Glucocorticoids

Overview

Endogenous Physiology

• Hypothalamus releases corticotropin-releasing hormone (CRH)
• Anterior pituitary releases ACTH
• Adrenal cortex releases cortisol, which feeds back to suppress both CRH and ACTH

Structure-Activity Relationships

• Adding a double bond in ring A (prednisone/prednisolone) enhances glucocorticoid activity without increasing mineralocorticoid activity
• 6α methylation produces methylprednisolone (further increases glucocorticoid activity)
• 9α fluorination yields triamcinolone
• Both 6α methylation and 9α fluorination together yield dexamethasone

Potency Comparison

Mechanism of Action

Genomic Pathways

1. cGCR-mediated genomic mechanism (Pathway I): Glucocorticoids are lipophilic and freely cross the cell membrane. In the cytosol, they bind to the cytosolic glucocorticoid receptor (cGCR), which is held in an inactive state by heat shock proteins (HSP90, HSP70) and Src kinase. Ligand binding causes dissociation of the chaperone complex. The glucocorticoid-receptor complex is chaperoned to the nucleus, where it binds to glucocorticoid response elements (GREs) in gene promoters or suppressors to activate or repress transcription.
2. Transrepression via NF-κB and AP-1: The glucocorticoid-receptor complex directly inhibits key pro-inflammatory transcription factors - NF-κB and AP-1 - thereby suppressing transcription of genes encoding cytokines (IL-1, IL-6, TNF-α), COX-2, iNOS, and adhesion molecules. This is considered a primary anti-inflammatory mechanism.
3. cGCR-mediated nongenomic mechanism (Pathway II): Released Src kinase from the HSP complex triggers rapid cytoplasmic signaling independently of gene transcription.

Nongenomic Pathways

1. Membrane glucocorticoid receptor (mGCR, Pathway III): Glucocorticoids bind membrane-associated receptors, producing rapid effects within seconds to minutes.
2. Nonspecific membrane effects (Pathway IV): High-dose glucocorticoids intercalate into cell membranes, altering membrane biophysics. This is the likely basis for the pronounced nongenomic effects of IV pulse methylprednisolone (which has >3-fold more nongenomic effects than prednisolone at equivalent doses).

Anti-Inflammatory and Immunological Effects

• Inhibit pro-inflammatory cytokines: IL-1β, IL-2, IL-6, IL-8, TNF-α, IFN-γ
• Inhibit pro-inflammatory enzymes: COX-2, phospholipase A2 (via lipocortin-1/annexin A1 induction), collagenase, elastase, plasminogen activator
• Decrease T-cell function and reduce circulating T-cell numbers
• Inhibit Fc receptor expression, reducing clearance of antibody-coated blood cells
• Increase circulating neutrophils (demargination from vessel walls) while impairing their migration to sites of inflammation
• Inhibit leukocyte adhesion to endothelial cells

Dosing Concepts

• Low dose: ≤7.5 mg/day
• Medium dose: >7.5 to ≤30 mg/day
• High dose: >30 to ≤100 mg/day
• Very high / pulse therapy: 250-1000 mg/day IV methylprednisolone for 3 days (for life- or organ-threatening disease)

Therapeutic Uses

Adverse Effects

Key Adverse Effects (dose-dependent)

• Glucocorticoid-induced osteoporosis (GIOP): The most devastating long-term complication. Up to 40% of users develop bone loss leading to fracture. Predominantly affects trabecular bone initially (vertebrae), later cortical bone (femoral neck). First-year bone loss can be 1.5-20% at ≤10 mg/day. Risk mitigation requires calcium/vitamin D supplementation and bisphosphonate therapy.
• Proximal myopathy: Muscle weakness, particularly in the thighs and shoulder girdle

• Hyperglycemia / steroid-induced diabetes mellitus
• Central (centripetal) obesity, moon facies, buffalo hump (Cushing-like features)
• Hypertriglyceridemia
• Negative calcium balance

• Hypertension (sodium and water retention)
• Peripheral edema

• Increased susceptibility to infection (bacterial, fungal, viral)
• Impaired wound healing

• HPA axis suppression (adrenal suppression) - risk of adrenal crisis on withdrawal
• Diminished sex hormone production

• Euphoria, emotional disturbances, depression, psychosis
• Insomnia

• Posterior subcapsular cataracts
• Glaucoma (raised intraocular pressure)

• Growth retardation (mechanism unknown, partly via growth hormone suppression; alternate-day dosing reduces this effect)

• Skin atrophy, ecchymosis, striae, telangiectasia

Discontinuation and Adrenal Suppression

• Doses must be tapered slowly according to individual tolerance
• Risk is present any time the HPA axis has been suppressed (typically courses >3 weeks or doses above physiologic replacement)
• Patients on chronic steroids may need stress dosing (increased dose) during surgery or serious illness

Drug Interactions

• Phenobarbital, phenytoin, rifampin: Induce CYP3A4, increasing glucocorticoid metabolism and reducing efficacy
• Concurrent aspirin: Accelerates salicylate metabolism, reducing salicylate levels
• NSAIDs: Additive GI risk (peptic ulceration)
• Antidiabetic drugs: Glucocorticoids antagonize their effects, requiring dose adjustments

Special Considerations

Glucocorticoids - Physiology

1. The Adrenal Gland: Source of Glucocorticoids

2. Biosynthesis: From Cholesterol to Cortisol

1. Circulating LDL taken up by receptor-mediated endocytosis (quantitatively dominant)
2. De novo synthesis from acetate

Five key enzymatic steps (zona fasciculata):

1. Cholesterol → Pregnenolone (mitochondria): Side-chain cleavage enzyme (P-450scc / 20,22-desmolase) removes carbons 22-27. This is the rate-limiting step.
2. Pregnenolone → Progesterone (SER): 3β-HSD oxidizes the hydroxyl group at C-3 to a ketone.
3. Progesterone → 17α-Hydroxyprogesterone (SER): 17α-hydroxylase (P-450c17/CYP17) adds -OH at C-17.
4. 17α-Hydroxyprogesterone → 11-Deoxycortisol (SER): 21α-hydroxylase (P-450c21/CYP21A2) adds -OH at C-21.
5. 11-Deoxycortisol → Cortisol (mitochondria): 11β-hydroxylase (P-450c11/CYP11B1) adds -OH at C-11.

Key enzyme absent from zona glomerulosa: 17α-hydroxylase is not substantially present in the glomerulosa, which is why that zone cannot make cortisol and instead makes aldosterone (using aldosterone synthase/CYP11B2). (Medical Physiology)

Clinical relevance - 21α-hydroxylase deficiency (most common congenital adrenal enzyme defect): Blocks synthesis of both cortisol and aldosterone. The resulting low cortisol removes negative feedback → ACTH rises → drives excessive production of adrenal androgens. Clinically: salt-wasting, hypoglycemia, and virilization (ambiguous genitalia in female infants).

3. Transport and Metabolism

• ~90% of circulating cortisol is protein-bound:
  • ~75% bound to corticosteroid-binding globulin (CBG / transcortin) - high affinity, low capacity
  • ~15% loosely bound to albumin
  • Only ~10% is free (biologically active)
• Synthetic glucocorticoids (dexamethasone, betamethasone, triamcinolone) have <1% affinity for CBG - they circulate largely free, contributing to greater biological activity per dose.
• Cortisol is metabolized in the liver. Prednisone (prodrug) requires hepatic conversion to active prednisolone by 11β-HSD. In severe liver disease, prednisolone is preferred over prednisone. (Rheumatology, 2-Volume Set)
• The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone in tissues like the kidney, protecting mineralocorticoid receptors from activation by cortisol (which has equal affinity for the mineralocorticoid receptor). Liquorice inhibits 11β-HSD2, causing apparent mineralocorticoid excess.

4. The HPA Axis: Regulation of Cortisol Secretion

Hypothalamus (paraventricular nucleus)
        ↓ CRH (41-amino acid neuropeptide)
Anterior Pituitary (corticotroph cells)
        ↓ ACTH (39-amino acid peptide)
Adrenal Cortex (zona fasciculata)
        ↓ Cortisol
⟲ Negative feedback → inhibits CRH & ACTH

CRH (Corticotropin-Releasing Hormone)

• Secreted by small-bodied neurons of the paraventricular nucleus (PVN) of the hypothalamus
• Released into the hypophyseal portal venous plexus → reaches anterior pituitary
• Binds CRH-R1 (GPCR) on corticotrophs → Gαs → ↑cAMP → PKA → opens L-type Ca²⁺ channels → exocytosis of pre-formed ACTH
• Over longer time: increases POMC gene transcription
• Arginine vasopressin (AVP) is a co-secretagogue from the PVN that potentiates CRH-induced ACTH release (important during stress involving dehydration or trauma)

ACTH (Adrenocorticotropic Hormone)

• A 39-amino acid peptide secreted by anterior pituitary corticotrophs
• Derived from pro-opiomelanocortin (POMC), a large precursor that also yields:
  • β-lipotropin (β-LPH)
  • α-MSH, γ-MSH (melanocyte-stimulating hormones - cause skin hyperpigmentation in Addison's disease via excess ACTH/POMC)
  • CLIP (corticotropin-like intermediate lobe peptide)
  • β-endorphin
• ACTH acts on adrenal fasciculata cells to stimulate cholesterol uptake and activate the rate-limiting step (P-450scc), rapidly driving cortisol synthesis
• Chronic ACTH excess causes adrenal hyperplasia; chronic ACTH deficiency causes adrenal atrophy

Negative Feedback

1. Anterior pituitary: Cortisol binds cytosolic GR → nucleus → binds GREs → inhibits POMC transcription and blocks synthesis of the CRH receptor; also inhibits release of pre-formed ACTH from vesicles.
2. Hypothalamus: Cortisol decreases CRH mRNA levels in PVN neurons and inhibits release of pre-formed CRH (less dominant than pituitary feedback).

5. Circadian Rhythm and Pulsatility

• ACTH secretory activity is greatest in the early morning and lowest late afternoon/evening
• Cortisol peaks at ~16 μg/dL around 8 AM and falls to near zero by midnight
• The rhythm is driven by the suprachiasmatic nucleus (receives retinal light input) - blind individuals lose circadian rhythms
• Superimposed on the circadian rhythm is pulsatile secretion driven by pulsatile CRH release
• ACTH pulses are sharper and briefer (shorter half-life); cortisol oscillations are broader and damped

6. Stress Response

• Hypoglycemia → stimulates CRH and ACTH → ↑cortisol → gluconeogenesis raises blood glucose
• Physical trauma, infection, surgery, major illness → activate ascending noradrenergic pathways → stimulate PVN CRH neurons
• The amplitude of CRH secretory bursts increases during stress (not frequency)
• Chronic stress → chronic ACTH elevation → adrenal hypertrophy
• Glucocorticoids are sometimes called "stress hormones" because they allow the body to cope with acute threats - but chronic activation is harmful

7. Physiological Actions of Cortisol

A. Carbohydrate Metabolism - "Diabetogenic"

• ↑ Gluconeogenesis in liver (key survival function during fasting)
• ↑ Protein catabolism in muscle → provides amino acids to liver as gluconeogenic substrates
• ↑ Lipolysis → provides glycerol to liver for gluconeogenesis; free fatty acids used as alternative fuel
• ↓ Glucose utilization by peripheral tissues (antagonizes insulin action)
• ↓ Insulin sensitivity of adipose tissue

In hypocortisolism (Addison's disease): hypoglycemia In hypercortisolism (Cushing's syndrome): hyperglycemia (Costanzo Physiology)

B. Protein Metabolism

• Catabolic in muscle, bone, connective tissue, skin - mobilizes amino acids
• Anabolic in the liver - stimulates synthesis of enzymes for gluconeogenesis
• Net effect of prolonged excess: muscle wasting, skin thinning, striae, poor wound healing

C. Fat Metabolism - Redistribution

• Excess cortisol causes characteristic fat redistribution:
  • ↑ Fat deposition: face (moon facies), trunk, supraclavicular, dorsal interscapular (buffalo hump)
  • ↓ Fat in extremities
• Mechanism: differential insulin sensitivity across fat depots; visceral fat is more glucocorticoid-sensitive

D. Anti-Inflammatory Actions

1. Induces lipocortin (annexin A1) - inhibits phospholipase A2, blocking release of arachidonic acid from membrane phospholipids → suppresses prostaglandin and leukotriene synthesis
2. Inhibits IL-2 production and T lymphocyte proliferation
3. Inhibits histamine and serotonin release from mast cells and platelets

E. Immune Suppression

• Suppresses cellular immunity via T-cell inhibition (IL-2 ↓)
• Reduces Fc receptor expression on macrophages
• Promotes neutrophilia (demargination from vessel walls) while impairing neutrophil migration to inflammatory sites
• Basis for glucocorticoid use in transplant rejection and autoimmune diseases

F. Cardiovascular - Permissive Role

• Up-regulates α₁-adrenergic receptors on arterioles (permissive effect)
• Allows arterioles to respond normally to catecholamines (norepinephrine, epinephrine)
• Without cortisol → hypotension (hallmark of Addison's disease - refractory to vasopressors)
• Excess cortisol → hypertension (Cushing's syndrome)

G. Bone and Calcium Metabolism

• Decreases synthesis of type I collagen (major bone matrix component)
• Decreases osteoblast function (bone formation ↓)
• Decreases intestinal Ca²⁺ absorption (interferes with vitamin D action)
• Net result: negative calcium balance and osteoporosis with chronic excess

H. Renal Effects

• Increases GFR by causing afferent arteriole vasodilation → ↑ renal blood flow
• Without cortisol, GFR falls; excess cortisol can contribute to hypertension via this mechanism and via sodium retention (weak mineralocorticoid effect of cortisol)

I. CNS Effects

• Glucocorticoid receptors are widely distributed in the CNS (hippocampus, prefrontal cortex, hypothalamus)
• Normal cortisol: needed for normal mood, cognition, and arousal
• Excess cortisol: euphoria, emotional lability, depression, psychosis, insomnia, decreased REM sleep
• Deficiency: fatigue, depression, cognitive impairment

8. Summary Table: Physiological Actions of Glucocorticoids

9. Clinical Correlates