My Lectures for Medical Students

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