CORTISOL: A
COMPREHENSIVE PHYSIOLOGICAL REVIEW
1. Introduction
Cortisol, also known as hydrocortisone, is the principal glucocorticoid
hormone in humans. It is essential for homeostasis, particularly in
stress adaptation, metabolism, immune modulation, and cardiovascular
regulation.
It is synthesized in the zona fasciculata of the adrenal cortex
and is widely recognized as the body’s primary stress hormone.
2. Chemical Nature
and Classification
- Class: Steroid hormone
(glucocorticoid)
- Derived from: Cholesterol
- Lipophilic → easily crosses cell
membranes
- Circulates:
- ~90% bound to cortisol-binding
globulin (CBG)
o
Remaining free fraction is biologically active
3. Synthesis of
Cortisol
3.1 Site of
Synthesis
- Adrenal cortex:
- Zona
fasciculata (primary)
- Zona reticularis (minor contribution)
3.2 Biosynthetic
Pathway
Cortisol is synthesized from cholesterol through enzymatic steps:
- Cholesterol
- Pregnenolone (rate-limiting
step: cholesterol desmolase)
- 17α-hydroxypregnenolone
- 17α-hydroxyprogesterone
- 11-deoxycortisol
- Cortisol (via 11β-hydroxylase)
4. Regulation of
Cortisol Secretion
4.1
Hypothalamic–Pituitary–Adrenal (HPA) Axis
The secretion of cortisol is tightly regulated by the HPA axis:
- Hypothalamus → CRH
(Corticotropin-releasing hormone)
- Anterior pituitary → ACTH
(Adrenocorticotropic hormone)
- Adrenal cortex → Cortisol
Negative Feedback
Cortisol inhibits:
- CRH release
(hypothalamus)
- ACTH release
(pituitary)
4.2 Circadian Rhythm
- Peak: Early
morning (~6–8 AM)
- Lowest:
Midnight
- Linked to
sleep–wake cycle
4.3 Stress Response
Stimuli increasing cortisol:
- Physical stress
(trauma, infection)
- Psychological
stress
- Hypoglycemia
Cortisol provides long-term adaptation to stress.
5. Mechanism of
Action
Cortisol acts via intracellular glucocorticoid receptors:
- Diffuses into
target cells
- Binds
cytoplasmic receptor
- Hormone–receptor
complex enters nucleus
- Binds DNA →
regulates gene transcription
This results in:
- Transactivation (anti-inflammatory proteins)
- Transrepression (suppression of inflammatory
genes)
6. Physiological
Actions of Cortisol
6.1 Effects on
Carbohydrate Metabolism
- ↑
Gluconeogenesis (liver)
- ↓ Peripheral
glucose uptake
- ↑ Blood glucose
levels
Mechanism:
- Activation of
key enzymes (e.g., PEPCK)
- Provides
substrates via proteolysis and lipolysis
6.2 Effects on
Protein Metabolism
- ↑ Protein
catabolism (muscle)
- ↑ Amino acids
for gluconeogenesis
- Leads to muscle
wasting in excess states
6.3 Effects on Lipid
Metabolism
- ↑ Lipolysis
(fat breakdown)
- Redistribution
of fat (central obesity in excess states)
6.4 Effects on
Immune System
Cortisol is strongly immunosuppressive:
- ↓ Cytokine
production
- ↓ T-cell and
B-cell activity
- ↑ Lymphocyte
apoptosis
- Inhibits NF-κB
pathway
Clinical relevance:
- Anti-inflammatory
drug use
- Increased
infection risk in excess
6.5 Cardiovascular
Effects
- Maintains
vascular tone
- Enhances
response to catecholamines
- ↑ Blood
pressure via vasoconstriction
6.6 Effects on
Central Nervous System
- Modulates:
- Mood
- Cognition
- Memory
- Acute: improves
alertness
- Chronic excess:
anxiety, depression, cognitive decline
6.7 Effects on
Kidney and Electrolytes
- Weak
mineralocorticoid action
- ↑ Sodium
retention (mild)
- ↑ Free water
clearance (↓ ADH effect)
6.8 Endocrine
Interactions
- ↓ Thyroid
function (↓ TSH, T3, T4)
- ↓ Growth
hormone effects
- Antagonizes
insulin
7. Cortisol in
Stress Physiology
Cortisol is part of the long-term stress response:
|
System |
Role |
|
SAM axis |
Immediate response
(catecholamines) |
|
HPA axis |
Sustained response (cortisol) |
Functions:
- Maintains
glucose supply to brain
- Conserves
energy
- Suppresses
non-essential functions (immunity, reproduction)
8. Transport,
Metabolism, and Excretion
- Transport:
- Bound to CBG
(transcortin)
- Metabolism:
- Liver
(inactive metabolites)
- Interconversion:
- Cortisol ↔
cortisone (via 11β-HSD enzymes)
- Excretion:
- Urine (as
metabolites)
9. Clinical
Correlations
9.1 Hypercortisolism
(Cushing Syndrome)
Causes:
- Pituitary
adenoma (ACTH-dependent)
- Adrenal tumors
- Exogenous
steroids
Features:
- Central obesity
- Moon face
- Hypertension
- Hyperglycemia
- Muscle wasting
9.2 Hypocortisolism
(Addison Disease)
Causes:
- Adrenal
insufficiency
- Autoimmune
destruction
Features:
- Fatigue
- Hypotension
- Weight loss
- Hyperpigmentation
10. Pharmacological
Importance
Synthetic glucocorticoids (e.g., prednisone, dexamethasone):
- Anti-inflammatory
- Immunosuppressive
Used in: - Autoimmune
diseases
- Allergies
- Transplant
rejection
But long-term use → adverse effects (Cushingoid features)
12. Conclusion
Cortisol is a multifunctional hormone critical for survival,
integrating metabolic, immune, and neuroendocrine responses. Its precise
regulation through the HPA axis ensures adaptation to stress while maintaining
internal stability. Dysregulation leads to profound systemic consequences,
making cortisol central to both physiology and clinical medicine.