This document discusses adrenocortical hormones and corticosteroids. It begins by describing how corticosteroids are derived from cholesterol and the different zones of the adrenal cortex that produce glucocorticoids, mineralocorticoids, and androgens. It then covers the mechanisms of action of glucocorticoids like cortisol via glucocorticoid receptors, their therapeutic uses to treat inflammatory and autoimmune disorders, and their potential side effects. The document also discusses mineralocorticoids like aldosterone, their effects on sodium reabsorption, and synthetic alternatives like fludrocortisone. Inhibitors of corticosteroid synthesis and antagonists of mineralocorticoid receptors

1. ENDOCRINOLOGY
Dr. Ashfaq Ahmad

2. ADRENOCORTICAL HORMONE
ADRENOCORTICOSTEROIDS
CORTICOSTEROIDS
Dr. Ashfaq Ahmad

3. DERIVATIVES OF CHOLESTEROL
Carbon atoms Parent Hydrocarbon Biologically imp. compound
• C18 Oestrane Oestrogen
• C19 Androstane Androgen
• C21 Pregnane
–Progesterone
–Adrenal hormones

4. Cyclo Pentano Perhydro Phenanthrine Ring
Steroid Nucleus

7. Cholesterol
Pregnenolone
Progesterone 17-hydroxy pregnenolone
17-hydroxy progesterone
Deoxy Cortocosteron DehydroEpiandrosterone
11-Deoxycortisol
Corticosterone Androstenedione
ALDOSTERONE CORTISOLE TESTOSTERONE
Cortisone ESTRADIOL

8. C21 Steroids
SELY’S TERMINOLOGY
Glucocorticoids ( Cortisole )
– Energy metabolism
• Carbohydrate, Protein,Fat
• Mineralocorticoids ( Aldosterone )
– Electrolytes
• Na, K, Fluid balance
• Synthetic
– Prednisolone
– Dexamethasone
– 9-a-Flourocortisole

9. Adrenocortical Hormones
Z. Fasicu Z. Glomeru Z. Reticulata
Glucocorticoids Aldosterone Androgen
(Hydrocorisone) (Renin-Angiotensinsystem.)
( Salt Retaining ) - DHEA, DHEAS,
( DEHYDROEPIANDROSTERONE )
-Androstenediole
Source of ESTROGEN
- IN Or AFTER
Menopause
Net effect - Defective/Absent Ovary
1. Antagonism of Insulin
2. CVS FUNCTIONS
3. GROWTH
4. immunity

10. Steroid Preparations
• An ideal Glucocorticoid should not have
Mineralocorticoid Activity
• By structural changes (many compounds)
– With minimal Mineralocorticoid Activity
– Greater Potency
– Longer duration of action
– Stability … Plasma Half life
– Rate of Elimination

12. • Injectable
– Betamethasone,
– Dexamethasone
– Methylprednisolone
– Prednisolone,
– Hydrocortsone,
– Triamacinolone
• Oral
– Betamethasone,
– Dexamethasone
– Methylprednisolone,
– Prednisolone,
– Prednisone.
– Fludricortisone
• Topical
– Clobetasol
– Flucinolon
– Mometasone
– Betamethasone
• Inhalational
– Beclomethasone
– Budesonide
– Flunisolide

13. Mechanism of Action
Specific Receptors
•GRs
•MRs
Two Genes Control the
formation of these receptors

14. • Alternative splicing of human GR Pre-mRNA generate two
isoforms
-- hGR alpha
in human, Classic form of GRs
( transcriptionly active )
--h GR beta
- Not transcriptionaly active
- Inhibit the effects of hormone-activated
hGR alpha effects
(Physiological Endogenous relevant inhibitor)
Two hGR alternative transcripts have
8 translation initiation sites …
16 GR alpha & GR beta Isoforms ……
256 homodiamers & heterodiamers

15. Glucocorticoid Receptor
• 800 Aminoacids
• 3 Functional Domains
– Glucocorticoid binding domain
• At carboxyl terminal of the molecule
– DNA binding domain
• Located in the middle, 9 cysteine Residues, Two
finger structure Stabilized by Zinc ions …
connected with cysteine. Form two terahedrones
– Transcription activating domain
• Amino terminal ( Transactivation of receptor &
Increase specificity)

18. • Ligand binding … conformational change … (hsp90)
• Diamerization
• Entry in nucleus
• In the Responsive Gene … promoter have receptor
Element (GRE) … attachment with GRE at specific site
• Ligand bound receptor form complexes with other
Transcription Factors (AP1, NF-KB) … non GRE containing
Promoters
Contribute to
- Regulation of Transcription of responsive Genes
- Regulation of
Growth factors, proinflammotory cytokines, Antigrowth, Anti-
inflammatory, Immunosuppressive effects of
glucocortciods

19. Coregulators
Proteins (several families) are
Involved in
Interaction of ligand bound GR with GREs &
other Transcription factors
Facilitate … (co activators)
Inhibit … (co repressors)

20. Effects 0f Glucocorticoids
• Direct Effects
– Gluconeogenesis (Net
effect mimic Diabetes)
• Homeostatic Response
In Response of
– Insulin, Glucagon
• Permissive Effects
(Normal / Physiological)
– Sensitization to
Catacholamine Actions
• Vascular SMs
• Bronchial SMs
• Fat Cells
– Sensitization to
• ACTH effects
• GH effects
• Fetal Lung Maturation
• CVS
– Steroid receptors on SMs
of vessels
– Direct effects on VMS
– By sensitazation to
catecholamines
– By increasin circulating
volume
– Direct effects on Heart &
Vessel tone
B.P. Regulation

21. Therapeutic Effects/uses
• Diagnostic … dexamethasone suppression Test
• Treatment
– Defficiency
• ( HRT ( Hormone Replacement Therapy )
– Anti-inflammatory
(all steps of inflammation are blocked ( basis of use )
• Rh. Arthritis - HIV related disorders
• Br. Asthma - Shock
• Hypersensitivity Reaction
• Nephrotic Synd - Leukemia
• SLE - Cronn’s Disease
• Bell’s Palsy

22. Effects on Events of Inflammation
Dramatically reduce inflammation
suppress cytokines, chemokines,
Affect leukocytes (conc. Dist. Function)
• Infiltration of leukocytes
• White cell adhesion molecules
In the Blood
– Neutrophils
– Mono, Baso, Eosino
– Lympho ( T, B )

23. • Immunosuppression
– Antigen Presenting ( Grafted Cells )
– Delay Vascularization
– Interfere with sensitization
– Cytotoxic T-Lymphocytes ( Decrease )
– Antibody Forming Cells ( Decrease )

24. Dexamethasone Suppression
Test
• For Diagnosis of Cushing Syndrome
& Depressive Psychatric Illness
• First Screening test
– 1mg at 11 PM …. Plasma sample in morning
• If more than 5mcg ( normal 3mcg)
• Then Suppression With Large Doses
– 0.5 mg oral 6hrly for 2 days …. Urine assay
– 8mg at11PM …. Plasma cortisol in the
morning

25. Therapeutic Uses of Corticosteroids

28. COMPLICATIONS
Side effects / Toxicity
• GIT
– Peptic Ulcer
– Fatty Liver
– Pancreatitis
– Nausea, Vomiting
• Ocular
– Increased IOP
– Post. Sub. Cap. Cataract
• Skin
– Thinning,
– Achne
– Hirsutism
– Striae Pupura
• CNS
– Insomnia
– Depression
– Psychosis
– Nervousness
• Fluid & Electrolytes
– Na Retension, K loss
– Hypertension
• GeneralMetabolic
– Hyperglycemia
• Musculoskeletal
– Myopathy, Growth Failure
– Osteopenia

29. Mineralocorticoid

30. Minrelocorticoids
• Natural
– Aldosterone ( zona glomeruloza )
– Deoxycoticosterone ( DOC ) … Not used
• Synthetic
– Fludrocortisone

31. Aldosterone
• Zona glomeruloza
• Relese is through ACTH ….. 50% feed
back controle on release as compared to
cortisole
• Angiotensin Maintain & regulate
secretion

32. Physiological & Pharmacological
Effects of Aldosterone
• Reabsorption Na from DCT, which is
loosely coupled to excretion of K & H ions
– Receptors in cytoplasm of target cells
– Drug receptor complex … MOA … As “ GC ”
– This receptors has same affinity for “ GC ”
– Metebolism is same as “GC”
– DOC (Deoxy corticosterone ) is precursor as
Aldosterone

33. Fludrocortisone
• Potent Steroid
• Both Mineralocorticoid & Glucocorticoid activity
Oral 0.1mg, two to seven times weekly
( potent salt retaining activity )
Used in INSUFFICIENCY
Dose is too small to have anti inflamatory, or
antigrowth activity

34. Adrenal Androgens
• DHEA …(Alternate source of Estrogen in
menopausal age )
• Androstendione
• Testosterone
Do not stimulate or support major
androgen puberty changes

35. Synthesis inhibitors &
Glucocorticoid Antagonist
• Aminoglutethemide ( Block conversion of
cholesterol to pregnenolone )
• Ketoconazole ( antifungal.. Also block synthesis)
• Metyrapone ( block cortisole & corticosterone synthesis
• Trilostane ( inhibit adrenal & Gonadal hormones)
• Abiraterone ( Synthesis Inhibitors )
• Mifepristone ( RU–486 )…(“GC” receptor Blocker)
• Mitotane ( Cytotoxic,DDT group, less toxic for human,
ORAL, toxic effect … may reduce dose, Withdrawn in
USA, Available on compassionate

36. Mineralocorticoid Antagonist
• Spironolactone ( K sparing Diuretic )
• Eplerenone ( more selective than
spironolactone, ( HTN 50-100mg/day)
• Drospirenone ( also progestin in “OCP”)

37. THANKS