proteins and Fats Metabolism

3. ADRENAL STEROID HORMONES:
Steroid Hormones Produced by Adrenal Cortex:
 About 50 steroids have been isolated from the adrenal cortex.
 Only 7 (seven) are important and known to possess physiologic activity.
 All derived from cholesterol.
 Contain the steroid nucleus, called “cyclo-pentano perhydro phenanthrene” nucleus.
 Seven important hormones are:
1) 11-dehydro corticosterone (DOC)
2) Corticosterone
3) Cortisone (Compound E)
4) Cortisol (17-OH corticosterone)  major adrenocortical hormone in human plasma
5) Aldosterone (mineralo-corticoid)
6) Androstenedione
7) Dehydroepiandrosterone (DHE)

4. Classification:
 According to Structure:
• Two C side chains
• Have Glucocorticoid
and mineralocorticoid
activity
• O2 atom or –OH group at
C-17
• Called as 17-oxosteroids
• Have androgenic activity

5. According to Function:
1. Glucocorticoids:
 Primarily affect metabolism of carbohydrates, proteins and lipids
and relatively minor effects on electrolytes and water metabolism.
 Cortisol, cortisone and corticosterone are examples.
2. Mineralo-corticoids:
 Primarily affect the reabsorption of Na+ and excretion of K+
(Mineral metabolism) and distribution of water in tissues.
 Aldosterone (chief mineralocorticoid), corticosterone, 11-
deoxycortisol and 11-deoxycorticosterone (DOC) are examples.
3. Cortical sex hormones:
 Primarily affect secondary sex characters.
 Androgens and estrogens are examples.

6. Relation of Structure with Functions:
 Three structural features are essential for all known
biological actions of the natural C21 adrenocortical
hormones:
1. A double bond at C4 and C5
2. A ketonic group (C = O) at C3
3. A ketonic group (C = O) at C20.
 Certain additional structural features have a profound
effect upon the biological activity of these
compounds:
1. An –OH group at C-21 enhances Na-retention and is
required for activity in carbohydrate metabolism.
2. The presence of ‘O’ either as –OH GR or as =O
group, i.e. hydroxyl or ketonic group of C11 is
necessary for carbohydrate activity and decreases
Na+ retention.
3. An –OH GR at C17 increases carbohydrate activity

7. Biosynthesis of Glucocorticoids:

8.  ACTION OF ACTH ON CORTISOL FORMATION:
 ACTH stimulates the synthesis and secretion of glucocorticoids by
1. Increasing the availability of “free cholesterol” in fasciculata cells through
 cAMP  activates the enzyme cholesteryl esterase, which hydrolyses
cholesterol esters and increases free cholesterol in cells.
 Increases transfer of free cholesterol from plasma lipoproteins into fasciculata
cells, probably by increasing “lipo-protein” receptors on plasma membrane of
fasciculata cells.
2. ACTH increases the conversion of cholesterol to pregnenolone, the “rate-
limiting” step.
3. ACTH also stimulates the HMP-shunt pathway by increasing the activity of G-
6-PD and phosphogluconate dehydrogenase  more NADPH is provided which
is required for hydroxylation reactions.
4. ACTH also increases the binding of cholesterol to mitochondrial Cyt-P450
necessary for hydroxylation reactions.

9. MECHANISM OF ACTION:
 All of the steroids act primarily at the level of cell nucleus to increase m-RNA and
protein synthesis.
 First step  binding of the steroids to a corresponding specific receptor protein present in
cytosol.
 Glucocorticoids pass into target cells through plasma membrane and binds to specific
glucocorticoid receptor protein present in cytosol.
 The receptors occur in a wide variety of target tissues, viz. liver, muscles, adipose tissue,
lymphoid tissue, skin, bone, fibroblasts, etc.
Types of Receptors in Humans:
 There are two types of receptor proteins:
1. α form: 777 amino acids
2. β form: 742 amino acids.
Both differ in amino acid sequence in the C- terminal end.

10. Mechanism of Glucocorticoid Action:
 Three distinct domains.
 A heat-shock protein, hsp90, binds to
the receptor in the absence of hormone
and prevents folding into the active
conformation of the receptor.
 Binding of a hormone ligand causes
dissociation of the hsp90 stabiliser and
permits conversion to the active
configuration.

11. METABOLIC ROLE OF GLUCOCORTICOIDS:
Points to note:
 In general, glucocorticoids have anti-insulin effect
 Glucocorticoids are catabolic to peripheral tissues and anabolic to liver.
1. Effects on Carbohydrate Metabolism:
Over-all effect increases blood glucose ↑ level (Hyperglycaemia).
Mechanism of hyperglycaemia:
1. Glucose uptake and utilisation in muscles, in adipocytes and lymphoid cells by
inhibiting the membrane transport of glucose into these cells.
2. Gluconeogenesis in liver.
 Induces the synthesis of key gluconeogenic enzymes such as pyruvate
carboxylase, PEP carboxykinase, fructose 1-6-bi-phosphatase and Glucose6-
phosphatase.
 By making available more of substrates required for gluconeogenesis by protein
catabolism in extrahepatic tissues.
 incorporation of amino acids in protein in peripheral tissues.

12.  Synthesis of some key enzymes required for amino acid catabolism like,
alanine transaminase, tyrosine transaminase, tryptophan pyrrolase, etc.
3. Glycolysis in peripheral tissues:
 In liver: Glucocorticoids are anabolic. It increases the glycogen store in
liver. This is due to: – Increase in gluconeogenesis from amino acids and
glycerol.
 Activates protein-phosphatase-1, which dephosphorylates and activates
glycogen synthase, the key enzyme for glycogen synthesis.
 Stimulates the synthesis of glycogen synthase also.

13. 2. Effects on Lipid Metabolism:
Net effect FFA in plasma and also glycerol.
 Glycerol is utilised for gluconeogenesis in liver.
In adipocytes:
 Glucocorticoids increases ‘lipolysis’ and liberates FFA and glycerol
by activating hormone sensitive TG lipase.
 As glucocorticoids decrease the uptake of glucose in adipose tissue,
there will be reduction in α-glycero-P, as a result esterification
suffers, hence net flow of FFA in plasma increases.

14. 3. Effects on Protein Metabolism:
 In peripheral extrahepatic tissues, cortisol is catabolic and increases
protein breakdown, leading to increased ‘amino acids’ availability
in plasma.
Reasons of increased catabolism:
 Enhances synthesis of key enzymes of amino acid catabolism like
Transaminases, Tyrosine transaminase, Tryptophan pyrrolase, etc.
 Decreased incorporation of amino acids in protein molecule.

15. In liver:
 Cortisol is anabolic, it increases protein synthesis.
It increases
 Hepatic uptake of amino acids.
 Incorporation of amino acids into ribosomal proteins.
 Increased m-RNA formation and synthesis of proteins including
plasma proteins.
 In liver, cortisol also enhances urea synthesis from amino acids.
 There is increased synthesis of enzymes necessary for urea cycle, e.g.
arginino succinate synthetase, arginase, etc.
 Over-all effect on protein metabolism by cortisol is “Negative
Nitrogen Balance”.

17. Other Actions:
1. Permissive Action:
 Required for adipokinetic activity of GH.
 Required for calorigenic action of glucagon and catecholamines.
2. Anti-inflammatory Action:
 Therapeutic doses exert an anti-inflammatory effect.
Mechanism: Three basic mechanisms are
1. Action on Lysosomes:
 Stabilises cell membrane of lysosomes and thus block the release of
lysosomal hydrolases.

18. 2. Action on Kinin Formation:
 Prevents formation of bradykinin which is produced by action of
Kallikrein, a proteolytic enzyme on α-globulin.
3. Action on Capillaries:
 Decreases permeability of capillary walls and prevent protein
leakage.
4. Decreases the formation of PGs, PG-I2, Tx and leukotrienes by
inhibiting phospholipase A2.
5. Prevents the release of histamine from mast cells.
6. Reduces fibroblastic proliferation and collagen synthesis.
7. Inhibits the release of “interleukin-I” from granulocytes.
8. Decreases the number of circulating lymphocytes (lymphopenia),
eosinophils and monocytes.

19. Immuno-suppressive Effect:
 Cortisol decreases immune response associated with infections and
allergic states.
 Also used for purpose of repressing antibody formation.
Effect on Exocrine Secretion:
 Chronic and prolonged treatment with glucocorticoids causes:
1. Increased secretion of HCl.
2. Increased secretion of pepsinogen in stomach
3. Increases trypsinogen secretion in pancreatic juice

20. Effect on Bones:
 Glucocorticoids reduce the osteoid matrix of bone, thus favouring
osteoporosis and there may be excessive loss of calcium from the
body.
Haematological Changes:
 Large doses of glucocorticoids causes destruction of lymphocytes.
 Shift lymphocytes to lymphoid tissues producing “Lymphopaenia”.
 Reduction in circulating monocytes and eosinophils.
 Hypofunctioning of adrenal cortex results in ‘Lymphocytosis’.