Visual Reference  ·  Chapter 28 Module 1
Adrenal Steroid Biochemistry, Receptor Mechanism, and Pharmacokinetics
Biosynthesis pathway · glucocorticoid receptor signaling · HPA axis · potency comparison
Adrenal Steroid Biosynthesis Pathway
START Cholesterol From LDL uptake; precursor for all adrenal steroids
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STEP 1 StAR protein Rate-limiting transport to inner mitochondrial membrane; driven by adrenocorticotropic hormone via cyclic adenosine monophosphate
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STEP 2 CYP11A1 Cholesterol → Pregnenolone (committed step)
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STEP 3 CYP17A1 Pregnenolone → 17-hydroxypregnenolone → DHEA (lyase) | Progesterone → 17-hydroxyprogesterone; absent in zona glomerulosa
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STEP 4 CYP21A2 17-hydroxyprogesterone → 11-deoxycortisol; deficiency = most common congenital adrenal hyperplasia
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STEP 5 CYP11B1 11-deoxycortisol → Cortisol; inhibited by metyrapone
Zona Glomerulosa Only
Aldosterone Pathway
  • Progesterone → 11-deoxycorticosterone → Aldosterone via CYP11B2 (aldosterone synthase)
  • Regulated by angiotensin II and potassium — NOT adrenocorticotropic hormone
  • CYP17A1 absent here: cannot produce cortisol or androgens
21-Hydroxylase Deficiency
Congenital Adrenal Hyperplasia (Most Common Form)
  • Block at CYP21A2: 17-hydroxyprogesterone accumulates
  • Substrate shunted to androgen synthesis → androgen excess
  • Cortisol deficiency → adrenocorticotropic hormone rises → adrenal hyperplasia
  • Diagnostic marker: elevated serum 17-hydroxyprogesterone
Glucocorticoid Receptor Signaling
Genomic — GRE Binding
Transactivation (Adverse Effects)
  • Glucocorticoid receptor homodimer binds glucocorticoid response element sequences
  • Recruits coactivators (CBP/p300, SRC-1) → enhances transcription
  • Drives: gluconeogenic enzymes (hyperglycemia), muscle ubiquitin ligases (atrophy), osteocalcin suppression (osteoporosis)
  • Onset: 30–60 min minimum; dominant during sustained therapy
Genomic — Tethered
Transrepression (Anti-Inflammatory)
  • Glucocorticoid receptor monomer binds p65 subunit of nuclear factor kappa-B without touching DNA
  • Blocks nuclear factor kappa-B target genes: COX-2, iNOS, interleukins, adhesion molecules
  • Also induces I-kappa-B transcription → sequesters nuclear factor kappa-B in cytoplasm
  • Tethers to activator protein-1 → inhibits matrix metalloproteinase transcription
HPA Axis and Suppression Risk
Feedback Loop
Hypothalamic-Pituitary-Adrenal Axis
  • Hypothalamus PVN → corticotropin-releasing hormone → anterior pituitary corticotrophs
  • Anterior pituitary → adrenocorticotropic hormone → zona fasciculata MC2R → cortisol synthesis
  • Negative feedback: cortisol represses corticotropin-releasing hormone (hypothalamus) and adrenocorticotropic hormone / pro-opiomelanocortin (pituitary) via glucocorticoid response element
  • Circadian peak: 30–60 min post-awakening; nadir ~midnight
  • Morning dosing rule: once-daily oral glucocorticoids in AM minimize axis suppression vs. same dose in PM
Suppression Risk Guide
Low risk: any systemic glucocorticoid <3 weeks; prednisone equivalent <5 mg/day at any duration; inhaled corticosteroids at standard adult doses.    High risk: prednisone equivalent >20 mg/day for >3 weeks; any systemic dose >3 months; Cushingoid features present. Requires taper and consideration of hypothalamic-pituitary-adrenal axis testing before discontinuation.
Clinical Glucocorticoids: Potency and Pharmacokinetics
Drug Anti-Inflam. Potency Mineralocorticoid Biologic Duration Key Clinical Use
Hydrocortisone 1x (reference) 1x 8–12 h Physiological replacement; adrenal crisis; stress dosing
Prednisone / Prednisolone 4x 0.8x 18–36 h Most oral anti-inflammatory indications; prednisone is a prodrug requiring hepatic activation
Methylprednisolone 5x Negligible 18–36 h Intravenous pulse therapy; preferred when sodium retention must be avoided
Dexamethasone 25–30x None 36–54 h Cerebral edema; fetal lung maturation; COVID-19 acute respiratory distress syndrome; diagnostic suppression testing
Budesonide ~200x topical Low systemic Varies Inhaled (asthma, COPD); oral controlled-release (Crohn disease); 85–90% first-pass inactivation limits systemic effects
CYP3A4 Drug Interaction Alert
Inducers (rifampin, phenytoin, carbamazepine): accelerate glucocorticoid metabolism → loss of effect or adrenal crisis in dependent patients.   Inhibitors (ritonavir, ketoconazole, clarithromycin): raise glucocorticoid levels → iatrogenic Cushing syndrome. Ritonavir + fluticasone inhaled corticosteroids = high risk; substitute beclomethasone (not a CYP3A4 substrate).