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Cortisol

SI UNITS (recommended)

CONVENTIONAL UNITS

(Primary Glucocorticoid – Marker for Adrenal Function, Stress Response & Cushing/Addison Evaluation)

Synonyms

  • Cortisol
  • Hydrocortisone
  • Serum cortisol
  • Plasma cortisol
  • Total cortisol
  • Circulating glucocorticoid

Units of Measurement

  • nmol/L
  • µg/L
  • µg/dL
  • µg/100 mL
  • µg%
  • ng/mL

1 µg/dL = 27.59 nmol/L
 1 µg/L = 0.1 µg/dL
 ng/mL = µg/L

Description

Cortisol is the main glucocorticoid produced by the adrenal cortex (zona fasciculata) under the regulation of:

  • Hypothalamus: CRH
  • Pituitary: ACTH
  • Adrenal cortex: cortisol synthesis

Functions include:

  • Stress response
  • Gluconeogenesis
  • Blood pressure maintenance
  • Anti-inflammatory action
  • Immune modulation
  • Salt/water balance (mild mineralocorticoid effect)

Cortisol secretion follows a diurnal rhythm:

  • Peak: 6–9 AM
  • Nadir: midnight

Cortisol measurement is central in diagnosing:

  • Adrenal insufficiency
  • Cushing syndrome
  • Adrenal tumors
  • Pituitary disorders

Physiological Role

  • Maintains fasting glucose
  • Increases vascular tone
  • Modulates inflammation
  • Increases protein catabolism
  • Helps body respond to physical/emotional stress

Cortisol circulates 90% bound (CBG + albumin) and 10% free (biologically active).

Clinical Significance

Low Cortisol (Hypocortisolism)

1. Primary Adrenal Insufficiency (Addison Disease)

  • High ACTH
  • Low cortisol
  • Hyperpigmentation
  • Hyponatremia, hyperkalemia

2. Secondary/Tertiary Adrenal Insufficiency

  • ACTH deficiency
  • Chronic steroid use → HPA axis suppression
  • Pituitary tumors

3. Congenital Adrenal Hyperplasia (21-OHD)

Cortisol deficiency → elevated 17-OHP.

Symptoms of Low Cortisol

  • Weakness
  • Weight loss
  • Hypotension
  • Hyponatremia
  • Hypoglycemia
  • Crisis: shock & coma

High Cortisol (Hyper-cortisolism)

1. Cushing Syndrome

  • ACTH-dependent
    • Pituitary adenoma (Cushing disease)
    • Ectopic ACTH (SCLC)
  • ACTH-independent
    • Adrenal adenoma/carcinoma

2. Stress / Illness

  • Infections
  • Surgery
  • Trauma
  • ICU patients

3. Pseudo-Cushing States

  • Alcoholism
  • Depression
  • Obesity
  • Poor sleep / shift work

4. Exogenous Steroids

Elevate cortisol physiology but suppress ACTH + endogenous cortisol.

Reference Intervals

(Tietz 8E + Endocrine Society + Mayo + ARUP)

Serum Cortisol (Total)

Morning (6–10 AM):

  • 140 – 690 nmol/L
  • 5 – 25 µg/dL

Afternoon (4 PM):

  • 83 – 359 nmol/L
  • 3 – 13 µg/dL

Midnight Cortisol

  • < 5 µg/dL (<138 nmol/L) essential for Cushing screening.

Diagnostic Cutoffs

1. ACTH Stimulation Test (250 µg Cosyntropin)

  • Peak cortisol ≥ 18 µg/dL (500 nmol/L) → normal
  • < 18 µg/dL → adrenal insufficiency

2. Low-Dose Dexamethasone Suppression Test

  • Cortisol < 1.8 µg/dL (50 nmol/L) → normal suppression
  • Failure to suppress → Cushing syndrome

3. Random Cortisol in Severe Illness

  • Cortisol <10 µg/dL → suggestive of adrenal insufficiency

Diagnostic Uses

1. Adrenal Insufficiency Testing

  • Morning cortisol
  • ACTH stimulation test

2. Cushing Syndrome Evaluation

  • Overnight dex suppression test
  • Late-night salivary cortisol
  • 24-hour urinary free cortisol

3. Monitoring Steroid Therapy

Evaluate adrenal suppression.

4. Congenital Adrenal Hyperplasia

Low cortisol with high ACTH + 17-OHP.

5. Critical Illness

Stress hypercortisolemia; diagnose CIRCI (critical illness–related corticosteroid insufficiency).

Analytical Notes

  • Serum preferred; draw in morning for basal measurement
  • Avoid hemolysis
  • CBG variations (pregnancy, estrogen) affect total cortisol
  • Free cortisol (salivary or urinary) avoids protein-binding issues
  • Immunoassays may show cross-reactivity; LC-MS/MS superior

Clinical Pearls

  • Always interpret cortisol with ACTH levels.
  • Midnight cortisol is a highly sensitive test for Cushing syndrome.
  • Prolonged steroid therapy → suppressed cortisol for weeks to months.
  • Cortisol peaks in the morning; a normal morning cortisol >15–18 µg/dL makes adrenal insufficiency unlikely.
  • Estrogen (OCPs/pregnancy) raises total cortisol, but free cortisol often normal.

Interesting Fact

Cortisol is known as the “stress hormone” but also regulates over 60% of the body’s metabolic pathways, making it essential for survival - absence leads rapidly to adrenal crisis.

References

  1. Tietz Clinical Chemistry & Molecular Diagnostics, 8th Edition - Steroid Hormones.
  2. Endocrine Society Clinical Practice Guidelines - Adrenal Insufficiency & Cushing Syndrome.
  3. AACE/ACE Guidelines - Adrenal Disorders.
  4. Mayo Clinic Laboratories - Cortisol.
  5. ARUP Consult - Adrenal Function Testing.
  6. MedlinePlus / NIH - Cortisol Test.
  7. Modern Endocrinology Texts - Adrenal Physiology.

Last updated: January 25, 2026

Reviewed by : Medical Review Board

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