corticosteroids

PART 1: INTRODUCTION TO CORTICOSTEROIDS

Section 1: Aims (Page 1)

By the end of this lecture, students will be able to:

• Understand the biosynthetic origins of glucocorticoid and mineralocorticoid steroids.

• Describe their effects in the body.

• Describe the process of control of their expression.

• Identify these steroidal ligands and the biosynthetic pathway as potential drug targets.

PART 2: GLUCOCORTICOIDS

Section 2: Overview of Glucocorticoids (Page 2)

• Main glucocorticoid: Cortisol (also known as hydrocortisone).

• Cortisone is a much less active metabolite of cortisol. It can be converted (back) to cortisol in the body (via 11β-hydroxysteroid dehydrogenase).

• Physiological Roles of Cortisol:

  • Regulates intermediate metabolism (carbohydrate, protein, fat metabolism).

  • Mediates the stress response.

  • Modulates some CNS functions.

  • Regulates aspects of immunity.

Section 3: Effects of Glucocorticoids (Pages 3-4)

3.1. Metabolic Effects (Page 3):

3.2. Anti-Inflammatory and Immunosuppressive Effects (Page 4):

Section 4: Main Medicinal Uses of Glucocorticoids (Page 5)

Section 5: Anti-Rheumatic and Anti-Inflammatory Uses (Page 6)

• Effects: Reduce swelling, heat, redness, tenderness.

• Mechanism: Interfere with prostaglandin biosynthesis (via inhibition of phospholipase A₂ and cyclooxygenase-2).

• Important: Suppress symptoms, do not cure the underlying disease.

• Long-term side effects:

  • Osteoporosis

  • Adrenal suppression

  • Ulcers

  • Fluid retention

  • Increased risk of infections

Section 6: Structure-Activity Relationships (SAR) of Glucocorticoids (Page 7)

Corticosteroid replacement drugs have been modified to increase activity and decrease unwanted side effects.

Section 7: Synthetic Considerations (Page 8)

7.1. The Challenge:

• How do we synthesise a complex steroid, considering the stereochemistry involved?

• Semi-synthesis using a steroid skeleton isolated from a plant source.

7.2. Example: Hecogenin from Sisal (Agave sisalana):

• Hecogenin has a 12α-hydroxy function that can be converted to the essential 11β-hydroxyl group (critical for glucocorticoid activity).

• Process:

  1. Bromination of 11α position.

  2. Treatment with base to give the 12-hydroxyl, 11-keto group.

  3. Hydride displacement using calcium in liquid ammonia.

  4. The key 11β-hydroxyl is then in place.

  5. Side chain degradation and modification follows.

• Alternative: Hydroxylation at C-11 can also be done via microbial fermentation.

• A-ring modifications (e.g., Δ¹ double bond) can then be made to improve activity.

Section 8: Glucocorticoid Production (Page 10)

• Source: Glucocorticoids and mineralocorticoids are biosynthesised from circulating cholesterol.

• Site: Cortisol is produced in the adrenal cortex.

• Biosynthesis: Cortisol is synthesised from 17α-hydroxyprogesterone by the addition of two hydroxyl groups:

  1. On the side chain (at C-17).

  2. Then on carbon 11.

Section 9: Glucocorticoid Circulation (Page 11)

• 80-90% of excreted glucocorticoids associate with cortisol-binding globulin (CBG) (similar to sex hormones).

• Only free (unbound) steroids can enter cells and bind to receptors.

• Not all synthetic glucocorticoids bind to globulin proteins.

  • Example: Dexamethasone does not bind significantly to CBG.

  • Clinical Implication: This affects the dose required to reach the same effect as, for example, cortisol (dexamethasone is much more potent).

PART 3: CONTROL OF GLUCOCORTICOID PRODUCTION – THE HPA AXIS

Section 10: Hypothalamic-Pituitary-Adrenal (HPA) Axis (Page 12)

10.1. Pro-opiomelanocortin (POMC):

• In the anterior pituitary, corticotrope cells synthesise a large protein – pro-opiomelanocortin (POMC) .

• POMC is cleaved to give three proteins:

10.2. ACTH Release:

• ACTH is released according to the circadian rhythm:

  • Greatest size and frequency: Morning.

  • Lower size and frequency: Early afternoon.

• ACTH enters circulation and binds to receptors in the cytoplasm of cells in the adrenal cortex.

• This causes:

  • Delivery of cholesterol from cellular stores to the inner mitochondrial membrane (the rate-limiting step in steroidogenesis).

  • Initiation of biosynthesis.

10.3. ACTH as a Growth Factor:

• ACTH acts as a growth factor for the adrenal cortex.

• ACTH deficiency causes:

  • Low cortisol concentration.

  • Atrophy of the adrenal cortex.

Section 11: Negative Feedback Control (Page 13)

• Cortisol production is suppressed by high plasma concentrations of glucocorticoids (negative feedback on the hypothalamus and pituitary).

• This control takes a long period (weeks) to be reversed.

• Clinical Implication: Exogenous glucocorticoids (e.g., drugs) must be gradually reduced (tapered) to allow the HPA axis to recover; otherwise, adrenal insufficiency may result.

PART 4: GLUCOCORTICOID RECEPTORS

Section 12: Glucocorticoid Receptor Types (Page 14)

• Receptor Locations: Liver, muscle, adipose tissue, bone, lymphocytes, pituitary.

Section 13: Mechanism of Action (Page 14)

• Receptors without a steroid ligand are associated with a chaperone protein, heat shock protein 90 (Hsp90) .

• After steroid binding:

  1. Heat shock protein dissociates.

  2. Receptors dimerise.

  3. Dimer binds to DNA – to the glucocorticoid response element (GRE) .

  4. Leads to gene activation and protein synthesis (genomic effects).

PART 5: MINERALOCORTICOIDS

Section 14: Overview of Mineralocorticoids (Page 15)

• Main mineralocorticoid: Aldosterone.

• Function: Regulates Na⁺/K⁺ concentrations in extracellular fluid.

• Site of Action: Acts on the renal tubule, promoting:

  • Na⁺ reabsorption

  • K⁺ excretion

Section 15: Main Medicinal Uses of Mineralocorticoids (Page 16)

• Replace endogenous mineralocorticoids for those with adrenal insufficiency (e.g., Addison's disease).

• Treat generally low aldosterone synthesis (hypoaldosteronism).

Section 16: Mineralocorticoid Production (Page 17)

• Aldosterone is synthesised in the adrenal cortex.

• It is synthesised from progesterone by the addition of:

  • One extra hydroxyl group.

  • Plus an extra ketone.

Section 17: Control of Aldosterone Production (Page 18)

• Aldosterone production is primarily controlled by the renin-angiotensin system (RAS).

• ACTH plays a secondary role.

• Does NOT associate with binding globulins (unlike cortisol).

• Can make weak non-specific interactions with proteins.

• Short half-life of a few minutes.

Section 18: Mineralocorticoid Receptor Binding (Page 19)

• Aldosterone binds to Type I glucocorticoid receptors (mineralocorticoid receptors) with a similar affinity as cortisol.

• However, stimulation of Type I receptors with either aldosterone or cortisol causes binding of the receptor dimer to different response elements.

• Aldosterone and cortisol stimulate different genes via the same receptors.

The Key Mechanism for Specificity:

• In mineralocorticoid-responsive tissue (e.g., kidney), there is a high concentration of 11β-hydroxysteroid dehydrogenase.

• This enzyme converts cortisol → cortisone (inactive).

• This ensures that aldosterone dominates the effects at mineralocorticoid receptors, despite cortisol being present at much higher concentrations in the blood.

SUMMARY TABLE: GLUCOCORTICOIDS VS. MINERALOCORTICOIDS

STRUCTURE-ACTIVITY RELATIONSHIP SUMMARY