Cortisol
Cortisol is the body’s primary stress hormone produced by the adrenal glands. Testing helps evaluate adrenal function and identify problems early — both underproduction (adrenal insufficiency) and overproduction (Cushing’s syndrome). Because cortisol follows a daily rhythm, timing of testing matters depending on what is being evaluated.
Cortisol is the body’s primary stress hormone, produced by the adrenal glands in response to signals from the pituitary and hypothalamus. Often called the “fight or flight” hormone, cortisol helps the body respond to stress, regulates metabolism, controls blood sugar, reduces inflammation, and influences memory and blood pressure. It’s essential for survival — but both too much and too little cortisol cause serious health problems.
Why does this matter? Cortisol disorders can be life-threatening if undiagnosed. Adrenal insufficiency (too little cortisol) causes fatigue, weakness, weight loss, and can lead to adrenal crisis — a medical emergency. Cushing syndrome (too much cortisol) causes weight gain, muscle weakness, high blood pressure, diabetes, and bone loss. Both conditions develop gradually and can be mistaken for other problems. Cortisol testing is essential for diagnosis and can be life-saving.
Key Benefits of Testing
Cortisol blood testing is the frontline assessment for adrenal function. A morning cortisol level can quickly screen for adrenal insufficiency — a low morning value strongly suggests the adrenal glands aren’t producing enough cortisol. This simple test can prompt life-saving treatment.
Testing also helps evaluate suspected cortisol excess. While screening for Cushing syndrome often uses other tests (late-night salivary cortisol, 24-hour urine cortisol), blood cortisol measurement plays a role in the diagnostic workup and in identifying the source of excess cortisol production.
What Does This Test Measure?
The cortisol blood test measures the concentration of cortisol hormone in your blood at the time of the draw. Most cortisol in blood is bound to proteins (mainly cortisol-binding globulin and albumin), with a small free fraction that’s biologically active. Standard tests measure total cortisol (bound plus free).
The HPA Axis
Cortisol production is controlled by the hypothalamic-pituitary-adrenal (HPA) axis:
| Level | Structure | Hormone | Action |
|---|---|---|---|
| 1 | Hypothalamus | CRH (corticotropin-releasing hormone) | Stimulates pituitary |
| 2 | Pituitary | ACTH (adrenocorticotropic hormone) | Stimulates adrenal glands |
| 3 | Adrenal cortex | Cortisol | Acts on tissues; feeds back to suppress CRH and ACTH |
This feedback loop maintains cortisol within a normal range. Disruption at any level — hypothalamus, pituitary, or adrenal — can cause cortisol excess or deficiency.
Cortisol’s Daily Rhythm
Cortisol follows a strong circadian (daily) pattern:
| Time of Day | Cortisol Level | Clinical Implication |
|---|---|---|
| Early morning (6-8 AM) | Highest (peak) | Best time to detect low cortisol |
| Throughout the day | Gradually declining | Midday values harder to interpret |
| Late evening/midnight | Lowest (nadir) | Best time to detect elevated cortisol |
This rhythm is critical for interpreting results. A morning cortisol that’s low is concerning because it should be at its peak. A late-night cortisol that’s elevated is concerning because it should be at its lowest.
What Cortisol Does
Cortisol has wide-ranging effects throughout the body:
- Metabolism: Increases blood glucose, promotes gluconeogenesis, influences fat distribution
- Immune function: Suppresses inflammation and immune responses
- Cardiovascular: Maintains blood pressure and vascular tone
- Stress response: Mobilizes energy and resources during stress
- Bone: In excess, decreases bone formation (causing osteoporosis)
- Brain: Affects mood, memory, and cognition
Why This Test Matters
Diagnosing Adrenal Insufficiency
Adrenal insufficiency means the adrenal glands don’t produce enough cortisol. This can be:
| Type | Problem Location | Cause Examples | ACTH Level |
|---|---|---|---|
| Primary (Addison’s disease) | Adrenal glands themselves | Autoimmune destruction, infections, hemorrhage | High (trying to stimulate failing adrenals) |
| Secondary | Pituitary gland | Pituitary tumor, surgery, radiation | Low or inappropriately normal |
| Tertiary | Hypothalamus or suppression | Long-term steroid use (most common), hypothalamic disease | Low |
Morning cortisol is the key screening test. A clearly low morning cortisol strongly suggests adrenal insufficiency. A normal or high morning cortisol effectively rules it out. Borderline values require further testing (ACTH stimulation test).
Evaluating Cushing Syndrome
Cushing syndrome results from prolonged cortisol excess. Blood cortisol testing is part of the workup, though screening often starts with late-night salivary cortisol or 24-hour urine free cortisol (which better capture the loss of normal daily rhythm or overall excess). Once Cushing syndrome is confirmed, blood cortisol and ACTH help determine the source:
| Pattern | Cortisol | ACTH | Suggests |
|---|---|---|---|
| ACTH-dependent | High | High or normal | Pituitary tumor (Cushing disease) or ectopic ACTH |
| ACTH-independent | High | Low (suppressed) | Adrenal tumor or hyperplasia |
| Exogenous | May be low (suppressed) | Low | Taking corticosteroid medications |
Monitoring Steroid Therapy
Patients on long-term corticosteroids (prednisone, hydrocortisone) have suppressed HPA axis function. Cortisol testing helps assess adrenal recovery when tapering steroids and guides replacement dosing in adrenal insufficiency.
Value of Testing When Symptoms Are Vague
Both cortisol excess and deficiency cause nonspecific symptoms — fatigue, weakness, mood changes — that can be attributed to many conditions. Patients may go years without diagnosis. A simple morning cortisol can identify adrenal insufficiency before it becomes a crisis. For suspected Cushing syndrome, appropriate testing can uncover a treatable condition causing weight gain, diabetes, hypertension, and bone loss. Testing when clinical suspicion exists prevents delayed diagnosis of these serious but treatable conditions.
Value of Early Testing
Adrenal insufficiency often develops gradually, with vague symptoms that worsen slowly over months or years. Patients frequently attribute their fatigue and malaise to stress, depression, or aging. The first presentation may be adrenal crisis during an illness or surgery — a life-threatening emergency. Testing cortisol when unexplained fatigue is persistent and profound, or when subtle signs like low blood pressure or salt craving appear, can diagnose adrenal insufficiency before crisis occurs. Similarly, early features of Cushing syndrome — gradual weight gain, new stretch marks, slow wound healing — often go uninvestigated until complications like diabetes and osteoporosis develop. Proactive testing when early warning signs appear allows treatment before serious damage accumulates.
What Can Affect Cortisol Levels?
Causes of High Cortisol
- Cushing syndrome:
- Pituitary adenoma secreting ACTH (Cushing disease)
- Ectopic ACTH from other tumors (lung cancer, carcinoid)
- Adrenal tumors (adenoma or carcinoma)
- Adrenal hyperplasia
- Exogenous steroids: Taking prednisone, dexamethasone, or other corticosteroids (most common cause of Cushing features)
- Pseudo-Cushing states: Severe depression, alcoholism, obesity can elevate cortisol without true Cushing syndrome
- Acute stress/illness: Critical illness, surgery, trauma appropriately elevate cortisol
- Pregnancy: Cortisol rises normally during pregnancy
Causes of Low Cortisol
- Primary adrenal insufficiency (Addison’s disease):
- Autoimmune adrenalitis (most common in developed countries)
- Infections (tuberculosis, fungal, HIV-related)
- Adrenal hemorrhage or infarction
- Metastatic cancer to adrenals
- Congenital adrenal hyperplasia
- Secondary/tertiary adrenal insufficiency:
- Long-term corticosteroid use (suppresses HPA axis) — most common cause overall
- Pituitary tumors, surgery, or radiation
- Hypothalamic disease
- Sheehan syndrome (postpartum pituitary necrosis)
Testing Considerations
Time of day matters enormously. Morning cortisol (ideally 6-8 AM) should be high. Evening cortisol should be low. Results must be interpreted in context of collection time.
Stress of blood draw. Anxiety about needles can acutely raise cortisol, potentially causing false normal results in someone with borderline adrenal function.
Medications affecting results: Estrogen (oral contraceptives, HRT) increases cortisol-binding globulin, raising total cortisol without increasing free cortisol. This can cause falsely elevated total cortisol.
When Should You Get Tested?
Symptoms Suggesting Adrenal Insufficiency
Fatigue that’s profound and unexplained — worse than typical tiredness, not relieved by rest.
Unintentional weight loss with decreased appetite.
Low blood pressure or dizziness when standing (orthostatic hypotension).
Salt cravings (in primary adrenal insufficiency).
Hyperpigmentation — darkening of skin, especially in creases, scars, and gums (primary adrenal insufficiency).
Nausea, vomiting, abdominal pain — particularly during illness or stress.
History of long-term steroid use — particularly when tapering or discontinuing.
Symptoms Suggesting Cushing Syndrome
Unexplained weight gain — especially central obesity with thin arms and legs.
Round “moon” face and fat pad on upper back (“buffalo hump”).
Purple striae — wide stretch marks on abdomen, thighs, breasts.
Easy bruising and thin fragile skin.
Muscle weakness — especially proximal (difficulty rising from chair, climbing stairs).
New or worsening diabetes and hypertension.
Osteoporosis — especially if unexpected for age.
Mood changes — depression, anxiety, cognitive difficulties.
Other Indications
Pituitary tumor evaluation — assessing whether tumor affects ACTH production.
Critical illness — evaluating adrenal function in severely ill patients.
Monitoring replacement therapy — in known adrenal insufficiency.
Understanding Your Results
Morning Cortisol Interpretation
| Morning Cortisol | Interpretation | Next Steps |
|---|---|---|
| Clearly low | Strongly suggests adrenal insufficiency | Check ACTH to classify; consider ACTH stimulation test; start treatment if symptomatic |
| Borderline/indeterminate | Cannot rule out partial insufficiency | ACTH stimulation test to assess adrenal reserve |
| Normal | Adrenal insufficiency unlikely | Look for other causes of symptoms |
| Elevated | May be normal stress response or suggest excess | If Cushing suspected, proceed with dedicated screening tests |
The Role of ACTH
ACTH, measured alongside cortisol, helps classify adrenal disorders:
- Low cortisol + High ACTH: Primary adrenal insufficiency (adrenals failing, pituitary compensating)
- Low cortisol + Low/normal ACTH: Secondary/tertiary insufficiency (pituitary not stimulating)
- High cortisol + High ACTH: ACTH-dependent Cushing (pituitary or ectopic source)
- High cortisol + Low ACTH: ACTH-independent Cushing (adrenal source)
Random Cortisol Limitations
A single random cortisol (not morning) is difficult to interpret due to normal daily variation. Afternoon values may be low normally. If possible, test first thing in the morning for the most interpretable results.
What to Do About Abnormal Results
For Low Morning Cortisol
Don’t delay if symptomatic. Adrenal insufficiency can be life-threatening. If cortisol is clearly low and symptoms are present, treatment may be started while confirmatory testing is arranged.
Confirmatory testing: ACTH stimulation test (Synacthen/cosyntropin test) — measures cortisol response to synthetic ACTH. Failure to respond confirms adrenal insufficiency.
Determine the cause: ACTH level distinguishes primary from secondary insufficiency. Additional testing (adrenal antibodies, imaging) identifies underlying cause.
Treatment: Cortisol replacement with hydrocortisone or other glucocorticoids. In primary insufficiency, mineralocorticoid (fludrocortisone) is also needed. Patients need education about stress dosing and emergency management.
For Elevated Cortisol Suggesting Cushing Syndrome
Confirm true Cushing syndrome: Additional testing — late-night salivary cortisol, 24-hour urine free cortisol, dexamethasone suppression test — confirms autonomous cortisol excess and rules out pseudo-Cushing states.
Identify the source: ACTH level determines if ACTH-dependent or independent. Imaging (pituitary MRI, CT of adrenals/chest) locates the source. Specialized testing (inferior petrosal sinus sampling) may be needed.
Treatment depends on cause:
- Pituitary adenoma: Transsphenoidal surgery
- Adrenal tumor: Adrenalectomy
- Ectopic ACTH: Treat underlying tumor
- Medications: Taper if possible
Related Health Conditions
Addison’s Disease (Primary Adrenal Insufficiency)
Addison’s disease occurs when the adrenal glands are damaged and can’t produce enough cortisol (and usually aldosterone). Most commonly autoimmune in developed countries. Symptoms include fatigue, weight loss, low blood pressure, salt craving, and characteristic skin darkening. Without treatment, adrenal crisis can be fatal. Lifelong hormone replacement is required.
Secondary Adrenal Insufficiency
When the pituitary doesn’t produce enough ACTH, the adrenal glands aren’t stimulated to make cortisol. Common causes include pituitary tumors, surgery, or radiation, and prolonged corticosteroid use. Symptoms are similar to Addison’s but without skin darkening or severe salt disturbances (aldosterone is usually preserved).
Cushing Syndrome
Chronic cortisol excess causes weight gain (central obesity), moon face, buffalo hump, purple striae, muscle weakness, thin skin, easy bruising, diabetes, hypertension, osteoporosis, and mood changes. Can result from pituitary tumors, adrenal tumors, ectopic ACTH, or corticosteroid medications. Treatment depends on cause.
Cushing Disease
Specifically refers to Cushing syndrome caused by a pituitary adenoma producing excess ACTH. This is the most common cause of endogenous Cushing syndrome. Treatment is usually transsphenoidal surgery to remove the pituitary tumor.
Adrenal Crisis
A life-threatening emergency occurring when cortisol levels are critically low, usually in someone with adrenal insufficiency who encounters stress (illness, surgery, trauma) without adequate cortisol increase. Symptoms include severe weakness, confusion, low blood pressure, abdominal pain, and shock. Requires immediate IV hydrocortisone and fluids.
Pituitary Tumors
Pituitary adenomas can cause cortisol abnormalities by either overproducing ACTH (causing Cushing disease) or by compressing normal pituitary tissue (causing ACTH deficiency and secondary adrenal insufficiency). Cortisol testing is part of pituitary tumor evaluation.
Related Biomarkers Often Tested Together
ACTH — Essential for classifying cortisol disorders as primary vs. secondary/pituitary-dependent vs. independent.
DHEA-S — Adrenal androgen; also reduced in adrenal insufficiency.
Aldosterone and Renin — Evaluate mineralocorticoid function in primary adrenal insufficiency.
Sodium and Potassium — Electrolyte abnormalities common in adrenal disorders.
Glucose — Hypoglycemia in adrenal insufficiency; hyperglycemia in Cushing syndrome.
Note: Information provided in this article is for educational purposes and doesn’t replace personalized medical advice.
Frequently Asked Questions
Cortisol is the body’s main stress hormone, produced by the adrenal glands. It helps regulate metabolism, blood sugar, inflammation, blood pressure, and the body’s response to stress. Both too much and too little cortisol cause health problems.
Cortisol follows a daily rhythm — highest in early morning, lowest at night. Morning testing captures the peak, making it easiest to detect deficiency (a low value when it should be high is clearly abnormal). Random daytime values are harder to interpret.
“Adrenal fatigue” is not a recognized medical diagnosis. While chronic stress can affect cortisol patterns, the concept of adrenals being “fatigued” from stress isn’t supported by evidence. True adrenal insufficiency is a specific, diagnosable condition requiring hormone replacement.
Yes. Acute stress (including anxiety about the blood draw) can raise cortisol. This usually isn’t a major problem for detecting low cortisol (stress would raise it, so a low value is still meaningful), but can cause elevated results in someone without true cortisol excess.
Prednisone and other corticosteroids suppress your natural cortisol production. Testing may be useful when assessing whether your adrenals have recovered after tapering steroids. Discuss timing with your doctor, as steroids affect test interpretation.
Blood cortisol measures total cortisol (bound plus free). Salivary cortisol measures free cortisol and is useful for late-night testing (convenient home collection) to screen for Cushing syndrome. Each has specific clinical applications.
Yes. Chronic cortisol excess (Cushing syndrome) causes characteristic central weight gain. Cortisol insufficiency often causes weight loss. However, normal stress-related cortisol variation doesn’t significantly cause weight gain — “stress weight” has more to do with behavior changes than cortisol alone.
References
Key Sources:
- Bornstein SR, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
- Nieman LK, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
- Fleseriu M, et al. Consensus on diagnosis and management of Cushing’s disease. Lancet Diabetes Endocrinol. 2021;9(12):847-875.
