ACTH is a polypeptide hormone released by the anterior pituitary gland that controls secretions of the adrenal cortex. CRH from the hypothalamus stimulates production and release of ACTH. The adrenal cortex is divided into three zones that synthesize and secrete different types of steroids: mineralocorticoids in the outer zone, glucocorticoids in the middle zone, and adrenal androgens in the inner zone. Glucocorticoids such as cortisol are involved in metabolism and stress response and have anti-inflammatory and immunosuppressive effects.

1. ACTH is a polypeptide hormone which controls the secretions of
adrenal cortex and is released by Anterior pituitary gland.
Corticotropin-Releasing Hormone (CRH) from hypothalamus is
responsible for the production and release of ACTH.
Regulation of Secretion
Secretion of ACTH is controlled by the hypothalamic Corticotropin
Releasing Hormone (CRH) that is released under the influence of
emotion, stress, trauma. Vasopressin and catecholamine also
stimulate ACTH secretion. On the other hand, ACTH secretion is
suppressed by adrenal corticosteroids (glucocorticoids), either by
direct action or by inhibiting CRH release
Adrenocorticotropic Hormone & Corticosteroids

4. The adrenal cortex is divided into three zones that synthesize
various steroids from cholesterol and then secrete them.
•The outer zona glomerulosa produces mineralocorticoids
(aldosterone), which are responsible for regulating salt and
water metabolism. Production of aldosterone is regulated
primarily by the renin- angiotensin system.
•The middle zona fasciculata synthesizes glucocorticoids
(cortisol), which are involved with normal metabolism and
resistance to stress.
•The inner zona reticularis secretes adrenal androgens
(dehydroepiandrosterone)

5. Corticosteroids
Corticosteroids are the class of steroid hormones. These are
produced in the adrenal cortex. These are the class of drugs that
lower the inflammation in the body. They also reduce the activity of
immune system.
Two types of corticosteroids are:
1) Glucocorticoids: These corticosteroids control carbohydrate, fat
and protein metabolism. They show anti-inflammatory action by
inhibiting phospholipidelease, reducing eosinophil action, and by
a number of other mechanisms.
2) Mineralocorticoids: These corticosteroids regulate the electrolyte
and water levels by stimulating sodium retention in the kidneys.

7. Glucocorticoids: They are classified into:
(i) Natural: Cortisol,
(ii) Synthetic: (a) Short acting e.g. Cortisone, Hydrocortisone
(b) Intermediate acting e.g. Prednisone, Prednisolone
(c) Long acting e.g. Betamethasone, Dexamethasone
Physiological action:
1. Carbohydrate metabolism: Stimulate the formation of glycogen in liver
and muscles and increase gluconeogenesis in liver.
2. Protein metabolism: It increases the rate of deamination and breakdown
of tissue proteins into amino acids. Thus body proteins are lost, increasing
nitrogen excretion.
3. Fat metabolism: They act directly to breakdown triglycerides to fatty acid
(lipolysis). However, they also indirectly increase the formation and storage of
fat (lipogenesis).
4. Other metabolism: Glucocorticoids have minimal action on mineral
metabolism causing sodium and water retention and increased excretion of
K+ and PO4.

8. Pharmacological action:
1. Anti-inflammatory: Glucocorticoids inhibits the inflammatory
responses of body tissue to all kind of noxious stimuli.
2. Immunosupressant: The corticosteroids inhibit antibody formation and
antibody reaction.
3. Anti-allergic activity: They suppress immediate hypersensitivity
reaction by interfearing the release of histamine and bradykinins.
4. Body growth: Large dose of glucocorticoids retard growth of children
5. Cardiovascular system: Corticosteroids exerts positive inotropic effect.
6. Central nervous system: Increases CNS excitability, euphoria, psychosis
7. Gastrointestinal system: Increase secretion of gastric hydrochloric acid,
pepsinogen and pancreatic trypsinogen
8. Skeletal muscle: Excess corticosteroid leads to skeletal muscles
weakness and fatigue rapidly.

9. Cellular mechanism of glucocorticoids: The natural and synthetic
glucocorticoids bind to specific intracellular receptors located on the cytoplasm
of the target cells to form steroid receptor complex. The complex is then
entering to the nucleus where it binds to the nuclear acceptor site. In the
nucleus the complex interacts with the DNA and alters transcription and
translation of proteins that produce various pharmacological effects.

10. Corticosteroid is present in the blood bound to the corticosteroid
binding globulin ( CBG ) and enters the cell as the free molecule.
The intracellular receptor is bound to the stabilizing proteins, including
heat shock protein 90 Hsp 90 and several others (X ). When the complex
binds a molecule of steroid, the Hsp 90 and associated molecules are
released .
The Steroid receptor complex enters the nucleus as a dimer , binds to
the glucocorticoid response element (GRE ) on the gene, and regulates
gene transcription by RNA polymerase 2 and associated transcription
factors.
The resulting mRNA is edited and exported to the cytoplasm for the
production of protein . that brings about the final hormone response

11. Therapeutic uses: Primary adrenocortical insuffiency, Rheumatoid arthritis,
Allergic disorders, Bronchial asthma.
Adverse effects: Prolong use for more than 2 weeks produce iatrogenic
Cushing’s syndrome, steroid induced glaucoma, adrenal suppression,
superinfection.
Contraindications: Peptic ulcer, infection, hypertension, psychosis, diabetes
mellitus, osteoporosis, glaucoma, pregnancy.

13. Clinical uses of Glucocorticoids
Adrenal disorders
§ Addison’s disease (chronic adrenal cortical insufficiency)
§ Acute adrenal insufficiency associated with life threatening shock,
infections or trauma.
§ Congenital adrenal hyperplasia (in which synthesis of abnormal forms
of corticosteroids are stimulated by ACTH).
Non-Adrenal disorders
§ Allergic reactions (e.g; bronchial asthma, angioneurotic edema -
swelling in larynx and respiratory system-, drugs reactions, urticaria,
allergic rhinitis)
§ Collagen vascular disorders: Auto-immune diseases against connective
tissues (e.g; rheumatoid arthritis, systemic lupus erythematous, giant cell
arteritis, poly myositis, mixed connective tissue syndrome)
§ Organ transplant: prevention and treatment of rejection-
immunosuppression.

14. Non-Adrenal disorders
§ GIT disorders: inflammatory bowel disease, non-tropical sprue.
§ Hematologic disorders: leukemia, multiple myeloma, acquired hemolytic
anemia, acute allergic purpura ‘auto-immune disease cause destruction in the
RBCs’.
§ Infections: acute respiratory distress syndrome, sepsis -high immune cells
release-
§ Neurologic disorders: to minimize cerebral edema after brain surgery,
multiple sclerosis
§ Pulmonary disease: e.g; aspiration pneumonia, bronchial asthma,
sarcoidosis accumulation of inflammatory cells inside the lungs and lymph
§ Thyroid diseases: malignant exophthalmos , subacute thyroiditis
§ Renal disorders: nephrotic syndrome
§ Miscellaneous: hypercalcemia to secrete Ca from the body, mountain
sickness

15. Mineralocorticoids: Aldosterone is the natural mineralocorticoid in
man, but unsuitable for medical use as it is inactivated when given
orally. Fludrocortisone, a synthetic corticosteroid, is the most often
used compound when mineralocorticoid treatment is required. It is the
only compound available for oral use, and is employed for the
management of chronic primary adrenocortical insufficiency and salt
losing forms of congenital adrenal hyperplasia.
Mechanism of Action: It produces its effect by binding to the
cytosolic aldosteron receptor, a nuclear receptor. The drug receptor
complex then enters into the nucleus and binds to the specific site of
the DNA and alters transcription and translation of the protein. The
protein produces desired pharmacological activity.
Adverse effect: Oedema, hypertension and hypokalaemia.
Aldosterone antagonist: e.g. Spironolactone is used clinically as
a potassium sparing diuretics

22. Inhibitors of adrenocorticoid biosynthesis
Several substances have proven to be useful as inhibitors of the synthesis of
adrenal steroids: metyrapone, aminoglutethimide, ketoconazole, trilostane,
spironolactone, and eplerenone. Mifepristone competes with
glucocorticoids for the receptor.
1. Metyrapone: Metyrapone is used for tests of adrenal function and can be
used for the treatment of pregnant women with Cushing's syndrome.
Metyrapone interferes with corticosteroid synthesis by blocking the final step
(11-hydroxylation) in glucocorticoid synthesis, leading to an increase in
11-deoxycortisol as well as adrenal androgens and the potent
mineralocorticoid 11-deoxycorticosterone. The adverse effects encountered
with metyrapone include salt and water retention, hirsutism, transient
dizziness, and gastrointestinal disturbances.

23. 2. Aminoglutethimide: This drug acts by inhibiting the conversion of
cholesterol to pregnenolone. As a result, the synthesis of all hormonally
active steroids is reduced. Aminoglutethimide has been used
therapeutically in the treatment of breast cancer to reduce or eliminate
androgen and estrogen production. In these cases, it is used in
conjunction with dexamethasone. However, it increases the clearance of
dexamethasone. Aminoglutethimide may also be useful in the treatment
of malignancies of the adrenal cortex to reduce the secretion of steroids.
Recent studies indicate it is an aromatase inhibitor.
3. Ketoconazole: Ketoconazole is an antifungal agent that strongly
inhibits all gonadal and adrenal steroid hormone synthesis. It is used in
the treatment of patients with Cushing's syndrome.

24. 3. Trilostane: Trilostane reversibly inhibits β-hydroxysteroid
dehydrogenase and, thus, affects aldosterone, cortisol, and gonadal
hormone synthesis. Its side effects are gastrointestinal.
4. Mifepristone: At high doses, mifepristone is a potent glucocorticoid
antagonist as well as an antiprogestin. It forms a complex with the
glucocorticoid receptor, but the rapid dissociation of the drug from the
receptor leads to a faulty translocation into the nucleus. Its use is
presently limited to the treatment of inoperable patients with ectopic
ACTH syndrome.

25. 5. Spironolactone: This antihypertensive drug competes for the
mineralocorticoid receptor and, thus, inhibits sodium reabsorption in the
kidney. It can also antagonize aldosterone and testosterone synthesis. It
is effective against hyperaldosteronism. Spironolactone is also useful in
the treatment of hirsutism in women, probably due to interference at
the androgen receptor of the hair follicle. Adverse effects include
hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes.
6. Eplerenone: Eplerenone specifically binds to the mineralocorticoid
receptor, where it acts as an aldosterone antagonist. This specificity
avoids the side effect of gynecomastia that is associated with the use of
spironolactone. It is approved as an antihypertensive.