Cortisol is the primary glucocorticoid produced by the adrenal cortex and serves as a cornerstone of the body’s response to physiological stress, metabolism, immune modulation, and circadian regulation. Understanding what “normal” looks like at different stages of life is essential for clinicians, researchers, and anyone interested in maintaining endocrine health. Below is a comprehensive overview of cortisol biology, how it is measured, and the reference ranges that apply from birth through old age.
Physiology of Cortisol and the HPA Axis
Cortisol synthesis is driven by the hypothalamic‑pituitary‑adrenal (HPA) axis. The hypothalamus releases corticotropin‑releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH binds to melanocortin‑2 receptors on adrenal zona fasciculata cells, activating the steroidogenic pathway that converts cholesterol to cortisol via a series of enzymatic steps (cholesterol side‑chain cleavage, 17α‑hydroxylation, 21‑hydroxylation, and 11β‑hydroxylation).
Cortisol exerts negative feedback on both the hypothalamus and pituitary, curbing further CRH and ACTH release. This feedback loop is rapid (minutes) and also involves slower genomic mechanisms that adjust receptor expression and sensitivity over hours to days.
Production and Regulation
- Circadian Rhythm – In healthy individuals, cortisol follows a robust diurnal pattern: concentrations peak shortly after waking (the “cortisol awakening response”) and decline progressively throughout the day, reaching a nadir around midnight.
- Ultradian Pulsatility – Superimposed on the circadian curve are shorter, roughly hourly pulses that reflect pulsatile ACTH secretion.
- Stress‑Induced Release – Acute physical or psychological stressors trigger a rapid surge in ACTH, leading to a transient rise in cortisol that can last from minutes to a few hours.
- Metabolic Influences – Glucose, insulin, and leptin modulate HPA activity; hypoglycemia, for example, is a potent stimulus for cortisol release.
- Developmental Shifts – The set‑point of the HPA axis evolves with age, resulting in distinct baseline levels and responsiveness in infants, children, adults, and the elderly.
Typical Cortisol Concentrations: Units and Sample Types
| Sample Type | Common Units | Typical Reporting Range |
|---|---|---|
| Serum (or plasma) | µg/dL (micrograms per deciliter) | 5–25 µg/dL (morning) |
| Saliva | nmol/L (nanomoles per liter) | 3–15 nmol/L (morning) |
| Urine (24‑hour) | µg/24 h | 20–90 µg/24 h |
| Hair (long‑term) | pg/mg (picograms per milligram) | 2–10 pg/mg (average over months) |
Serum is the gold standard for acute assessment, while salivary cortisol is increasingly used for its non‑invasive nature and ability to capture free (biologically active) hormone. Urinary collections reflect integrated secretion over a full day, and hair analysis provides a retrospective view of chronic exposure.
Age‑Specific Reference Ranges
Because the HPA axis matures and later declines, reference intervals must be age‑adjusted. The following tables summarize widely accepted ranges derived from large population studies and clinical laboratory consensus. Values are presented for the morning (08:00–09:00) sample, which is the most commonly used time point for screening.
Infancy (0–12 months)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 0–3 months | 10–30 |
| 4–6 months | 8–25 |
| 7–12 months | 6–22 |
Infants exhibit higher basal cortisol due to the rapid development of the adrenal cortex and heightened sensitivity to ACTH. Levels gradually decline as the HPA axis stabilizes.
Early Childhood (1–5 years)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 1–2 years | 5–18 |
| 3–5 years | 4–16 |
The axis reaches a relatively stable plateau during this period, with modest inter‑individual variability.
School‑Age Children (6–12 years)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 6–8 years | 4–15 |
| 9–12 years | 3.5–14 |
Pre‑pubertal children maintain low‑to‑moderate cortisol levels, reflecting a mature but not yet hormonally amplified HPA axis.
Adolescents (13–19 years)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 13–15 years | 3–13 |
| 16–19 years | 2.5–12 |
Puberty introduces a transient increase in ACTH drive, but overall morning cortisol remains within the adult lower range.
Adults (20–50 years)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 20–30 years | 5–20 |
| 31–40 years | 4.5–19 |
| 41–50 years | 4–18 |
In the prime adult years, the HPA axis operates with a well‑defined circadian rhythm and relatively narrow reference intervals. Slight gender differences may appear (women often have marginally higher morning values), but these are generally within the same clinical range.
Middle‑Aged Adults (51–64 years)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 51–55 years | 4–18 |
| 56–60 years | 3.5–17 |
| 61–64 years | 3–16 |
A gradual downward shift in the upper limit is observed, reflecting age‑related attenuation of adrenal responsiveness.
Older Adults (≥65 years)
| Age | Serum Cortisol (µg/dL) |
|---|---|
| 65–70 years | 2.5–15 |
| 71–80 years | 2–14 |
| >80 years | 1.5–13 |
Elderly individuals often display a blunted cortisol awakening response and a modestly lower overall morning concentration. However, the diurnal decline may be less pronounced, leading to relatively higher evening values compared with younger adults.
Factors That Influence Measured Levels
Even within the same age bracket, several physiological and methodological variables can shift cortisol readings:
| Factor | Direction of Effect | Mechanism |
|---|---|---|
| Acute illness (infection, trauma) | ↑ | Stress‑induced ACTH surge |
| Recent vigorous exercise (within 2 h) | ↑ | Sympathetic activation |
| Sleep deprivation (≥24 h) | ↑ | Disruption of negative feedback |
| Chronic glucocorticoid therapy | ↓ (suppressed endogenous) | Exogenous feedback inhibition |
| Oral contraceptives / estrogen therapy | ↑ (especially salivary) | Increased cortisol‑binding globulin (CBG) alters total serum levels |
| CBG deficiency (e.g., liver disease) | ↓ total, ↑ free | Less carrier protein, more free hormone |
| Time of sample collection | Variable | Reflects circadian rhythm |
| Sample handling (delayed centrifugation, temperature) | ↑ or ↓ (artifact) | Enzymatic degradation or in‑vitro conversion |
Understanding these modifiers is crucial when interpreting a single cortisol measurement.
Interpreting a Single Cortisol Result
- Confirm Timing – Verify that the sample was drawn within the intended window (usually 08:00–09:00).
- Check Medications – Document any glucocorticoids, hormonal contraceptives, or drugs affecting CBG.
- Compare to Age‑Specific Reference – Use the appropriate table above; a value outside the range warrants further evaluation.
- Assess Clinical Context – Correlate with signs of hypercortisolism (e.g., weight gain, hypertension) or hypocortisolism (e.g., fatigue, hypotension).
- Consider Repeat Testing – Because cortisol fluctuates, a second morning sample or an alternative matrix (saliva, urine) can clarify ambiguous results.
When Values Deviate: Common Clinical Scenarios
| Pattern | Typical Interpretation | Next Diagnostic Step |
|---|---|---|
| Elevated morning serum cortisol (>20 µg/dL) with suppressed ACTH | Possible adrenal adenoma or cortisol‑producing tumor | Low‑dose dexamethasone suppression test; imaging of adrenal glands |
| Elevated cortisol with high ACTH | Primary or secondary Cushing syndrome (e.g., pituitary adenoma) | High‑dose dexamethasone test; CRH stimulation test |
| Low morning cortisol (<3 µg/dL) with low ACTH | Secondary adrenal insufficiency (e.g., pituitary disease) | Cosyntropin (ACTH) stimulation test |
| Low cortisol with high ACTH | Primary adrenal insufficiency (Addison disease) | Cosyntropin test; adrenal antibody panel |
| Normal morning cortisol but blunted diurnal decline | Subclinical HPA dysregulation; may precede overt disease | 24‑hour urinary free cortisol or late‑night salivary cortisol |
These pathways are intentionally concise; detailed endocrine work‑ups should be individualized.
Laboratory Considerations and Best Practices
- Assay Selection – Immunoassays are widely used but can cross‑react with cortisol metabolites; liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) offers higher specificity, especially for salivary and urinary samples.
- Sample Integrity – Serum should be separated within 30 minutes of collection and frozen at ≤‑20 °C if not analyzed immediately. Saliva samples must be kept on ice and processed promptly to avoid bacterial degradation.
- Reference Calibration – Laboratories should calibrate against international standards (e.g., WHO cortisol reference material) to ensure comparability.
- Reporting Free vs. Total Cortisol – Total cortisol reflects bound and free fractions; free cortisol (measured in saliva or by equilibrium dialysis) is more physiologically relevant when CBG levels are abnormal.
- Quality Control – Participation in external proficiency programs (e.g., CAP, UKNEQAS) helps maintain assay accuracy across the lifespan spectrum.
Key Take‑aways
- Cortisol follows a well‑defined circadian rhythm, with a pronounced morning peak and nocturnal nadir.
- Normal morning concentrations differ markedly from newborns (10–30 µg/dL) to the elderly (≈2–15 µg/dL).
- Age‑specific reference ranges are essential; using adult adult ranges for infants or seniors can lead to misdiagnosis.
- Multiple physiological, pharmacological, and technical factors can shift measured values; careful documentation of context is mandatory.
- When a result falls outside the expected range, a structured follow‑up—often involving repeat testing, ACTH measurement, and dynamic suppression or stimulation tests—guides accurate diagnosis.
- Modern analytical methods (LC‑MS/MS) improve specificity, especially for non‑serum matrices, and should be preferred when available.
By grounding cortisol interpretation in age‑appropriate reference data and a clear understanding of the HPA axis’s regulatory mechanisms, clinicians and health‑conscious individuals can more reliably distinguish normal physiological variation from pathologic dysregulation.
